| 2021 | A Semimechanistic Pharmacokinetic Model for Depot Medroxyprogesterone Acetate and Drug-Drug Interactions With Antiretroviral and Antituberculosis Treatment. | Clin Pharmacol Ther | Depot medroxyprogesterone acetate is an injectable hormonal contraceptive, widely used by women of childbearing potential living with HIV and/or tuberculosis. As medroxyprogesterone acetate is a cytochrome P450 (CYP3A4) substrate, drug-drug interactions (DDIs) with antiretroviral or antituberculosis treatment may lead to subtherapeutic medroxyprogesterone acetate concentrations (< 0.1 ng/mL), resulting in contraception failure, when depot medroxyprogesterone is dosed at 12-week intervals. A pooled population pharmacokinetic analysis with 744 plasma medroxyprogesterone acetate concentrations from 138 women treated with depot medroxyprogesterone and antiretroviral/antituberculosis treatment across three clinical trials was performed. Monte Carlo simulations were performed to predict the percentage of participants with subtherapeutic medroxyprogesterone acetate concentrations and to derive alternative dosing strategies. Medroxyprogesterone acetate clearance increased by 24.7% with efavirenz coadministration. Efavirenz plus antituberculosis treatment (rifampicin + isoniazid) increased clearance by 52.4%. Conversely, lopinavir/ritonavir and nelfinavir decreased clearance (28.7% and 15.8%, respectively), but lopinavir/ritonavir also accelerated medroxyprogesterone acetate's appearance into the systemic circulation, thus shortening the terminal half-life. A higher risk of subtherapeutic medroxyprogesterone acetate concentrations at Week 12 was predicted on a typical 60-kg woman on efavirenz (4.99%) and efavirenz with antituberculosis treatment (6.08%) when compared with medroxyprogesterone acetate alone (2.91%). This risk increased in women with higher body weight. Simulations show that re-dosing every 8 to 10 weeks circumvents the risk of subtherapeutic medroxyprogesterone acetate exposure associated with these DDIs. Dosing depot medroxyprogesterone every 8 to 10 weeks should eliminate the risk of subtherapeutic medroxyprogesterone acetate exposure caused by coadministered efavirenz and/or antituberculosis treatment, thus reducing the risk of contraceptive failure. |
| 2019 | Flow-Based Three-Dimensional Co-Culture Model for Long-Term Hepatotoxicity Prediction. | Micromachines (Basel) | We developed concave microwell arrays to establish a size-controllable 3-D co-culture liver model for in vitro drug toxicity testing, to predict hepatotoxicity. The interaction of hepatocytes with hepatic stellate cells (HSCs) was investigated by co-culturing primary 3-D hepatocyte spheroids and HSCs (heterosphere), using 3-D liver-on-a-chip. The effect of HSCs was investigated during spheroid formation; they were involved in controlling the organization of spheroidal aggregates and the formation of tight cell-cell contacts. Scanning electron microscopy (SEM) images showed that co-cultured spheroids with smoother surfaces in the flow chip aggregated more tightly and rapidly, compared to mono-cultured spheroids, until 13 days. Metabolic function analysis revealed that heterospheres secreted 40% more albumin and urea than hepatospheres on day 13. Additionally, an acetaminophen (AAP) and isoniazid (INH) concentration-dependent increase in CYP3A4 expression was detected in the 3-D cultures, and an increase in Lactate dehydrogenase (LDH) release after AAP and INH treatment was observed. CYP1A2, Mrp1 and UGT1A5 mRNA expression levels in the heterospheres and hepatospheres were evaluated from days 3 to 13. To examine the potential for toxicity testing in the flow-conditioned culture of the heterospheres, we evaluated cytotoxicity using the endpoint LDH release in the heterospheres and hepatospheres. IC values for AAP and INH after 24 h of exposure were calculated from the dose-response curves of the compounds. Flow-conditioned heterosphere culture results suggest that it may be suitable for long-term culture and cytotoxicity testing. Thus, our co-culture system closely resembles the in vivo environment and allows long-term in vitro hepatotoxicity prediction. |
| 2019 | 3--Methyl-Alkylgallates Inhibit Fatty Acid Desaturation in Mycobacterium tuberculosis. | Antimicrob Agents Chemother | In the quest for new antibacterial lead structures, activity screening against identified antitubercular effects of gallic acid derivatives isolated from the Nigerian mistletoe Structure-activity relationship studies indicated that 3--methyl-alkylgallates comprising aliphatic ester chains with four to eight carbon atoms showed the strongest growth inhibition against , with a MIC of 6.25 μM. Furthermore, the most active compounds (3--methyl-butyl-, 3--methyl-hexylgallate, and 3--methyl-octylgallate) were devoid of cytotoxicity against various human cell lines. Furthermore, 3--methyl-butylgallate showed favorable absorption, distribution, metabolism, and excretion (ADME) criteria, with a of 6.2 × 10cm/s, and it did not inhibit P-glycoprotein (P-gp), CYP1A2, CYP2B6 or CYP3A4. Whole-genome sequencing of spontaneous resistant mutants indicated that the compounds target the stearoyl-coenzyme A (stearoyl-CoA) delta-9 desaturase DesA3 and thereby inhibit oleic acid synthesis. Supplementation assays demonstrated that oleic acid addition to the culture medium antagonizes the inhibitory properties of gallic acid derivatives and that sodium salts of saturated palmitic and stearic acid did not show compensatory effects. The moderate bactericidal effect of 3--methyl-butylgallate in monotreatment was synergistically enhanced in combination treatment with isoniazid, leading to sterilization in liquid culture. |
| 2019 | Assessment of preclinical drug interactions of bedaquiline by a highly sensitive LC-ESI-MS/MS based bioanalytical method. | J Chromatogr B Analyt Technol Biomed Life Sci | A continuous effort has been given to find out a new drug that is effective against tuberculosis (TB) from both susceptible and resistant strains of Mycobacterium tuberculosis. Bedaquiline represents a recently approved anti-TB drug, which has a unique mechanism of action to fight against multi drug resistance (MDR). Some severe side effects and drug-drug interactions are associated with the treatment of bedaquiline. Moreover, World Health Organisation (WHO) has also been provided guidelines in the year of 2013 for the use of bedaquiline and encourages additional investigation into it. Hence, the pharmacokinetics of bedaquiline upon coadministration with the drug has to be explored in the preclinical model and for which a liquid chromatography tandem mass spectrometry (LC-MS/MS) based bioanalytical method for quantitation of bedaquiline will be useful. A simple, sensitive and rapid LC-MS/MS method was developed, validated and successfully applied to drug interactions of bedaquiline upon coadministration with cytochrome P450 3A4 (CYP3A4) inducers/inhibitors orally in Wistar rats. Results reveal that ciprofloxacin and fluconazole have marked effect to hinder the pharmacokinetics of bedaquiline but isoniazid, verapamil and carbamazepine have no significant effect on bedaquiline pharmacokinetics. Overall, this new bioanalytical method for estimation of bedaquiline in rat plasma was found to be helpful to assess the pharmacokinetics of bedaquiline and very much useful for evaluation of preclinical drug-drug interaction before considering costly and perilous clinical exploration. |
