Expression of CYP3A4, CYP3A5 and CYP3A7 in human duodenal tissue

Kivistö, Kari T.; Bookjans, Gerhard; Fromm, Martin F.; Griese, Ernst-Ulrich; Münzel, Peter A.; Kroemer, Heyo K.

doi:10.1046/j.1365-2125.1996.42615.x

Cited by 86 publications

(51 citation statements)

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“…In this study, we found that oral apparent clearance increased but t 1/2 did not change in the CYP3A5 homozygous wild-type group compared with the CYP3A5 homozygous dysfunctional group. Since CYP3A5 is present in the gut (Kivistö et al, 1996) and represents up to more than 50% of total CYP3A content in liver (Kuehl et al, 2001) in individuals who express CYP3A5, we suspect that the reduced maraviroc AUC in the CYP3A5 homozygous wild-type group may be a result of decreased bioavailability due to enhanced CYP3A5-mediated maraviroc oxidative metabolism in the gut and liver of those with this genotype, which was suggested by the lower AUC maraviroc /AUC M1 ratio compared with the homozygous dysfunctional group. The higher AUC maraviroc /AUC M1 ratio in the homozygous dysfunctional group is concordant with our previous in vitro observation that CYP3A5 was the major enzyme responsible for M1 formation.…”

Section: Discussionmentioning

confidence: 99%

CYP3A5 Genotype Impacts Maraviroc Concentrations in Healthy Volunteers

Fuchs

Hendrix

et al. 2014

Drug Metab Dispos

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CYP3A5 plays a prominent role in the metabolism of maraviroc, an approved drug for human immunodeficiency virus (HIV)-1 treatment and a candidate for HIV-1 prevention. We studied the effect of the CYP3A5 genotype on pharmacokinetics of maraviroc and a primary CYP3A5-dependent metabolite of maraviroc denoted as metabolite 1 (M1). Volunteers were screened for health status and CYP3A5 genotype (wild-type allele *1 and dysfunctional alleles *2, *3, *6, and *7) to obtain 24 evaluable subjects in three groups (n = 8 each): homozygous dysfunctional (two dysfunctional alleles), heterozygous (one *1 allele and one dysfunctional allele), and homozygous wild-type (two *1 alleles). Subjects received 300 mg maraviroc orally followed by blood collection for 32 hours. The homozygous wild-type group exhibited lower mean plasma maraviroc concentrations at almost all sampling times. The median (interquartile range) maraviroc area under the plasma concentration-time curves from time 0 to infinity (AUC 0-inf ) were 2099 (1422-2568) ng×h/ml, 1761 (931-2640) ng×h/ml, and 1238 (1065-1407) ng×h/ml for the homozygous dysfunctional, heterozygous, and homozygous wildtype groups, respectively. The homozygous wild-type group had 41% lower maraviroc AUC 0-inf and 66% higher apparent clearance compared with the homozygous dysfunctional group (P = 0.02). The AUC 0-inf ratios of maraviroc to M1 in heterozygous and homozygous wild-type subjects were lower by 51 and 64% relative to the homozygous dysfunctional group, respectively (P < 0.001). In conclusion, the lower maraviroc concentrations in the homozygous wild-type group indicate that maraviroc may be underdosed in people homozygous for the CYP3A5*1 allele, including almost onehalf of African Americans.

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Section: Discussionmentioning

confidence: 99%

CYP3A5 Genotype Impacts Maraviroc Concentrations in Healthy Volunteers

Fuchs

Hendrix

et al. 2014

Drug Metab Dispos

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“…All these findings suggested that GLS4 was a sensitive substrate of CYP3A, and first-pass metabolism played an important role in GLS4 elimination. Although the function of the gut wall in the presystemic metabolism of GLS4 is unknown, the interactions between GLS4 and CYP3A modulators possibly occur in the duodenal wall, as shown by the extensive expression of CYP3A in the duodenal wall [24] and more significant effects on C max and AUC of GLS4 than T 1/2 .…”

Section: Discussionmentioning

confidence: 99%

Effects of ketoconazole and rifampicin on the pharmacokinetics of GLS4, a novel anti-hepatitis B virus compound, in dogs

