Metabolism of carbamazepine by CYP3A6: A model for in vitro drug interactions studies

Mesdjian, E; Sérée, Eric; Charvet, Benjamin; Mirrione, A.; Bourgarel-Rey, Véronique; Desobry, A.; Barra, Yves

doi:10.1016/s0024-3205(99)00004-1

Cited by 27 publications

(17 citation statements)

References 23 publications

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“…Although inhibitory antibodies against rabbit CYP3A were not available to us at the time these experiments were performed, the 10-hydroxylation of R-warfarin in rabbit liver microsomal incubations was nearly completely inhibited by ketoconazole, and to a lesser extent, by troleandomycin (Table 1). Both ketoconazole and troleandomycin are selective inhibitors of human CYP3A and also were shown to inhibit rabbit CYP3A6 when carbamazepine and N-desethylamiodarone were evaluated as substrates (Mesdjian et al, 1999;Kozlik et al, 2001). These data collectively suggest that CYP3A enzymes are responsible for the 10-hydroxylation of R-warfarin in rats, rabbits, and monkeys.…”

Section: R-warfarin Metabolism In Liver Microsomalmentioning

confidence: 82%

Effect of Quinidine on the 10-Hydroxylation of R-Warfarin: Species Differences and Clearance Projection

Chen

Tan²,

Strauss³

et al. 2004

The Journal of Pharmacology and Experimental Therapeutics

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Stimulation by quinidine of warfarin metabolism in vitro was first demonstrated with liver microsomal preparations. We report herein that this drug interaction is reproducible in an animal model but that it exhibits profound species differences. Thus, using rabbit liver microsomes and a kinetic model incorporating two binding sites, the hepatic intrinsic clearance of R-warfarin via the 10-hydroxylation pathway (CL int W ) was projected to be 6 Ϯ 1 and 128 Ϯ 51 l/min/g liver, respectively, in the absence and presence of 21 M unbound quinidine. These estimates were consistent with the results from studies in which rabbit livers (n ϭ 5) were perfused in situ with R-warfarin or R-warfarin plus quinidine. The CL int W increased from 7 Ϯ 3 to 156 Ϯ 106 l/min/g liver after increasing the hepatic exposure of unbound quinidine from 0 to 21 M. In contrast, when liver microsomes or intact livers from rats were examined, R-warfarin metabolism was inhibited by quinidine, the CL int W decreasing to 26% of the control value after exposure of perfused rat livers (n ϭ 5) to 22 M unbound quinidine. The third example involved monkey liver microsomes, in which the rate of 10-hydroxylation of Rwarfarin was little affected in the presence of quinidine (Ͻ2-fold increase). In all three species, the 10-hydroxylation of R-warfarin was catalyzed primarily by members of CYP3A, based on immuno-and chemical inhibition analyses. These findings not only highlight the variability of drug interactions among different species but also suggest that changes in hepatic clearance resulting from stimulation of cytochrome P450 activity may be projected based on estimates generated from corresponding liver microsomal preparations.The mammalian cytochromes P450 (P450s) constitute a family of enzymes distributed primarily in liver, kidney, and intestinal tissues that often are responsible for the metabolic clearance of therapeutic agents in humans (Wrighton and Stevens, 1992;Guengerich, 1997a). As a result, either inhibition or induction of a P450 in patients receiving polytherapy has the potential to precipitate clinically important drug interactions. Whereas P450 inhibition may lead to drugrelated adverse effects that result from substantial increases in systemic concentrations of one or other of the drugs, P450 induction by one agent can decrease circulating levels of a second due to enhanced metabolic clearance and thereby compromise therapeutic effects of the latter (Lin and Lu, 1998). A relatively newer field of P450 research pertinent to drug interactions is that of heterotropic enhancement of P450 activity, in which the metabolism of a substrate is stimulated by an effector Hutzler and Tracy, 2002). An example of enzyme behavior of this type is found with CYP3A4 in human liver microsomes whose activity, measured by the rate of 10-hydroxylation of R-warfarin, increased severalfold in the presence of quinidine (Ngui et al., 2001). On the basis of such observations, it seems likely that enhancement of P450 activity could result in pharmacolog...