| 2018 | Sagittaria sagittifolia polysaccharide protects against isoniazid- and rifampicin-induced hepatic injury via activation of nuclear factor E2-related factor 2 signaling in mice. | J Ethnopharmacol | The Sagittaria sagittifolia L. polysaccharide (SSP) is a purified form of a homogeneous polysaccharide isolated from the root tubers of S. sagittifolia, which has been used as a protectant against hepatotoxicity induced by coadministration of isoniazid and rifampicin. However, the protective effect of SSP against isoniazid- and rifampicin-induced liver injury has never been studied.In this study, the hepatoprotective effect of SSP and its underlying mechanism were investigated in mice with isoniazid- and rifampicin-induced liver injury.Liver injury was induced in mice by intragastric administration of isoniazid and rifampicin, and the mice were divided into the following six groups: standard control (administration of saline by gavage), model (intragastric administration of isoniazid and rifampicin at 100 mg/kg/day each), positive control (100 mg/kg/day silymarin by gavage 4 h after isoniazid and rifampicin administration), and SSP-treated (200, 400, or 800 mg/kg/day SSP by gavage after isoniazid and rifampicin administration). Subsequently, blood and liver samples were collected from all the animals and were assessed.SSP significantly alleviated the liver injury, as evidenced by decreased activities of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase in the serum and a decreased level of malondialdehyde in the liver, as well as by an increased level of glutathione and increased activities of superoxide dismutase and catalase in the liver. SSP also effectively reduced the pathological tissue damage. The gene and protein expression of cytochrome P450 (CYP) 2E1 and CYP3A4 was inhibited by SSP. The gene and protein expression of nuclear factor erythroid 2-related factor 2 (NRF2), glutamate-cysteine ligase, and heme oxygenase-1 were induced by SSP, whereas that of Kelch-like ECH-associated protein 1 was inhibited.SSP exerts a protective effect against isoniazid- and rifampicin-induced liver injury in mice. The underlying mechanisms may involve activation of NRF2 and its target antioxidant enzymes and inhibition of the expression of CYPs. |
| 2017 | Modulation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) activation by ursolic acid (UA) attenuates rifampin-isoniazid cytotoxicity. | Phytomedicine | Interactions between transcriptional inducers of cytochrome P450 (CYP450) enzymes and therapeutic drugs may be prevented by antagonizing the activation of a nuclear receptor (NR), pregnane X receptor (PXR, NR1I2), thus improving therapeutic efficacy.In the present study, we aim to identify that ursolic acid (UA), a widely distributed pentacyclic triterpene, may act as an effective antagonist of PXR and its sister NR receptor, constitutive androstane receptor (CAR, NR1I3).The hepatocellular carcinoma cell line, HepG2, was used to evaluate the promoter activity of PXR and CAR target genes, CYP3A4 and CYP2B6, respectively. Catalytic activities, mRNA, and protein expression of CYP3A4 and CYP2B6 were evaluated in a differentiated HepaRG cell line. Coregulation of PXR with coregulators on CYP3A4 promoter response elements was also been characterized.Transient transfection assays showed that UA effectively attenuated CYP3A4 and CYP2B6 promoter activities mediated by rifampin (RIF, human PXR agonist) and CITCO (human CAR agonist). These inhibitory effects were well correlated with the expression and catalytic activities of CYP3A4 and CYP2B6. Furthermore, the interaction of co-regulators with PXR and the transcriptional complexes in the CYP3A4 promoter activity and CYP3A4 promoter xenobiotic response element (everted repeat 6, ER6), respectively, were disrupted in the presence of UA. UA showed an antagonistic effect against PXR, and reversed the cytotoxic effects of isoniazid (INH) induced by RIF. Taken together, these results show that UA inhibits the transactivation effects of PXR and CAR, and reduces the expression and function of CYP3A4 and CYP2B6.The present study suggests that UA could be a powerful agent for reducing potentially dangerous interactions between transcriptional inducers of CYP enzymes and therapeutic drugs. |
| 2017 | Oleanolic Acid-Mediated Inhibition of Pregnane X Receptor and Constitutive Androstane Receptor Attenuates Rifampin-Isoniazid Cytotoxicity. | J Agric Food Chem | Interactions between transcriptional inducers of cytochrome P450 (CYP450) and pharmacological agents might decrease drug efficacy and induce side effects. Such interactions could be prevented using an antagonist of the pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Here, we aimed to determine the antagonistic effect of oleanolic acid (OA) on PXR and CAR. OA attenuated the promoter activities, expressions, and enzyme catalytic activities of CYP3A4 and CYP2B6 mediated by rifampin (RIF) and CITCO. Moreover, OA displayed species specificity for rodent PXR. Interaction of coregulators with PXR and transcriptional complexes on the CYP3A4 promoter was disrupted by OA. Additionally, OA reversed the cytotoxic effects of isoniazid induced by RIF. These data demonstrate that OA inhibited the transactivation of PXR and CAR, reduced the expression and function of CYP3A4 and CYP2B6, and may therefore serve as an effective agent for reducing probability adverse interactions between transcriptional inducers of CYP450 and therapeutic drugs. |
