Hepatic but not intestinal CYP3A4 displays dose‐dependent induction by efavirenz in humans

Mouly, Stéphane; Lown, Kenneth S.; Kornhauser, David M.; Joseph, Jeffrey L.; Fiske, William D.; Benedek, Irma H.; Watkins, Paul B.

doi:10.1067/mcp.2002.124519

Cited by 193 publications

(181 citation statements)

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“…The possibility that TPM also induces the intestinal metabolism, which was not addressed in our studies, cannot be ruled out. Whereas most compounds that induce hepatic CYP3A4 also induce the intestinal enzyme, a few notable exceptions exist to this observation (18). Currently the unavailability of an appropriate in vitro tool to study intestinal CYP induction is a major limitation to investigating this possibility.…”

Section: Discussionmentioning

confidence: 99%

“…In a cohort of 12 women with epilepsy receiving stable dosages of valproic acid (VPA) along with a combination norethindrone, 1 mg/ethinyl estradiol, 35-µg tablet, TPM administered at doses of 200 mg/day, 400 mg/day, and 800 mg/day caused a statistically significant dose-related increase in the mean oral serum clearance (CL/F was 14.7-33% higher) of ethinyl estradiol (2). The mean C max value for ethinyl estradiol decreased by [15][16][17][18][19][20][21][22][23][24][25].4%, and the area under the curve (AUC 0−24 ) decreased by 18-30% at the 200-to 800-mg/day dose level. The pharmacokinetics of norethindrone remained unchanged.…”

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confidence: 99%

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Dose‐dependent Induction of Cytochrome P450 (CYP) 3A4 and Activation of Pregnane X Receptor by Topiramate

et al. 2003

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Summary: Purpose:In clinical studies, topiramate (TPM) was shown to cause a dose-dependent increase in the clearance of ethinyl estradiol. We hypothesized that this interaction results from induction of hepatic cytochrome P450 (CYP) 3A4 by TPM. Accordingly, we investigated whether TPM induces CYP3A4 in primary human hepatocytes and activates the human pregnane X receptor (hPXR), a nuclear receptor that serves as a regulator of CYP3A4 transcription.Methods: Human hepatocytes were treated for 72 h with TPM (10, 25, 50, 100, 250, and 500 µM) and known inducers, phenobarbital (PB; 2 mM), and rifampicin (10 µM). The rate of testosterone 6β-hydroxylation by hepatocytes served as a marker for CYP3A4 activity. The CYP3A4-specific protein and mRNA levels were determined by using Western and Northern blot analyses, respectively. The hPXR activation was assessed with cellbased reporter gene assay. Results:Compared with controls, TPM (50-500 µM)-treated hepatocytes exhibited a considerable increase in the CYP3A4 activity (1. 6-to 8.2-fold), protein levels (4.6-to 17.3-fold), and mRNA levels (1.9-to 13.3-fold). Comparatively, rifampicin (10 µM) effected 14.5-, 25.3-, and a 20.3-fold increase in CYP3A4 activity, immunoreactive protein levels, and mRNA levels, respectively. TPM (50-500 µM) caused 1.3-to 3-fold activation of the hPXR, whereas rifampicin (10 µM) caused a 6-fold activation.Conclusions: The observed induction of CYP3A4 by TPM, especially at the higher concentrations, provides a potential mechanistic explanation of the reported increase in the ethinyl estradiol clearance by TPM. It also is suggestive of other potential interactions when high-dose TPM therapy is used. Key Words: CYP3A4-Enzyme induction-HepatocyteshPXR-Topiramate.Topiramate [TPM; Topamax; 2, 3:4, 5-bis-0-(1-methylethylidene)-β-D-fructopyranose sulfamate] is a sulfamate-substituted monosaccharide derived from Dfructose and is structurally unrelated to other antiepileptic drugs (AEDs). Compared with many other AEDs, TPM appears to have several distinct advantages. First, it has anticonvulsant activity against a broad spectrum of seizure types and a good safety profile. Second, it exhibits linear disposition over the dosing range used clinically. Third, TPM appears to have few drug-drug interactions (1).However, one of these drug-drug interactions occurs with oral contraceptives. In a cohort of 12 women with epilepsy receiving stable dosages of valproic acid (VPA) along with a combination norethindrone, 1 mg/ethinyl Accepted August 4, 2003. Address correspondence and reprint requests to Dr. P. B. Desai at College of Pharmacy, University of Cincinnati Medical Center, 3223 Eden Avenue, Mail Location #0004, Cincinnati, OH 45267, U.S.A. Email: desaipb@ucmail.uc.edu estradiol, 35-µg tablet, TPM administered at doses of 200 mg/day, 400 mg/day, and 800 mg/day caused a statistically significant dose-related increase in the mean oral serum clearance (CL/F was 14.7-33% higher) of ethinyl estradiol (2). The mean C max value for ethinyl estradiol decreased by 15-25...