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Section: R-warfarin Metabolism In Liver Microsomalmentioning

confidence: 82%

Effect of Quinidine on the 10-Hydroxylation of R-Warfarin: Species Differences and Clearance Projection

Chen

Tan²,

Strauss³

et al. 2004

The Journal of Pharmacology and Experimental Therapeutics

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“…CYP3A4 is the most important enzyme involved in the metabolism of CBZ as it leads to the formation of the active metabolite CBZ 10,11-epoxide, which appears to contribute to the toxicity and efficacy of CBZ 20,21 . CYP3A6 is responsible for CBZ metabolism in the rabbit 22 . The rabbit CYP3A6 and human CYP3A4 isoform have similar p-450 predominance and substrate specificity and both are induced by rifampicin 23 .…”

Section: Resultsmentioning

confidence: 99%

Untitled

2014

IJPSR

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ABSTRACT:The aim of this article was to evaluate the effect of valerian on a single dose kinetic of carbamazepine in rabbits. Five healthy male rabbits in a randomized, two-crossover design were enrolled in this study. Rabbits were divided into two groups; the first received a single dose of 100 mg carbamazepine (CBZ) suspension. The second group received CBZ 100 mg suspension concurrently with valerian (VAL) 25 mg dry extract. After a washout period of one week the doses were given in a reverse manner. Blood samples were collected over a period of 24 hours. Serum was assayed for CBZ using chemiluminescent enzyme immunoassay (CLEIA). Pharmacokinetic (PK) parameters were determined for CBZ in both cases using non-compartmental analysis. Statistically insignificant differences P ≥ 0.05 were found in PK parameters when CBZ was given alone or concurrently with VAL; the values were C max 6.52 ± 1.6 µg/ml versus 5.32 ± 1.4 µg/ml, t max 2.6 ± 0.9 h versus 3.3 ± 0.9 h, AUC 0-24 83.80 ± 28.8 µg·h/ml versus 60.4 ± 12 µg·h/ml, AUC 0-∞ 166.20 ± 74 µg·h/ml versus 104.75 ± 12 µg·h/ml, k e 0.033 ± 0.006 h -1 versus 0.038 ± 0.012 h -1 and t 1/2 21.81 ± 3.96 h versus 20.71 ± 10.09 h respectively. The result of the study demonstrated that valerian does not affect PK of CBZ, there are no cautions, regarding to dose or administration pattern of CBZ with valerian should be taken.

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“…The basis for studying the interaction between carbamazepine and artemisinin compounds was the common metabolic pathway in involving the isoenzyme CYP3A4. In rabbits, it has been seen that the isoenzyme CYP3A6 corresponds to CYP3A4 activity in human hepatocytes [10] . Hence, drugs like carbamazepine that are metabolized by CYP3A4 in humans will be biotransformed by CYP3A6 in rabbits.…”

Section: Discussionmentioning

confidence: 99%

“…Carbamazepine is metabolized by CYP3A4 and can also induce this cytochrome [9] . In rabbits, CYP3A6 is the cytochrome responsible for carbamazepine metabolism and corresponds to CYP3A4 activity in human hepatocytes [10] . In areas endemic for resistant malaria, patients on chronic therapy with carbamazepine for epilepsy are likely to receive artemisinin compounds if an episode of malaria occurs.…”

Section: Effect Of Artemisinin Compounds On Pharmacokinetics Of Carbamentioning

confidence: 99%

Effects of Artemisinin, Artemether, Arteether on the Pharmacokinetics of Carbamazepine

Sukhija

Medhi²,

Pandhi³

2006

Pharmacology

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The effect of artemisinin, artemether and arteether on the pharmacokinetics of carbamazepine in rabbits was studied. In a cross-over study, carbamazepine 40 mg/kg/day orally was given daily for 7 days. On day 7, blood samples were taken at various time intervals between 0 and 24 h. In the artemisinin group, carbamazepine was administered for 7 days as above. On day 8, artemisinin 82 mg/kg followed by 41 mg/kg on the 9th and 10th day along with carbamazepine 40 mg/kg/day was administered and blood samples drawn as above. Artemether 10 mg/kg i.m. was given on day 8 followed by 5 mg/kg i.m. for 2 days. Arteether 10 mg/kg i.m. was given from day 8 for 3 days. Plasma carbamazepine levels were assayed by high-performance liquid chromatography and pharmacokinetic parameters calculated. In all the groups there was an increase in the AUC_0–∞ when carbamazepine was co-administered with artemisinin, artemether or arteether. The increase in AUC_0–∞ (22.78 ± 4.71 to 63.10 ± 12.29), C_max (2.76 ± 0.77 to 7.02 ± 1.08), T_max (2.83 ± 0.17 to 4.16 ± 0.40) was statistically significant when artemether was given along with carbamazepine (p < 0.05). In the other groups the increase was not significant. These results suggest artemisinin compounds alter the pharmacokinetics of carbamazepine with significant change in the bioavailability. Confirmation of these results in human studies will warrant changes in carbamazepine dose or frequency when either of these antimalarials is co-administered with it.

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Metabolism of carbamazepine by CYP3A6: A model for in vitro drug interactions studies

Cited by 27 publications

References 23 publications

Effect of Quinidine on the 10-Hydroxylation of R-Warfarin: Species Differences and Clearance Projection

Effect of Quinidine on the 10-Hydroxylation of R-Warfarin: Species Differences and Clearance Projection

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Effects of Artemisinin, Artemether, Arteether on the Pharmacokinetics of Carbamazepine

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