| 2016 | Delamanid Coadministered with Antiretroviral Drugs or Antituberculosis Drugs Shows No Clinically Relevant Drug-Drug Interactions in Healthy Subjects. | Antimicrob Agents Chemother | Delamanid is a medicinal product approved for treatment of multidrug-resistant tuberculosis. Three studies were conducted to evaluate the potential drug-drug interactions between delamanid and antiretroviral drugs, including ritonavir, a strong inhibitor of CYP3A4, and selected anti-TB drugs, including rifampin, a strong inducer of cytochrome P450 (CYP) isozymes. Multiple-dose studies were conducted in parallel groups of healthy subjects. Plasma samples were analyzed for delamanid, delamanid metabolite, and coadministered drug concentrations, and pharmacokinetic (PK) parameters were determined. The magnitude of the interaction was assessed by the ratio of the geometric means and 90% confidence intervals. Coadministration of delamanid with tenofovir or efavirenz did not affect the PK characteristics of delamanid. Coadministration of Kaletra (lopinavir/ritonavir) with delamanid resulted in an approximately 25% higher delamanid area under the concentration-time curve from time 0 to the end of the dosing interval (AUCτ). Tenofovir, efavirenz, lopinavir, and ritonavir exposure were not affected by delamanid. Coadministration of delamanid with the TB drugs (ethambutol plus Rifater [rifampin, pyrazinamide, and isoniazid]) resulted in lower delamanid exposures (47 and 42% for the AUCτ and Cmax [maximum concentration of a drug in plasma] values, respectively), as well as decreased exposure of three primary metabolites (approximately 30 to 50% lower AUCτ values). Delamanid did not affect rifampin, pyrazinamide, and isoniazid exposure; the ethambutol AUCτ and Cmax values were about 25% higher with delamanid coadministration. The lack of clinically significant drug-drug interactions between delamanid and selected antiretroviral agents (including the strong CYP inhibitor ritonavir) and a combination of anti-TB drugs was demonstrated. Although there was a decrease in the delamanid concentrations when coadministered with ethambutol plus Rifater, this is likely related to decreased delamanid absorption and not to CYP induction. |
| 2015 | Inhibitory Potential of Twenty Five Anti-tuberculosis Drugs on CYP Activities in Human Liver Microsomes. | Biol Pharm Bull | The direct inhibitory potential of twenty five anti-tuberculosis drugs on eight CYP-specific reactions in human liver microsomes was investigated to predict in vivo drug-drug interactions (DDIs) from in vitro data. Rifampicin, rifabutin, and thioacetazone inhibited one CYP reaction. Isoniazid and clofazimine had inhibitory effects on four CYP reactions, and rifapentine, ethionamide, and prothionamide widely inhibited CYP reactions. Based on the inhibition constant (Ki) and the therapeutic total inhibitor concentrations [I]max of eight drugs in human plasma, [I]max/Ki values were calculated to evaluate clinical DDIs. The [I]max/Ki values were 0.20 or less for rifampicin, rifabutin, and thioacetazone; 0.15-2.0 for isoniazid; 0.14-1.5 for rifapentine; 0.29-1.4 for ethionamide; 0.41-2.2 for prothionamide; and 0.12-6.3 for clofazimine. The highest [I]max/Ki values were 2.0 for isoniazid on CYP3A4 [testosterone (T)]; 1.5 for rifapentine on CYP3A4 [midazolam (M)]; 1.4 for ethionamide on CYP2C8; 2.2, 1.8, and 1.3 for prothionamide on CYP2B6, CYP2C19, and CYP2C8, respectively; and 6.3 and 5.7 for clofazimine on CYP3A4 (M) and CYP3A4 (T), respectively. These drugs with high [I]max/Ki values lead to clinical DDIs. Considering the drug regimens for tuberculosis (TB) and co-infection with TB and human immunodeficiency virus, the inhibitory potential for CYP3A4 and CYP2B6 is particularly important. These results suggest that clofazimine and prothionamide are likely to cause clinically relevant DDIs when co-administered with products metabolized by CYP3A4 and CYP2B6, respectively. Isoniazid and rifapentine may cause DDIs with drugs metabolized by CYP3A4. |
| 2015 | Synthesis and biological activities of some new isonicotinic acid 2-(2-hydroxy-8-substituted-tricyclo[7.3.1.0(2.7)]tridec-13-ylidene)-hydrazides. | Bioorg Med Chem | A series of several new isoniazid derivatives, isonicotinic acid 2-(2-hydroxy-8-substituted-tricyclo[7.3.1.0(2.7)]tridec-13-ylidene)-hydrazides, were synthesized and fully characterized. These new isoniazid derivatives were studied regarding their antibacterial activity and cytotoxicity, as well as their influences on some metabolizing enzymes. The best anti-mycobacterial activity was observed in the case of compounds containing alkyl side chains in the 8 position of tricyclo[7.3.1.0(2.7)]tridec-13-ylidene group. On contrary, the antimicrobial activity of these new compounds against various non-tuberculosis strains showed the best activity to be with the phenyl side chain of compound 6. It proved also to be the most toxic, inducing apoptosis and blocking the cell cycle in G0/G1 phase. The cell cycle was blocked in G0/G1 phase also by compound 3, but this compound did not show any toxicity. All compounds induced the expression of NAT1 and NAT2 genes in HT-29 cell line, and the expression of CYP1A1 in HT-29 and HCT-8 cell lines. The expression level of CYP3A4 was increased by compounds 1, 6 and 7 in HCT-8 cells. These results indicated that the activation of other metabolizing pathways, apart from those of isoniazid, take place. It might also point out the possibility of an increased isoniazid acetylation ratio by co-administration with new compounds in slow acetylators. |
| 2014 | Inhibition of cytochrome P450 by ethambutol in human liver microsomes. | Toxicol Lett | Although cytochrome P450 inhibition is the major drug-drug interaction (DDI) mechanism in clinical pharmacotherapy, DDI of a number of well-established drugs have not been investigated. Rifampicin, isoniazid, pyrazinamide and ethambutol combination therapy inhibits clearance of theophylline in patients with tuberculosis. We determined the inhibitory effects of ethambutol on the activities of nine CYP isoforms including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 in pooled human liver microsomes (HLM). As measured by liquid chromatography-electrospray ionization tandem mass spectrometry, ethambutol exhibited strong inhibitory potential against CYP1A2 and CYP2E1, moderate against CYP2C19 and CYP2D6 and weak against CYP2A6, CYP2C9 and CYP3A4, based on the IC50 values. The K(i) value of ethambutol for CYP1A2 was 1.4 μM and for CYP2E1 was 2.9 μM. Inhibition of CYP1A2 and CYP2E1 was not increased by preincubation with ethambutol and β-nicotinamideadenine dinucleotide phosphate (NADPH), suggesting that the ethambutol-induced CYP inhibition may not be metabolism-dependent. Kinetic analysis showed that the inhibition of CYP1A2 and CYP2E1 by ethambutol was best fit to a competitive inhibition model. Formation of 1-methylxanthene and 1,3-dimethyluric acid from theophylline in HLM was decreased to 47% and 36%, respectively, by 3.0 μM ethambutol, which is comparable to its IC50 value against CYP1A2. Considering its maximal plasma concentrations of ~10 μM and long half-life of ~22 h, our findings raise the possibility that ethambutol causes significant DDIs in clinical situations with drugs with narrow therapeutic index, such as theophylline, in clinical situations. |