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Section: Discussionmentioning

confidence: 99%

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Dose‐dependent Induction of Cytochrome P450 (CYP) 3A4 and Activation of Pregnane X Receptor by Topiramate

et al. 2003

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“…However, it is unlikely interactions between PIs and P-gp play a role in this phenomenon. Recent studies showed that efavirenz was not a P-gp substrate on P-gp-expressing LS180 V cells [30], nor did it modulate intestinal P-gp expression in healthy volunteers [31]. There are two possibilities:…”

Section: Discussionmentioning

confidence: 99%

“…According to a pilot clinical study [31], there was no correlation between efavirenz systemic exposure and CYP3A4 activity in healthy volunteers. An intensive in vitro study indicated the efavirenz is metabolized by CYP2B6 with some involvement of CYP3A [3].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers

Forrest

Rosenkranz

et al. 2007

Biopharm & Drug Disp

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The combination of efavirenz with HIV-1 protease inhibitors (PI) results in complex interactions secondary to mixed induction and inhibition of oxidative metabolism. ACTG A5043 was a prospective, open-label, controlled, two-period, multiple-dose study with 55 healthy volunteers. The objective of the present study was to evaluate the potential pharmacokinetic interaction between efavirenz and dual PIs. The subjects received a daily dose of 600 mg efavirenz for 10 days with amprenavir 600 mg twice daily added at day 11 and were randomized to receive nelfinavir, indinavir, ritonavir, saquinavir, or no second PI on days 15-21. Intensive pharmacokinetic studies were conducted on day 14 and 21. Efavirenz plasma concentrations were fit to candidate models using weighted non-linear regression. The disposition of efavirenz was described by a linear two-compartment model with first order absorption following a fitted lag time. Apparent clearance (CL t /F), volume of distribution at steady state (V ss /F), intercompartmental clearance, and the central and peripheral volume of distribution were estimated. The mean CL t /F and V ss /F of efavirenz were 0.126 l/h/kg and 4.412 l/kg, respectively. Both AUC and CL t /F of efavirenz remained unchanged after 7 days of dual PI dosing. The mean V ss /F of efavirenz increased an average of 89% across arms, ranging from 52% (nelfinavir) to 115% (indinavir) relative to efavirenz with amprenavir alone. Increases were also observed in V p /F after the addition of nelfinavir, indinavir, ritonavir and saquinavir by 85%, 170%, 162% and 111%, respectively. In conclusion, concomitant administration of dual PIs is unlikely to have any clinically significant effect on the pharmacokinetics of CYP2B6 substrates in general or oral efavirenz specifically.

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“…The result can be obtained in <1 h and provide a reliable and reproducible measure of liver CYP3A4 activity and of the effect of modulators on the basal activity of the enzyme in humans. The ERMBT has been extensively used to evaluate the role of liver CYP3A4 activity in the pharmacokinetics of numerous drugs, including the anticancer agent docetaxel [19], the immunosuppressant ciclosporin [20], the antibiotic rifampin [21] and more recently the human immunodeficiency virus (HIV) non-nucleoside reverse transcriptase inhibitors delavirdine [22] and efavirenz [23].The ERMBT also reliably described the effects of inducers and inhibitors on liver CYP3A4 activity [21][22][23]. In addition, in a recent study conducted in HIV-infected patients [24], the ERMBT results correlated with the in vitro inhibition of CYP3A4 by the Liver 3A4 and P-gp in gefitinib-phenytoin interaction Br J Clin Pharmacol / 68:2 / 227 HIV-protease inhibitor nelfinavir.…”

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confidence: 99%

Gefitinib–phenytoin interaction is not correlated with the ¹⁴C‐erythromycin breath test in healthy male volunteers

