Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Bupropion, an antidepressant and smoking cessation drug, is metabolized to its active metabolite, 4-hydroxybupropion, almost exclusively by CYP2B6.• Metamizole, a pyrazolone derivative with analgesic properties, was shown in an in vitro study to increase significantly the expression of CYP2B6 and bupropion hydroxylase activity.• The effect of metamizole on bupropion hydroxylation has not been investigated and drug interactions may occur between metamizole and bupropion. WHAT THIS PAPER ADDS• Oral administration of metamizole for 4 days significantly altered the pharmacokinetics of both bupropion and its active metabolite, 4-hydroxybupropion, and significantly increased the CYP2B6-catalyzed bupropion hydroxylation in all of the subjects.• Dosage adjustment of bupropion may be needed in patients when metamizole is concomitantly administered. AIMSThis study aimed to investigate the effect of metamizole on bupropion hydroxylation related to different CYP2B6 genotype groups in healthy volunteers. METHODSSixteen healthy male volunteers (6 CYP2B6*1/*1, 6 CYP2B6*1/*6 and 4 CYP2B6*6/*6) received orally administered bupropion alone and during daily treatment with metamizole 1500 mg day -1 (500 mg tablet taken three times daily) for 4 days. Serial blood samples were obtained up to 48 h after each bupropion dose. RESULTSAfter metamizole treatment relative to bupropion alone, the geometric mean ratios (GMRs) and 90% confidence interval (CI) of the AUC(0,•) ratio of 4-hydroxybupropion over bupropion were 1.99 (1.57, 2.55) for the CYP2B6*1/*1 group, 2.15 (1.53, 3.05) for the CYP2B6*1/*6 group and 1.86 (1.36, 2.57) for the CYP2B6*6/*6 group. The GMRs and 90% CI of bupropion were 0.695 (0.622, 0.774) for AUC(0,•) and 0.400 (0.353, 0.449) for Cmax, respectively. The corresponding values for 4-hydroxybupropion were 1.43 (1.28, 1.53) and 2.63 (2.07, 2.92). The t1/2 value was significantly increased for bupropion and decreased for 4-hydroxybupropion. The tmax values of bupropion and 4-hydroxybupropion were both significantly decreased. The mean percentage changes in pharmacokinetic parameters among the CYP2B6 genotype groups were not significantly different. CONCLUSIONSOral administration of metamizole for 4 days significantly altered the pharmacokinetics of both bupropion and its active metabolite, 4-hydroxybupropion, and significantly increased the CYP2B6-catalyzed bupropion hydroxylation in all of the subjects. Cautions should be taken when metamizole is co-administered with CYP2B6 substrate drugs.

Auto-induction of phase I and phase II metabolism of artemisinin in healthy Chinese subjects after oral administration of a new artemisinin-piperaquine fixed combination

“…After an oral administration of two probe drugs, the dose-normalized AUC of BUP (0.35 ± 0.23 h kg/L) and its metabolite OH-BUP (3.98 ± 1.45 h·kg/L) corresponded with reported data obtained in healthy Chinese [24], Korean [25] and Caucasian volunteers [26]. The metabolic capability of CYP2B6 was 13.4 ± 5.2, which was in agreement with reported data (6.3-15.3).…”

Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance

“…Since other CYPs are regulated by overlapping sets of nuclear receptors, CYP2B6 is often co-induced with CYP2C enzymes and CYP3A4. CYP2B6 inducers identified to date include cyclophosphamide (Gervot et al, 1999), hyperforin (Goodwin et al, 2001), artemisinin antimalarials (Simonsson et al, 2003; Burk et al, 2005), carbamazepine (Oscarson et al, 2006; Desta et al, 2007), metamizole (Saussele et al, 2007; Qin et al, 2012), ritonavir (Kharasch et al, 2008), the insect repellent N , N -diethyl- m -toluamide (DEET; Das et al, 2008), statins (Feidt et al, 2010), efavirenz (Ngaimisi et al, 2010; Habtewold et al, 2011). Interestingly, in the latter study, gender influenced the inducibility of efavirenz 8-hydroxylation, which was higher in women than in the men (Ngaimisi et al, 2010).…”

Amenamevir: Studies of Potential CYP2C8‐ and CYP2B6‐Mediated Pharmacokinetic Interactions With Montelukast and Bupropion in Healthy Volunteers

“…A sample size of 24 subjects was selected for the bupropion study based on a statistical power calculation. Two previous studies of single doses of 150 mg bupropion gave within‐subject estimates of %CV for C max and AUC 0–∞ between 15% and 30% . Statistical power was estimated by simulation (the number of simulations was 10,000) using the model below.…”

“…Two previous studies of single doses of 150 mg bupropion gave within-subject estimates of %CV for C max and AUC 0-Ý between 15% and 30%. 20,21 Statistical power was estimated by simulation (the number of simulations was 10,000) using the model below. The model included treatment (bupropion in combination with amenamevir and bupropion alone) as a fixed effect and subject as a random effect.…”