| 2014 | Bedaquiline: a review of human pharmacokinetics and drug-drug interactions. | J Antimicrob Chemother | Bedaquiline has recently been approved for the treatment of pulmonary multidrug-resistant tuberculosis (TB) as part of combination therapy in adults. It is metabolized primarily by the cytochrome P450 isoenzyme 3A4 (CYP3A4) to a less-active N-monodesmethyl metabolite. Phase I and Phase II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant TB have assessed the pharmacokinetics and drug-drug interaction profile of bedaquiline. Potential interactions have been assessed between bedaquiline and first- and second-line anti-TB drugs (rifampicin, rifapentine, isoniazid, pyrazinamide, ethambutol, kanamycin, ofloxacin and cycloserine), commonly used antiretroviral agents (lopinavir/ritonavir, nevirapine and efavirenz) and a potent CYP3A inhibitor (ketoconazole). This review summarizes the pharmacokinetic profile of bedaquiline as well as the results of the drug-drug interaction studies. |
| 2013 | The pharmacokinetics of nevirapine when given with isoniazid in South African HIV-infected individuals. | Int J Tuberc Lung Dis | Isoniazid preventive therapy (IPT) is recommended in patients on antiretroviral treatment. Isoniazid (INH) inhibits CYP3A4, which metabolises nevirapine (NVP). Administration of INH may cause higher NVP concentrations and toxicity. We studied the effect of INH on NVP concentrations in 21 patients randomised to either placebo (n = 13) or INH (n = 8) in an ongoing trial of IPT in patients on ART. INH was associated with a 24% increase in median NVP area under the plasma concentration-time curve for the 12 h dosing interval, which was not statistically significant (P = 0.66). |
| 2011 | Development of a highly sensitive cytotoxicity assay system for CYP3A4-mediated metabolic activation. | Drug Metab Dispos | Drug-induced hepatotoxicity, which is a rare but serious adverse reaction to a large number of pharmaceutical drugs, is sometimes associated with reactive metabolites produced by drug-metabolizing enzymes. In the present study, we constructed a cell-based system to evaluate the cytotoxicity of reactive metabolites produced by CYP3A4 using human hepatoma cells infected with an adenovirus vector expressing human CYP3A4 (AdCYP3A4). When seven hepatoma cell lines (HepG2, Hep3B, HLE, HLF, Huh6, Huh7, and Fa2N4 cells) were infected with AdCYP3A4, HepG2 cells showed the highest CYP3A4 protein expression and testosterone 6β-hydroxylase activity (670 pmol · min(-1) · mg(-1)). With the use of AdCYP3A4-infected HepG2 cells, the cytotoxicities of 23 drugs were evaluated by the 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt assay, and the cell viability when treated with 11 drugs (amiodarone, desipramine, felbamate, isoniazid, labetalol, leflunomide, nefazodone, nitrofurantoin, tacrine, terbinafine, and tolcapone) was significantly decreased. Moreover, the transfection of siRNA for nuclear factor erythroid 2-related factor 2 (Nrf2) to decrease the cellular expression level of Nrf2 exacerbated the cytotoxicity of some drugs (troglitazone, flutamide, acetaminophen, clozapine, terbinafine, and desipramine), suggesting that the genes regulated by Nrf2 are associated with the detoxification of the cytotoxicities mediated by CYP3A4. We constructed a highly sensitive cell-based system to detect the drug-induced cytotoxicity mediated by CYP3A4. This system would be beneficial in preclinical screening in drug development and increase our understanding of the drug-induced cytotoxicity associated with CYP3A4. |
| 2005 | [The combined effect of isoniazid and rifampicin on the activities of CYP4501A2 and CYP4503A4 in primary hepatocytes from healthy human adults]. | Zhonghua Jie He He Hu Xi Za Zhi | To study the combined effect of isoniazid and rifampicin on the activities of CYP1A2 and 3A4 in primary hepatocytes from healthy human adults.The primary hepatocytes were isolated from adult healthy human livers, and cultured for 3 days. Then the cells were divided into 15 groups including two negative control groups (culture media alone) and 13 drug intervention groups, to which the following drugs were added: isoniazid (25 micromol/L, 50 micromol/L), rifampicin (12.5 micromol/L, 25 micromol/L) or both of them with different concentrations (CYP 1A2: rifampicin 12.5 micromol/L + isoniazid 50 micromol/L, rifampicin 25 micromol/L + isoniazid 50 micromol/L; CYP3A4: rifampicin 12.5 micromol/L + isoniazid 50 micromol/L, rifampicin 25 micromol/L + isoniazid 25 micromol/L, rifampicin 25 micromol/L + isoniazid 50 micromol/L) respectively. All the concentrations were consistent with the range of maximum clinical blood concentrations. After culture for 2 days, substrates (phenacetin for CYP1A2 , testosterone for CYP3A4) were added, and then the peak area (unit: mAU. min) of their metabolites was measured with high performance liquid chromatography (HPLC) to assess the activities of CYP450 1A2 and 3A4.(1) The activity of CYP1A2 in isoniazid groups with concentrations of 25 micromol/L and 50 micromol/L was (3.33 +/- 0.65), (3.03 +/- 0.38) mAU.min respectively, significantly different compared with that in the negative control group [(5.23 +/- 0.31) mAU.min, P < 0.01]. The activity of CYP450 1A2 in rifampicin groups with a concentration of 12.5 micromol/L was (6.07 +/- 0.55) mAU.min, which had significant difference compared with that in the negative control group (P < 0.05). There was no statistical difference of CYP1A2 activity between rifampicin with 25 micromol/L [(4.93 +/- 0.57) mAU.min] and the negative control group (P > 0.05). The activity of CYP1A2 of groups with two kinds of different concentrations of isoniazid and rifampicin combined groups was (3.27 +/- 0.96), (3.97 +/- 0.25) mAU.min respectively, which had significant difference compared with that in the negative control group (P < 0.05). (2) The activity of CYP3A4 in isoniazid groups with concentrations of 25 micromol/L and 50 micromol/L was (5.40 +/- 1.35), (2.63 +/- 0.06) mAU.min respectively, which had significant difference compared with that in the negative control group [(12.53 +/- 0.51) mAU.min, P < 0.01]. The activity of CYP3A4 in rifampicin groups with concentrations of 12.5 micromol/L and 25 micromol/L was (165.17 +/- 11.47), (120.20 +/- 15.73) mAU.min respectively, which had significant difference compared with that in the negative control group (P < 0.01). The activity of CYP3A4 in the three isoniazid and rifampicin combined groups with three kinds of different concentrations was (118.37 +/- 8.90), (77.53 +/- 6.91), (68.73 +/- 4.72) mAU.min respectively, which had significant difference compared with that in the negative control group (P < 0.01), but they were lower than those in rifampicin groups with corresponding concentrations (P < 0.05).Isoniazid and rifampicin in the range of maximum clinical blood concentration have no significant inducing or inhibiting effect on the activity of CYP1A2 of healthy adult human primary hepatocytes. Isoniazid in the range of maximum clinical blood concentration can inhibit the activity of CYP3A4, while rifampicin can induce the activity of CYP3A4; the combined effect of isoniazid and rifampicin being the induction of CYP3A4 activity, but the inducing effect was less than that of rifampicin alone with the same concentration. |
