Variability in drug metabolizing enzyme activity in HIV-infected patients

Abstract

Aims-To evaluate variability in cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A, Nacetyltransferase 2 (NAT2), and xanthine oxidase (XO) activity in HIV-infected patients and compare this with data from uninfected, healthy volunteers.Methods-Ten HIV-infected men and seven women on medication affecting CYP enzyme activity were phenotyped four times over 2 months using caffeine, dextromethorphan, and midazolam. Urinary caffeine and dextromethorphan metabolite ratios were used to phenotype CYP1A2, NAT2, XO, and CYP2D6 activity and midazolam plasma clearance was used to phenotype CYP3A activity. Plasma and urine samples were analyzed by validated LC/UV or LC/MS methods for midazolam, caffeine, and dextromethorphan. Noncompartmental pharmacokinetics and nonparametric statistical analyses were performed, and the data compared with those of healthy volunteer historic controls.Results-Compared with age and sex-matched healthy volunteers, HIV-infected subjects had 18% lower hepatic CYP3A4 activity, 90% lower CYP2D6 activity, 53% lower NAT2 activity, and 22% higher XO activity. No significant difference was found in CYP1A2 activity. Additionally, 25% genotype-phenotype discordance in CYP2D6 activity was noted in HIV-infected subjects. Intraindividual variability in enzyme activity increased by 42-62% in HIV-infected patients for CYP1A2, NAT2, and XO, and decreased by 33% for CYP2D6. Interindividual variability in enzyme activity increased by 27-63% in HIV-infected subjects for CYP2D6, CYP1A2, and XO, and decreased by 38% for NAT2. Higher plasma TNFα concentrations correlated with lower CYP2D6 and CYP3A4 activity.Conclusions-Infection with HIV or stage of HIV infection may alter Phase I and II drug metabolizing enzyme activity. HIV infection was related to an increase in variability of these drugmetabolizing enzymes. Altered metabolism may be a consequence of immune activation and cytokine exposure.

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

“…One study investigated (four times over a 2 month period) the effect of HIV infection on the activity of various DMEs and correlated the phenotype with the genotype (Jones et al, 2010). Urinary caffeine and dextromethorphan metabolic ratios were used to phenotype for CYP1A2, NAT2, xanthine oxidase, and CYP2D6 activities and midazolam plasma clearance was used to phenotype for CYP3A activity.…”

Selective Modulation of Hepatic Cytochrome P450 and Flavin Monooxygenase 3 Expression duringCitrobacter rodentiumInfection in Severe Combined Immune-Deficient Mice

“…Changes in P450-mediated drug clearance, associated with inflammation, have been demonstrated in humans with various infections including influenza and HIV (Chang et al, 1978;Jones et al, 2010), as well as in patients with cancer and heart failure (Frye et al, 2002;Rivory et al, 2002). In both humans and laboratory animals, most P450 enzymes studied are down-regulated (Aitken et al, 2006), primarily by pretranslational mechanisms.…”

Do activities of cytochrome P450 (CYP)3A, CYP2D6 and P-glycoprotein differ between healthy volunteers and HIV-infected patients?

“…Another comparison of the activities of CYP3A and CYP2D6 has just recently been published [39]. The authors state that hepatic CYP3A-and CYP2D6-activities in patients were approximately 20% and 90% lower, respectively, than in healthy volunteers.…”