title: Plasma 4beta-hydroxycholesterol: an endogenous CYP3A metric?
abstract: 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.
authors.affiliation: Department of Pharmacology, Clinical Pharmacology Unit, University of Cologne, Cologne, Germany. dorota.tomalik-scharte@uk-koeln.de
authors.forename: D
authors.initials: D
authors.lastname: Tomalik-Scharte
authors.forename: D
authors.initials: D
authors.lastname: Lütjohann
authors.forename: O
authors.initials: O
authors.lastname: Doroshyenko
authors.forename: D
authors.initials: D
authors.lastname: Frank
authors.forename: A
authors.initials: A
authors.lastname: Jetter
authors.forename: U
authors.initials: U
authors.lastname: Fuhr
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001561:Benzilates / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006679:HIV Seropositivity / Q000097:blood* / Q000188:drug therapy; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood*; D007262:Infusions, Intravenous; D061466:Lopinavir; D008297:Male; D008874:Midazolam / Q000494:pharmacology; D008875:Middle Aged; D010641:Phenotype; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology; D019438:Ritonavir / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D001561:Benzilates; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D006888:Hydroxycholesterols; D011744:Pyrimidinones; C099828:cholest-5-ene-3,4-diol; D061466:Lopinavir; C015586:propiverine; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir; D008874:Midazolam