| 2005 | Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs. | Clin Pharmacokinet | Consistent with its highest abundance in humans, cytochrome P450 (CYP) 3A is responsible for the metabolism of about 60% of currently known drugs. However, this unusual low substrate specificity also makes CYP3A4 susceptible to reversible or irreversible inhibition by a variety of drugs. Mechanism-based inhibition of CYP3A4 is characterised by nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)-, time- and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYP isoenzymes to reactive metabolites capable of irreversibly binding covalently to CYP3A4. Approaches using in vitro, in silico and in vivo models can be used to study CYP3A4 inactivation by drugs. Human liver microsomes are always used to estimate inactivation kinetic parameters including the concentration required for half-maximal inactivation (K(I)) and the maximal rate of inactivation at saturation (k(inact)). Clinically important mechanism-based CYP3A4 inhibitors include antibacterials (e.g. clarithromycin, erythromycin and isoniazid), anticancer agents (e.g. tamoxifen and irinotecan), anti-HIV agents (e.g. ritonavir and delavirdine), antihypertensives (e.g. dihydralazine, verapamil and diltiazem), sex steroids and their receptor modulators (e.g. gestodene and raloxifene), and several herbal constituents (e.g. bergamottin and glabridin). Drugs inactivating CYP3A4 often possess several common moieties such as a tertiary amine function, furan ring, and acetylene function. It appears that the chemical properties of a drug critical to CYP3A4 inactivation include formation of reactive metabolites by CYP isoenzymes, preponderance of CYP inducers and P-glycoprotein (P-gp) substrate, and occurrence of clinically significant pharmacokinetic interactions with coadministered drugs. Compared with reversible inhibition of CYP3A4, mechanism-based inhibition of CYP3A4 more frequently cause pharmacokinetic-pharmacodynamic drug-drug interactions, as the inactivated CYP3A4 has to be replaced by newly synthesised CYP3A4 protein. The resultant drug interactions may lead to adverse drug effects, including some fatal events. For example, when aforementioned CYP3A4 inhibitors are coadministered with terfenadine, cisapride or astemizole (all CYP3A4 substrates), torsades de pointes (a life-threatening ventricular arrhythmia associated with QT prolongation) may occur.However, predicting drug-drug interactions involving CYP3A4 inactivation is difficult, since the clinical outcomes depend on a number of factors that are associated with drugs and patients. The apparent pharmacokinetic effect of a mechanism-based inhibitor of CYP3A4 would be a function of its K(I), k(inact) and partition ratio and the zero-order synthesis rate of new or replacement enzyme. The inactivators for CYP3A4 can be inducers and P-gp substrates/inhibitors, confounding in vitro-in vivo extrapolation. The clinical significance of CYP3A inhibition for drug safety and efficacy warrants closer understanding of the mechanisms for each inhibitor. Furthermore, such inactivation may be exploited for therapeutic gain in certain circumstances. |
| 2005 | CYP3A4 is a vitamin D-24- and 25-hydroxylase: analysis of structure function by site-directed mutagenesis. | J Clin Endocrinol Metab | Studies were performed to identify the microsomal enzyme that 24-hydroxylates vitamin D, whether 25-hydroxylation occurs, and structure function of the enzyme. Sixteen hepatic recombinant microsomal cytochrome P450 enzymes expressed in baculovirus-infected insect cells were screened for 24-hydroxylase activity. CYP3A4, a vitamin D-25-hydroxylase, and CYP1A1 had the highest 24-hydroxylase activity with 1 alpha-hydroxyvitamin D(2) (1 alpha OHD(2)) as substrate. The ratio of rates of 24-hydroxylation of 1 alpha-hydroxyvitamin D(3) (1 alpha OHD(3)), 1 alpha OHD(2), and vitamin D(2) by CYP3A4 was 3.6/2.8/1.0. Structures of 24-hydroxyvitamin D(2), 1,24(S)-dihydroxyvitamin D(2), and 1,24-dihydroxyvitamin D(3) were confirmed by HPLC and gas chromatography retention time and mass spectroscopy. In characterized human liver microsomes, 24-hydroxylation of 1 alpha OHD(2) by CYP3A4 correlated significantly with 6 beta-hydroxylation of testosterone, a marker of CYP3A4 activity. 24-Hydroxylase activity in recombinant CYP3A4 and pooled human liver microsomes showed dose-dependent inhibition by ketoconazole, troleandomycin, alpha-naphthoflavone, and isoniazid, known inhibitors of CYP3A4. Rates of 24- and 25-hydroxylation of 1 alpha OHD(2) and 1 alpha OHD(3) were determined in recombinant wild-type CYP3A4 and site-directed mutants and naturally occurring variants expressed in Escherichia coli. Substitution of residues showed the most prominent alterations of function at residues 119, 120, 301, 305, and 479. Thus, CYP3A4 is both a 24- and 25-hydroxylase for vitamin D(2), 1 alpha OHD(2), and 1 alpha OHD(3). |