Chhun

Verstuyft

Rizzo-Padoin

et al. 2009

Brit J Clinical Pharma

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AIMSWe aimed to describe the pharmacokinetic interaction between phenytoin, a potent CYP3A4 and P-glycoprotein (P-gp) (ABCB1) inducer, and gefitinib, a CYP3A4, CYP2D6 and P-gp substrate. METHODSAn open-label, randomized, two-phase crossover study was conducted. Eighteen healthy male volunteers (nine homozygous CC and nine homozygous TT as determined by their ABCB1 C3435T polymorphism in exon 26) received a single oral dose of 250 mg gefitinib alone or after 5 days treatment with phenytoin (5 mg kg -1 daily). Gefitinib plasma concentrations were determined by high-performance liquid chromatography. Hepatic CYP3A4 activity was evaluated by the 14 C-erythromycin breath test (ERMBT) and the ABCB1 and CYP2D6 genetic polymorphisms were determined by the TaqMan allelic discrimination assay and long polymerase chain reaction, respectively. RESULTSFollowing treatment with phenytoin, mean gefitinib Cmax and AUC0-• decreased by 26 Ϯ 44% [95% confidence interval (CI) for the difference 5-48%, P = 0.005] and 47 Ϯ 26% (95% CI for the difference 34-60%, P = 0.001), respectively, and apparent oral clearance increased by 126 Ϯ 93% (95% CI for the difference 80-172%, P = 0.004). Concomitantly, phenytoin increased the mean ERMBT by 91 Ϯ 44% (95% CI 75-105%, P < 0.001) from baseline, but the extent of liver CYP3A4 induction was not correlated to the extent of interaction. Furthermore, this interaction was independent of ABCB1 genetic polymorphism. The CYP2D6 genotype was slightly but significantly related to gefitinib clearance (P = 0.04) during the control phase. CONCLUSIONSThe significant interaction between gefitinib and phenytoin was not correlated with the erythromycin breath test and was independent of ABCB1 polymorphism, but may involve presystemic CYP3A-mediated intestinal first-pass.British Journal of Clinical Pharmacology DOI:10.1111DOI:10. /j.1365DOI:10. -2125DOI:10. .2009 226 / Br J Clin Pharmacol / 68:2 / 226-237 IntroductionGefitinib (ZD 1839) is the first available oral quinazoline compound referred to as a 'selective' epidermal growth factor (EGF) receptor-tyrosine kinase inhibitor [1]. It provides an antiproliferative effect by blocking signal transduction from the EGF receptor and has been recently approved as third-line monotherapy in Japan for the treatment of cancer patients who present with locally advanced inoperable or recurrent non-small cell lung carcinoma. Gefitinib systemic exposure is rather complex and highly variable between subjects [1]. Gefitinib is a high-extraction drug with a mean volume of distribution of about 1500 l in humans and is subject to complex and extensive presystemic first-pass [1]. Drug-transport proteins including P-glycoprotein (P-gp) and drug-metabolizing enzymes, e.g. cytochromes P450 (CYP), are relevant factors affecting the pharmacokinetic profile of gefitinib. Preclinical studies performed with human liver microsomes suggested that CYP3A4 was the major enzyme involved in gefitinib metabolism.The 3A4 isoform accounts for as much as 35% of total CYPs expressed in the liver and...

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Hepatic but not intestinal CYP3A4 displays dose‐dependent induction by efavirenz in humans

Cited by 193 publications

References 13 publications

Dose‐dependent Induction of Cytochrome P450 (CYP) 3A4 and Activation of Pregnane X Receptor by Topiramate

Dose‐dependent Induction of Cytochrome P450 (CYP) 3A4 and Activation of Pregnane X Receptor by Topiramate

Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers

Gefitinib–phenytoin interaction is not correlated with the ¹⁴C‐erythromycin breath test in healthy male volunteers

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Hepatic but not intestinal CYP3A4 displays dose‐dependent induction by efavirenz in humans

Cited by 193 publications

References 13 publications

Dose‐dependent Induction of Cytochrome P450 (CYP) 3A4 and Activation of Pregnane X Receptor by Topiramate

Dose‐dependent Induction of Cytochrome P450 (CYP) 3A4 and Activation of Pregnane X Receptor by Topiramate

Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers

Gefitinib–phenytoin interaction is not correlated with the 14C‐erythromycin breath test in healthy male volunteers

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Gefitinib–phenytoin interaction is not correlated with the ¹⁴C‐erythromycin breath test in healthy male volunteers