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.