| 2004 | Therapeutic drugs that behave as mechanism-based inhibitors of cytochrome P450 3A4. | Curr Drug Metab | Cytochrome P450 (CYP) 3A4 is not only the most abundant isoform in human liver but also metabolizes approximately 60% of the therapeutic drugs. This feature renders CYP3A4 highly susceptible to both reversible and irreversible (mechanism-based) inhibition. The latter is characterized by NADPH-, time- and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYPs to reactive metabolites. Mechanism-based inactivation of CYP3A4 by drugs can be due to the chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. The clinical pharmacokinetic effect of a CYP3A4 inactivator is a function of its KI, kinact and partition ratio and the synthesis rate of new or replacement enzyme. Predicting drug-drug interactions involving CYP3A4 inactivation is possible when proper pharmacokinetic principles are followed. However, the prediction may become difficult, since the clinical outcomes due to CYP3A4 inactivation depend on many factors associated with the enzyme, drugs and the patients. A number of clinically important drugs have been identified to be mechanism-based CYP3A4 inhibitors. These include antibiotics (e.g. erythromycin and isoniazid), anticancer drugs (e.g. tamoxifen), antidepressants (e.g. fluoxetine and midazolam), anti-HIV agents (e.g. ritonavir and delavirdine), antihypertensives (e.g. dihydralazine and verapamil), steroids and their receptor modulators (e.g. gestodene and raloxifene), and some herbal constituents (e.g. bergamottin and glabridin). Compared to reversible inhibition, mechanism-based inhibitors of CYP3A4 more frequently cause unfavorable drug-drug interactions, as the inactivated CYP3A4 has to be replaced by newly synthesized CYP3A4 protein. Most CYP3A4 inactivators are also PgP substrates/inhibitors, confounding the in vitro-in vivo extrapolation. Clinicians should have good knowledge on these CYP3A4 inactivators and avoid their combination use. |
| 2004 | Mechanism-based inactivation of human cytochrome P4502C8 by drugs in vitro. | J Pharmacol Exp Ther | Studies were conducted to evaluate the potential mechanism-based inactivation of recombinant and human liver microsomal CYP2C8 by clinically used drugs. Several tricyclic antidepressants, calcium channel blockers, monoamine oxidase inhibitors, and various other known CYP3A4 inhibitors exhibited greater inhibition of CYP2C8 (paclitaxel 6alpha-hydroxylation) following preincubation, consistent with mechanism-based inactivation. Inactivation of recombinant CYP2C8 by phenelzine, amiodarone, verapamil, nortriptyline, fluoxetine, and isoniazid was of the pseudo-first order type and was characterized by respective inactivation kinetic constants (KI and kinact) of 1.2 microM and 0.243 min(-1), 1.5 microM and 0.079 min(-1), 17.5 microM and 0.065 min(-1), 49.9 microM and 0.036 min(-1), 294 microM and 0.083 min(-1), and 374 microM and 0.042 min(-1). Spectral scanning of recombinant CYP2C8 demonstrated the formation of metabolite-intermediate complexes with verapamil, nortriptyline, fluoxetine, and isoniazid, but not amiodarone. In contrast, inactivation by phenelzine resulted from heme destruction by free radicals. Studies with human liver microsomes (HLMs) revealed that nortriptyline, verapamil, and fluoxetine were not mechanism-based inactivators (MBIs) of CYP2C8. Simultaneous inactivation of CYP2C8 and CYP3A4 (paclitaxel 3'-phenyl-hydroxylation) was observed using amiodarone, isoniazid, and phenelzine with the efficiency of inactivation greater for the CYP3A4 pathway. With the exception of phenelzine, glutathione and superoxide dismutase failed to protect CYP2C8 (recombinant and HLMs) or CYP3A4 from inactivation by MBIs. However, the alternate CYP2C8 substrate, torsemide, prevented CYP2C8 inactivation in all cases. These data are consistent with mechanism-based inactivation of CYP2C8 by a range of commonly prescribed drugs, several of which have been implicated in clinically important drug-drug interactions. |
| 2004 | CYP3A4 is a human microsomal vitamin D 25-hydroxylase. | J Bone Miner Res | The human hepatic microsomal vitamin D 25-hydroxylase protein and gene have not been identified with certainty. Sixteen hepatic recombinant microsomal enzymes were screened for 25-hydroxylase activity; 11 had some 25-hydroxylase activity, but CYP3A4 had the highest activity. In characterized liver microsomes, 25-hydroxylase activity correlated significantly with CYP3A4 testosterone 6beta-hydroxylase activity. Activity in pooled liver microsomes was inhibited by known inhibitors of CYP3A4 and by an antibody to CYP3A2. Thus, CYP3A4 is a hepatic microsomal vitamin D 25-hydroxylase.Studies were performed to identify human microsomal vitamin D-25 hydroxylase.Sixteen major hepatic microsomal recombinant enzymes derived from cytochrome P450 cDNAs expressed in baculovirus-infected insect cells were screened for 25-hydroxylase activity with 1alpha-hydroxyvitamin D2 [1alpha(OH)D2], 1alpha-hydroxyvitamin D3 [1alpha(OH)D3], vitamin D2, and vitamin D3 as substrates. Activity was correlated with known biological activities of enzymes in a panel of 12 characterized human liver microsomes. The effects of known inhibitors and specific antibodies on activity also were determined.CYP3A4, the most abundant cytochrome P450 enzyme in human liver and intestine, had 7-fold greater activity than that of any of the other enzymes with 1alpha(OH)D2 as substrate. CYP3A4 25-hydroxylase activity was four times higher with 1alpha(OH)D2 than with 1alpha(OH)D3 as substrate, was much less with vitamin D2, and was not detected with vitamin D3. 1alpha(OH)D2 was the substrate in subsequent experiments. In a panel of characterized human liver microsomes, 25-hydroxylase activity correlated with CYP3A4 testosterone 6beta-hydroxylase activity (r = 0.93, p < 0.001) and CYP2C9*1 diclofenac 4'-hydroxylase activity (r = 0.65, p < 0.05), but not with activity of any of the other enzymes. Activity in recombinant CYP3A4 and pooled liver microsomes was dose-dependently inhibited by ketoconazole, troleandomycin, isoniazid, and alpha-naphthoflavone, known inhibitors of CYP3A4. Activity in pooled liver microsomes was inhibited by antibodies to CYP3A2 that are known to inhibit CYP3A4 activity.CYP3A4 is a vitamin D 25-hydroxylase for vitamin D2 in human hepatic microsomes and hydroxylates both 1alpha(OH)D2 and 1alpha(OH)D3. |
| 2003 | Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. | Drug Metab Dispos | Cultured human hepatocytes are a valuable in vitro system for evaluating new molecular entities as inducers of cytochrome P450 (P450) enzymes. The present study summarizes data obtained from 62 preparations of cultured human hepatocytes that were treated with vehicles (saline or dimethylsulfoxide, 0.1%), beta-naphthoflavone (33 microM), phenobarbital (100 or 250 microM), isoniazid (100 microM) and/or rifampin (20 or 50 microM), and examined for the expression of P450 enzymes based on microsomal activity toward marker substrates, or in the case of CYP2C8, the level of immunoreactive protein. The results show that CYP1A2 activity was markedly induced by beta-naphthoflavone (on average 13-fold, n = 28 preparations), and weakly induced by phenobarbital (1.9-fold, n = 25) and rifampin (2.3-fold, n = 22); CYP2A6 activity tended to be increased with phenobarbital (n = 7) and rifampin (n = 3) treatments, but the effects were not statistically significant; CYP2B6 was induced by phenobarbital (6.5-fold, n = 13) and rifampin (13-fold, n = 14); CYP2C8 was induced by phenobarbital (4.0-fold, n = 4) and rifampin (5.2-fold, n = 4); CYP2C9 was induced by phenobarbital (1.8-fold, n = 14) and rifampin (3.5-fold, n = 10); CYP2C19 was markedly induced by rifampin (37-fold, n = 10), but relatively modestly by phenobarbital (7-fold, n = 9); CYP2D6 was not significantly induced by phenobarbital (n = 5) or rifampin (n = 5); CYP2E1 was induced by phenobarbital (1.7-fold, n = 5), rifampin (2.2-fold, n = 5), and isoniazid (2.3-fold, n = 5); and, CYP3A4 was induced by phenobarbital (3.3-fold, n = 42) and rifampin (10-fold, n = 61), but not by beta-naphthoflavone. Based on these observations, we generalize that beta-naphthoflavone induces CYP1A2 and isoniazid induces CYP2E1, whereas rifampin and, to a lesser extent phenobarbital, tend to significantly and consistently induce enzymes of the CYP2A, CYP2B, CYP2C, CYP2E, and CYP3A subfamilies but not the 2D subfamily. |
