Inhibition of Efavirenz Metabolism by Sertraline and Nortriptyline and Their Effect on Efavirenz Plasma Concentrations

Abstract

Between 22 and 45% of HIV-positive subjects are likely to report symptoms of depression. Considering this background, a potential pharmacokinetic interaction between the nonnucleoside reverse transcriptase inhibitor efavirenz (EFV) and two antidepressants, sertraline (SRT) and nortriptyline (NT), was studied. Rats were administered EFV alone or together with the antidepressants, and changes in the plasma levels and pharmacokinetic parameters of EFV were analyzed. Additional in vitro experiments with rat and human hepatic microsomes were carried out to evaluate the inhibitory effect of SRT and NT on EFV metabolism by determining the formation rate of the major EFV metabolite (8-OH-EFV). In vivo studies showed similar increases in the plasma levels of EFV when it was coadministered with SRT or NT. However, the studies using rat hepatic microsomes showed a more potent inhibitory effect of NT than of SRT on the metabolism of EFV, with values for the 50% inhibition constant (IC 50 ) and inhibitory constant (K i ) for NT about 9-fold lower than those for SRT. An equation was deduced that explains the similar in vivo effects of SRT and NT in spite of the different in vitro performance data. Using human hepatic microsomes, the strongest inhibitory effect was observed with SRT. In summary, pharmacokinetic interactions between EFV, SRT, and NT, associated with the inhibition of hepatic metabolism of EFV, have been detected in rats. Both antidepressants also inhibit EFV metabolism in human hepatic microsomes, but additional in vivo studies in humans are required to evaluate the clinical implication of this interaction. H uman immunodeficiency virus infection/AIDS (HIV/AIDS)is, at present, an incurable disease, and the use of antiretroviral therapy is essential to obtain durable viral suppression, improved immune function, and a good quality of life in infected individuals (1).Current treatment guidelines recommend the use of a drug combination consisting of at least three antiretroviral drugs of multiple classes, known as highly active antiretroviral therapy (HAART). Combining different anti-HIV agents has proven to be beneficial in terms of sustained efficacy and long-term safety, provided there are no significant negative pharmacokinetic drugdrug interactions. At present, preferred regimens of HAART consist of two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) with either a protease inhibitor (PI) or a nonnucleoside reverse transcriptase inhibitor (NNRTI) although other combinations are possible (2, 3).Efavirenz (EFV) is an NNRTI of human immunodeficiency virus type 1 (HIV-1) and is one of the preferred components of first-line antiretroviral regimens. It is widely used as a component of initial HAART (except in infected pregnant women) since it has demonstrated potent and sustained activity in HIV-infected patients as it induces a rapid suppression of the HIV-1 viral load and increases the CD4 cell count (1).In vitro studies with human hepatic microsomes, as well as in vivo studies, have demonstrated that EFV un...

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PharmGKB summary: sertraline pathway, pharmacokinetics

“…Sertraline does not inhibit CYP1A2 [78,95,96,103] but may act as a CYP1A2 inducer [104]. There is some evidence that sertraline inhibits CYP2B6 and impacts the pharmacokinetics of efavirenz and methadone, which are both CYP2B6 substrates [105][106][107]. This inhibition is reduced when the increased-function CYP2B6*4 allele or decreased-function CYP2B6*6 allele are present [105].…”