1 INTRODUCTION
Bupropion (BUP) is an effective nor-epinephrine and dopamine uptake inhibitor that is often used for inhibiting depression and smoking behavior. This drug can be metabolized into three major metabolites (Fig.1), namely, hydroxybupropion (HBUP), threohydrobupropion (TBUP), and erythrohydrobupropion (EBUP)[1,2]. Among these metabolites, HBUP is identified as the primary active metabolite for curbing depression and smoking behavior among humans[3]. BUP is also metabolized by the CYP3A4 system into either TBUP or EBUP, but their contents are limited[4]. CYP2B6 is the most effective enzyme in the second subgroup of cytochrome P450 and its genes are prone to mutation[5,6]. The predominant haplotypes associated with BUP mediation include allele*4, allele*6, and allele*9 inCYP2B6 . The A785G and G516T variants exist in allele*4 and allele*9, respectively, and both exist in allele*6[7].
The inductive or inhibitive effects on CYP2B6 activity as reflected by BUP hydroxylation have been extensively studied[8, 9]. Both in vivo and in vitro studies have shown that allele*4 is related to a higher catalytic activity, which, in turn, accelerates the transformation of BUP into HBUP[2]. Compared with wild-type CYP2B6*1 variants,CYP2B6*4 variants increase the catalytic activity of CYP2B6 and the BUP clearance[10]. Consistent with the results of previous studies, the homozygous and heterozygousCYP2B6*6 have a lower HBUP concentration compared with their wild-type variants[2, 11].
Other studies have established a strong correlation between allele*6 variants and the BUP clearance or HBUP plasma levels[7,11]. CYP2B6*6 alleles and their wild-type variants show a similar extent of induction for bupropion hydroxylation by metamizole[12]. The presence ofCYP2B6*6 decreased the function of CYP2B6 and consequently increased the plasma BUP concentration in allele*6 variants relative to the wild-type variants, but the opposite trend was observed for HBUP concentration[2]. Increasing the frequency of G516T polymorphism would enable allele*9 to reduce the enzymatic function and enhance the plasma BUP concentration[13]. However, no study has examined the effects of a combination of feeding and CYP2B6 genotypes on the pharmacokinetics of BUP and HBUP among Chinese subjects. Therefore, this study aimed to investigate the effects of high-fat diet andCYP2B6 mutants on the pharmacokinetics of BUP and HBUP among Chinese subjects.