| 2002 | Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes. | Eur J Clin Pharmacol | In order to evaluate the inhibitory effects of isoniazid on cytochrome P450 (CYP) mediated drug metabolism, the in vitro inhibitory potency and specificity as well as the reduced nicotinamide adenine dinucleotide phosphate (NADPH)-, time- and concentration dependency of isoniazid as an inhibitor of the activity of the major human CYP isoforms were studied.Using pooled human liver microsomes, the in vitro inhibitory effects of isoniazid on CYP1A2 (phenacetin O-deethylation), CYP2A6 (coumarin 7-hydroxylation), CYP2C9 (tolbutamide hydroxylation), CYP2CI9 (S-mephenytoin 4'-hydroxylation), CYP2D6 (dextromethorphan O-demethylation), CYP2E1 (chlorzoxazone 6-hydroxylation) and CYP3A4 (midazolam 1'-hydroxylation) activities were examined.After a 15-min preincubation without NADPH, isoniazid reversibly inhibited microsomal CYP2C19- and CYP3A4-mediated reactions with apparent Ki values of 36 microM and 73 microM, respectively. However, isoniazid had only weak inhibitory effects on the five other CYP-mediated reactions (Ki > 110 microM). After a 15-min preincubation with NADPH, isoniazid showed an increased inhibitory potency toward CYP1A2, CYP2A6, CYP2C19 and CYP3A4 activities (Ki = 56, 60, 10 and 36 microM, respectively). In addition, the inactivation of CYP1A2, CYP2A6, CYP2C19 and CYP3A4 by isoniazid was NADPH-, time- and concentration dependent, and was characterised by Kinact values of 0.11, 0.13, 0.09 and 0.08 min(-1), and K1 values of 285, 173, 112 and 228 microM, respectively.As the peak plasma concentrations of isoniazid are around 30-50 microM, isoniazid at clinically relevant concentrations reversibly inhibits CYP2C19 and CYP3A4 activities, and mechanistically inactivates CYP1A2, CYP2A6, CYP2C19 and CYP3A4 in human liver microsomes. Co-administration of isoniazid and drugs that are primarily metabolised by these CYP isoforms, particularly by CYP2C19 and CYP3A4, may result in significant drug interactions. |
| 2000 | Metabolic activation of o-phenylphenol to a major cytotoxic metabolite, phenylhydroquinone: role of human CYP1A2 and rat CYP2C11/CYP2E1. | Xenobiotica | 1. The in vitro metabolic activation of o-phenylphenol has been evaluated as yielding a toxic metabolite, 2,5-dihydroxybiphenyl (phenylhydroquinone), by p-hydroxylation in liver microsomes of rat and human. The involvement of rat CYP2C11, CYP2E1 and human CYP1A2 in the p-hydroxylation of o-phenylphenol is suggested. 2. 2,3- and phenylhydroquinone, which induced DNA single-strand scission in the presence of 1 microM CuCl2, were the most cytotoxic chemicals examined to cultured mammalian cell lines among o-phenylphenol, m-phenylphenol, p-phenylphenol, 2,2'-, 4,4'-, 2,3- and phenylhydroquinone. 3. Rat and human liver microsomes catalysed the formation of phenylhydroquinone, but not 2,3-dihydroxybiphenyl, using o-phenylphenol as a substrate. A higher rate of metabolic activation of o-phenylphenol was observed with livers of the male than the female rats by 5.6- and 2.6-fold respectively. 4. Inhibitory antibodies against the male-specific CYP2C11 inhibited hepatic o-phenylphenol p-hydroxylation in the male F344 and Sprague-Dawley rat by > 70%. Liver microsomes from the isoniazid-treated rats produced 1.8- and 3-fold induction of o-phenylphenol p-hydroxylation and chlorzoxazone 6-hydroxylation (a CYP2E1-dependent activity) respectively. 5. Human CYP1A2, expressed by baculovirus-mediated cDNA expression systems, exhibited a remarkably higher capacity for o-phenylphenol p-hydroxylation at concentrations of 5 (> 5-fold), 50 (> 2-fold) and 500 microM (> 2-fold) than CYP2A, CYP2B, CYP2Cs, CYP2D6, CYP2E1 and CYP3A4 on the basis of pmol P450. 6. Among various CYP inhibitors tested here, 7,8-benzoflavone and furafylline, typical human CYP1A2 inhibitors, inhibited the microsomal p-hydroxylation of o-phenylphenol in human livers most potently by 70 and 50% respectively. 7. The results thus indicate the involvement of rat CYP2C11/CYP2E1 and human CYP1A2 in the hepatic p-hydroxylation of o-phenylphenol. |
| 2000 | Drug interactions with cisapride: clinical implications. | Clin Pharmacokinet | Cisapride, a prokinetic agent, has been used for the treatment of a number of gastrointestinal disorders, particularly gastro-oesophageal reflux disease in adults and children. Since 1993, 341 cases of ventricular arrhythmias, including 80 deaths, have been reported to the US Food and Drug Administration. Marketing of the drug has now been discontinued in the US; however, it is still available under a limited-access protocol. Knowledge of the risk factors for cisapride-associated arrhythmias will be essential for its continued use in those patients who meet the eligibility criteria. This review summarises the published literature on the pharmacokinetic and pharmacodynamic interactions of cisapride with concomitantly administered drugs, providing clinicians with practical recommendations for avoiding these potentially fatal events. Pharmacokinetic interactions with cisapride involve inhibition of cytochrome P450 (CYP) 3A4, the primary mode of elimination of cisapride, thereby increasing plasma concentrations of the drug. The macrolide antibacterials clarithromycin, erythromycin and troleandomycin are inhibitors of CYP3A4 and should not be used in conjunction with cisapride. Azithromycin is an alternative. Similarly, azole antifungal agents such as fluconazole, itraconazole and ketoconazole are CYP3A4 inhibitors and their concomitant use with cisapride should be avoided. Of the antidepressants nefazodone and fluvoxamine should be avoided with cisapride. Data with fluoxetine is controversial, we favour the avoidance of its use. Citalopram, paroxetine and sertraline are alternatives. The HIV protease inhibitors amprenavir, indinavir, nelfinavir, ritonavir and saquinavir inhibit CYP3A4. Clinical experience with cisapride is lacking but avoidance with all protease inhibitors is