Author(s): Zeruesenay Desta [[dagger]] 1 , Tanja Saussele 2 , Bryan Ward 1 , Julia Blievernicht 2 , Lang Li 1 , Kathrin Klein 2 , David A Flockhart 1 , Ulrich M Zanger [[dagger]] 2
AIDS; bupropion; CYP2B6; cytochrome P450; efavirenz; genetic polymorphism; HIV; NNRTI; non-nucleoside reverse transcriptase inhibitor; variant allele
Efavirenz is a potent non-nucleoside reverse transcriptase inhibitor of HIV type 1 (HIV-1) that plays a pivotal role in the treatment of HIV-1 infections in a variety of clinical settings as part of highly active antiretroviral therapy (HAART) regimens. In combination with two nucleoside reverse transcriptase inhibitors, efavirenz is the most frequently prescribed and preferred initial therapy of HIV-1 infection  . However, efavirenz pharmacokinetics exhibits large interpatient variability [2-4] , contributing to the variable clinical response seen among HIV patients taking efavirenz-based therapy. The recommended therapeutic range of efavirenz is 1-4 mg/l  . Clinical studies have suggested that patients with plasma concentrations below 1 mg/l are at increased risk for failure of antiretroviral therapy [2,3,5] , and those with concentrations higher than 4 mg/l experience more frequent CNS side effects including severe and sudden late neuropsychiatric events [5-9] . Therefore, the key challenge in efavirenz-based therapy is to maintain maximum virally suppressive efavirenz concentrations that will prevent the emergence of resistance and avoid treatment failure, while also ensuring an adverse event profile that is not only safe, but does not significantly compromise overall quality of life.
Efavirenz is predominantly cleared by metabolism  . The principal routes of efavirenz elimination in humans are shown in Figure 1. The major oxidative metabolite of efavirenz in vivo and in vitro human liver microsomal preparations is 8-hydroxyefavirenz, which is then further hydroxylated to 8,14-dihydroxyefavirenz, while 7-hydroxyefavirenz represents a minor pathway; these metabolites are excreted predominantly in the urine as glucuronides and to some extent as sulphate conjugates [10,11] . In our recent in vitro study we have shown that CYP2B6 is the principal catalyst of efavirenz 8-hydroxylation, and that this metabolite is further oxidized by the same enzyme to 8,14-dihydroxyefavirenz, whereas the specific enzyme responsible for efavirenz 7-hydroxylation remained unidentified  .
CYP2B6 expression and activity are widely variable in human liver in vitro [12-18] . In part, these differences are due to the fact that CYP2B6 expression or function is readily influenced by exposure to inducer  and inhibitor [20,21] drugs or other chemicals. In addition, our group [12,18,22,23] and other authors [14,16,24] have identified numerous polymorphisms of the CYP2B6 gene that show pronounced frequency differences depending on the ethnic population studied (for allele summary and references see CYP Allele Nomenclature homepage  ). The clinical importance of some CYP2B6 genetic variants for efavirenz treatment has been convincingly demonstrated in a number of recent pharmacokinetic studies with HIV patients. These studies consistently found that patients with the c.516G>T polymorphism (a marker of the common *6 and a few more rare alleles) in homozygous constellation (i.e. most likely genotype *6/*6 ) had severely elevated efavirenz plasma concentrations and, in some cases, this was also associated with an increased risk of CNS side effects [4,6,8,25-27] . Although no metabolites had been...