ritonavir 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

Objective Since the majority of direct-acting antivirals (DAAs) that are used in the treatment of hepatitis C virus (HCV) infection are mainly metabolized by CYP3A4, it is hypothesized that inter-individual differences in CYP3A4 activity may be associated with the bioavailability of these agents. Methods The level of serum 4β-hydroxycholesterol (4βHC), a surrogate marker of CYP3A4 activity, was determined by LC-MS/MS in samples obtained from patients with HCV infection (CHCs) as well as healthy control subjects (CTLs). Serum samples obtained from patients treated with either asunaprevir/daclatasvir (ASV/DCV) or ombitasvir/paritaprevir/ritonavir (OTV/PTV/r) were used for additional assays. Results The serum 4βHC level in CHCs was significantly higher than that in CTLs, and a gender difference was seen among CHCs. In patients treated with OTV/PTV/r, the serum 4βHC level was observed to gradually decrease during the treatment period. In the cohort treated with ASV/DCV, 4 of 83 patients showed virological treatment failure. In pretreatment testing, an Invader assay detected a low prevalence of resistance-associated variants in these four patients. The average serum concentration of DCV/ASV in the treatment-failed group tended to be lower than that in the sustained virological response (SVR) group. The pretreatment serum 4βHC level in patients with treatment failure was significantly higher than that in patients with an SVR but in whom the prevalence of resistance-associated variants was low in the pretreatment setting. Conclusion The evaluation of CYP3A4 activity by measuring 4βHC before treatment may provide additional information that can potentially be used to select cost- and efficacy-optimized treatment of HCV.

Topics: Aged; Anilides; Antiviral Agents; Carbamates; Case-Control Studies; Cyclopropanes; Cytochrome P-450 CYP3A; Drug Therapy, Combination; Female; Genotype; Hepatitis C; Hepatitis C, Chronic; Humans; Hydroxycholesterols; Imidazoles; Interferons; Isoquinolines; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Pyrrolidines; Ritonavir; Sex Factors; Sulfonamides; Treatment Failure; Valine

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