recommended, although saquinavir is thought to have clinically insignificant effects on CYP3A4. Delavirdine is also a CYP3A4 inhibitor and should be avoided with cisapride. We also recommend avoiding coadministration of cisapride with amiodarone, cimetidine (alternatives are famotidine, nizatidine, ranitidine or one of the proton pump inhibitors), diltiazem and verapamil (the dihydropyridine calcium antagonists are alternatives), grapefruit juice, isoniazid, metronidazole, quinine, quinupristin/dalfopristin and zileuton (montelukast is an alternative). Pharmacodynamic interactions with cisapride involve drugs that have the potential to have additive effects on the QT interval. We do not recommend use of cisapride with class Ia and III antiarrhythmic drugs or with adenosine, bepridil, cyclobenzaprine, droperidol, haloperidol, nifedipine (immediate release), phenothiazine antipsychotics, tricyclic and tetracyclic antidepressants or vasopressin. Vigilance is advised if anthracyclines, cotrimoxazole (trimethoprim-sulfamethoxazole), enflurane, halothane, isoflurane, pentamidine or probucol are used with cisapride. In addition, uncorrected electrolyte disturbances induced by diuretics may increase the risk of torsade de pointes. Patients receiving cisapride should be promptly treated for electrolyte disturbances. |
| Pharmacokinetic drug interactions of vinca alkaloids: summary of case reports. | Pharmacotherapy | Involvement of the cytochrome P450 (CYP) 3A subfamily in the metabolism of vincristine is well established. However, information is limited regarding vincristine's drug interaction profile. All the substrates and inhibitors of CYP3A4 such as the azole antifungals (itraconazole, ketoconazole), cyclosporine, isoniazid, and nifedipine have very high propensity to interfere with vincristine metabolism. The proposed mechanism is most likely attributed to either inhibition of 3A4 enzymes or blockade of P-glycoprotein pumps. These interactions are clinically significant and can lead to severe vincristine toxicity if not detected. Although case reports discussed here exclusively involve vincristine, it is important to assume that all vinca alkaloids interact in the same manner until proved otherwise, because they share similar metabolism pathways. |
| 1996 | Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. | Clin Pharmacokinet | Carbamazepine is one of the most commonly prescribed antiepileptic drugs and is also used in the treatment of trigeminal neuralgia and psychiatric disorders, particularly bipolar depression. Because of its widespread and long term use, carbamazepine is frequently prescribed in combination with other drugs, leading to the possibility of drug interactions. The most important interactions affecting carbamazepine pharmacokinetics are those resulting in induction or inhibition of its metabolism. Phenytoin, phenobarbital (phenobarbitone) and primidone accelerate the elimination of carbamazepine, probably by stimulating cytochrome P450 (CYP) 3A4, and reduce plasma carbamazepine concentrations to a clinically important extent. Inhibition of carbamazepine metabolism and elevation of plasma carbamazepine to potentially toxic concentrations can be caused by stiripentol, remacemide, acetazolamide, macrolide antibiotics, isoniazid, metronidazole, certain antidepressants, verapamil, diltiazem, cimetidine, danazol and (dextropropoxyphene) propoxyphene. In other cases, toxic symptoms may result from elevated plasma concentrations of the active metabolite carbamazepine-10,11-epoxide, due to the inhibition of epoxide hydrolase by valproic acid (sodium valproate), valpromide, valnoctamide and progabide. Carbamazepine is a potent inducer of CYP3A4 and other oxidative enzyme system in the liver, and it may also increase glucuronyltransferase activity. This results in the acceleration of the metabolism of concurrently prescribed anticonvulsants, particularly valproic acid, clonazepam, ethosuximide, lamotrigine, topiramate, tiagabine and remacemide. The metabolism of many other drugs such as tricyclic antidepressants, antipsychotics, steroid oral contraceptives, glucocorticoids, oral anticoagulants, cyclosporin, theophylline, chemotherapeutic agents and cardiovascular drugs can also be induced, leading to a number of clinically relevant drug interactions. Interactions with carbamazepine can usually be predicted on the basis of the pharmacological properties of the combined drug, particularly with respect to its therapeutic index, site of metabolism and ability to affect specific drug metabolising isoenzymes. Avoidance of unnecessary polypharmacy, selection of alternative agents with lower interaction potential, and careful dosage adjustments based on serum drug concentration monitoring and clinical observation represent the mainstays for the minimisation of risks associated with these interactions. |
| 1995 | Isoflurane-chlorodifluoroethene interaction in human liver microsomes. Role of cytochrome P4502B6 in potentiation of haloethene metabolism. | Drug Metab Dispos | Short-chain saturated halocarbons, including isoflurane and the chlorofluorocarbon substitute HCFC-123, can strongly potentiate the cytochrome P450-dependent oxidation of gaseous haloethenes, such as 2-chloro-1,1-difluoroethene (CDE) and vinyl chloride, in vivo and in vitro. P450 isozyme specificity in this effect is suggested by the fact that the interaction is pronounced in microsomes from rats treated with phenobarbital, but does not occur in microsomes of isoniazid- or beta-naphthoflavone-treated animals. We examined the effect of isoflurane on CDE defluorination in liver microsomes from 10 human organ donors to determine whether saturated halocarbon/haloethene interactions also occur in humans and, if so, to determine the cytochromes P450 involved. Three of the samples exhibited isoflurane-stimulated increases (24, 32, and 41%) in CDE defluorination; isoflurane either inhibited or had no effect on CDE metabolism in the other seven samples. Two samples in which isoflurane potentiated CDE metabolism to the greatest rates had higher coumarin 7-hydroxylase (indicative of CYP2A6), 7-ethoxycoumarin O-deethylase (CYP2B6), and nifedipine oxidase (CYP3A4) activities than the other eight samples. However, all 10 subjects had similar rates of phenacetin O-deethylation (CYP1A2) and chlorzoxazone 6-hydroxylation (CYP2E1). In microsomes from cells transfected with cDNAs coding for individual human P450s, CDE metabolism by CYP2B6 was stimulated (216%) by isoflurane, whereas isoflurane did not stimulate CDE metabolism by human CYP2A6, CYP3A4, CYP2D6, or CYP2E1. Isoflurane highly increased CDE defluorination in purified rat CYP2B1 (470%).(ABSTRACT TRUNCATED AT 250 WORDS) |