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

Abstract

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...

Population pharmacokinetics modeling of oxcarbazepine to characterize drug interactions in Chinese children with epilepsy

“…The isoforms of UGT involved in MHD glucuronidation have not yet been identified [24] , thus this hypothesis requires further validation. Some studies [14,25] showed a modest inducing effect of higher doses (up to 200 mg/d) of TPM on CYP3A4 and possible effects on the activity of UGTs. Thus, the CYP and UGT-mediated metabolism of MHD might also be induced by a high dose of TPM.…”

CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications

“…The time-and dose-dependent induction of CYP3A4 by rifampicin has also been demonstrated in primary cultures of human hepatocytes (11,13,160,161). In human hepatocytes treated with rifampicin, the induction of CYP3A4 activity (measured by testosterone 6b-hydroxylation) was concentration dependent, and the EC 50 for rifampicin was estimated to be 0.3Y0.5 mM (162).…”

Blood-Brain Barrier P450 Enzymes and Multidrug Transporters in Drug Resistance: A Synergistic Role in Neurological Diseases

“…The metabolism of carbamazepine is decreased by the co-administration of valproic acid, leading to an increased risk of carbamazepine toxicity [26,39,40]. On the other hand, oxcarbazepine and topiramate (second generation AEDs) are considered weak CYP2C19 and CYP3A4/5 substrates [46] while lamotrigine and levetiracetam are not CYP substrates [37,47]. Levetiracetam lacks of liver Phase I P450 metabolism and does not induce P450 enzymes in vitro [37,47].…”