Zhou

Gao

et al. 2013

Acta Pharmacol Sin

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Aim: To investigate the metabolism of GLS4, a heteroaryldihydropyrimidine compound with anti-hepatitis B virus activity, in dog and human liver microsomes in vitro and evaluate the effects of ketoconazole (a potent CYP3A inhibitor) or rifampicin (a potent CYP3A inducer) on GLS4 pharmacokinetics in dogs. Methods: Dog and human liver microsomes and CYP3A4 were incubated with [14 C]GLS4 for 15 min and then analyzed using a HPLCdynamic online radio flow detection method. Two groups of beagle dogs were used for in vivo studies. Group A were orally administered a single dose of GLS4 (15 mg/kg) with or without ketoconazole pretreatment (100 mg/d for 8 consecutive days). Group B were orally administered a single dose of GLS4 (15 mg/kg) with or without rifampicin pretreatment (100 mg/d for 8 consecutive days). Plasma was sampled after GLS4 dosing. GLS4 concentrations were determined by HPLC-tandem mass spectrometry. Results: The metabolic profile of [14 C]GLS4 in human and dog liver microsomes and CYP3A4 was similar. The major metabolites were morpholine N-dealkylated GLS4 and morpholine N,N-di-dealkylated GLS4. Pretreatment with ketoconazole or rifampicin significantly affected the plasma concentrations of GLS4 in dogs: ketoconazole increased the area under the concentration-time curve from 0 to infinity and peak concentration of GLS4 by 4.4 and 3.3 folds, respectively, whereas rifampicin decreased these parameters by 88.5% and 83.2%, respectively. Conclusion: GLS4 is a sensitive substrate of CYP3A. CYP3A inhibitors or inducers cause considerable change of GLS4 plasma concentrations in dogs, which should be considered in clinical practice.

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“…This is of considerable interest since hepatic CYP3A5 is expressed in an appreciable amount in only 25% of the population and then could actively participate to the overall metabolism of amprenavir. Furthermore, CYP3A5 is also expressed in a non-negligible amount in the intestine and could increase the elimination of amprenavir (Kivisto et al, 1996). CYP3A7, the third member of the CYP3A subfamily had virtually no activity.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Metabolism of Amprenavir in the Human Liver. Effect of the CYP3A Maturation

Tréluyer

Bowers²,

Cazali³

et al. 2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Amprenavir is a human immunodeficiency virus-1 (HIV-1) protease inhibitor intended to be used to treat HIV-infected children. Although a pediatric dosage is proposed by the manufacturer, no data are currently available on the pharmacokinetics of amprenavir in neonates and infants. Amprenavir being primarily eliminated after oxidative biotransformation, we explored its in vitro metabolism by cytochrome P450 (P450)-dependent monooxygenases. In our conditions, five metabolites were formed in vitro and subsequently analyzed by liquid chromatography-mass spectrometry; P450-dependent oxidations occurred either on the tetrahydrofuran ring (M3 and M4), the aniline ring (M5), and the aliphatic chain (M2) or resulted from the N-dealkylation and loss of the tetrahydrofuran ring (M1). The two major metabolites, respectively M3 and M2 were formed by human liver microsomes with K m between 10 and 70 M. CYP3A4 and to a lesser extent CYP3A5 were major contributors for the formation of M2, M3, and M5 metabolites, whereas CYP3A7 had no or little activity. This assumption was confirmed by inhibition with ketoconazole and ritonavir (two potent inhibitors of CYP3A) whereas sulfaphenazole (2C9 inhibitor) and quinidine (2D6 inhibitor) were inefficient. The metabolism of amprenavir was negligible in microsomes from either fetuses or neonates and steadily increased after the first weeks of life in relation with the maturation of CYP3A4/5. In conclusion, results demonstrated that the capacity of the human liver to oxidize amprenavir is low during the first weeks after birth and that dosage could be substantially reduced during the early neonatal period.

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Expression of CYP3A4, CYP3A5 and CYP3A7 in human duodenal tissue

Cited by 86 publications

References 0 publications

CYP3A5 Genotype Impacts Maraviroc Concentrations in Healthy Volunteers

CYP3A5 Genotype Impacts Maraviroc Concentrations in Healthy Volunteers

Effects of ketoconazole and rifampicin on the pharmacokinetics of GLS4, a novel anti-hepatitis B virus compound, in dogs

Oxidative Metabolism of Amprenavir in the Human Liver. Effect of the CYP3A Maturation

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