pyrimidinones and cholest-5-ene-3-4-diol

A member of the major human cytochrome P450 superfamily of hemoproteins, CYP3A4/5, converts cholesterol into 4beta-hydroxycholesterol. We studied plasma 4beta-hydroxycholesterol levels prior to and 4 weeks after initiating antiretroviral therapy that included efavirenz, ritonavir-boosted atazanavir or ritonavir-boosted lopinavir with the aim of exploring the usefulness of plasma 4beta-hydroxycholesterol levels as an endogenous biomarker of CYP3A activity. Efavirenz is an inducer of CYP3A, whereas the ritonavir-boosted regimens are net inhibitors of CYP3A.. In patients treated with efavirenz, the median plasma 4beta-hydroxycholesterol level increased by 46 ng/mL (p = 0.004; n = 11). In contrast, patients given ritonavir-boosted atazanavir showed a median decrease in plasma 4beta-hydroxycholesterol of -9.4 ng/mL (p = 0.0003; n = 22), and those given ritonavir-boosted lopinavir showed a median change from baseline of -5.8 ng/mL (p = 0.38; n = 19). There were significant between-group differences in the effects of antiretroviral treatment on plasma 4beta-hydroxycholesterol levels (p < 0.0001).. Changes in plasma 4beta-hydroxycholesterol following the initiation of efavirenz- or atazanavir/ritonavir-based antiretroviral therapy reflected the respective net increase and decrease of CYP3A activity of these regimens. The plasma 4beta-hydroxycholesterol level did not indicate a net CYP3A inhibition in the lopinavir/ritonavir arm, possibly because of concomitant enzyme induction.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP3A; Drug Therapy, Combination; Enzyme Induction; Enzyme Inhibitors; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxycholesterols; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; Young Adult

We assessed the suitability of 4beta-hydroxycholesterol (4betaOH-C) as an endogenous cytochrome P450 3A (CYP3A) phenotyping metric. 4betaOH-C and its ratio to cholesterol (4betaOH-C/C) were determined in five cocktail phenotyping studies, with and without co-medication with a potential CYP3A inhibitor. These parameters were compared with established midazolam-based CYP3A metrics: clearance after intravenous (i.v.) administration (M-Cl) and apparent clearance after oral administration (M-Cl/F), reflecting hepatic and overall activity, respectively. In a common evaluation of periods without co-medication, there was a slight positive correlation of 4betaOH-C and 4betaOH-C/C with midazolam metrics: M-Cl (r = 0.239 and 0.348, respectively) and M-Cl/F (r = 0.267 and 0.353, respectively); P (one-sided) < 0.05. Co-medication with lopinavir/ritonavir caused a strong decrease in midazolam metrics and a mild decrease in cholesterol metrics. However, the intake of propiverine resulted in opposite trends for midazolam-based and cholesterol-based metrics. The information currently available does not justify the use of 4betaOH-C for estimation of basal CYP3A activity. Further studies to address the temporal variations in local CYP3A activity are needed to assess its role as a biomarker during CYP3A inhibition.

Topics: Administration, Oral; Adult; Benzilates; Cholesterol; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Female; HIV Protease Inhibitors; HIV Seropositivity; Humans; Hydroxycholesterols; Infusions, Intravenous; Lopinavir; Male; Midazolam; Middle Aged; Phenotype; Pyrimidinones; Ritonavir