Dataset Information

Validation of 4?-hydroxycholesterol and evaluation of other endogenous biomarkers for the assessment of CYP3A activity in healthy subjects.

ABSTRACT: This study aimed to assess changes in the plasma concentrationss of 4?-hydroxycholesterol (4?HC) against intravenous (i.v.) and oral midazolam (MDZ) pharmacokinetics (PK) after administration of a potent CYP3A inhibitor [ketoconazole (KETO)] and inducer [rifampicin (RIF)].Thirty-two healthy subjects (HS) were allocated into three groups of 12 each in KETO and RIF and 10 in a placebo group (PLB). All HS were randomized to receive oral and i.v. MDZ on day 1 or 2 and on day 15 or 16 after receiving RIF (600?mg once daily), KETO (400?mg once daily) or PLB for 2 weeks. Subjects were followed until day 30. The effect of treatments on 4?HC was assessed by analyzing % change from baseline using a linear spline mixed effects model.Compared with PLB, KETO decreased 4?HC mean values up to 13% (P = 0.003) and RIF increased 4?HC mean values up to 220% (P < 0.001). Within 14 days of stopping KETO and RIF, 4?HC had either returned to baseline (KETO) or was still returning to baseline (RIF). Compared with baseline, mean oral MDZ AUC increased by 11-fold (90% CI ranging from 9-fold to 13-fold increase) and decreased by 92% (90% CI ranging from 90% to 95% decrease) after KETO and RIF, respectively. Similar trends were observed for 6?-hydroxycortisol?:?cortisol (6?HCL?:?CL) urinary ratios.Changes in plasma 4?HC can be utilized as a surrogate for MDZ PK after multiple doses of potent CYP3A inducers. There is a more limited dynamic range for 4?HC for assessment of potential CYP3A inhibitors. 4?HC is a valuable tool for the assessment of potential CYP3A inducers in early drug development.

SUBMITTER: Kasichayanula S

PROVIDER: S-EPMC4243887 | biostudies-other | 2014 Nov

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Validation of 4β-hydroxycholesterol and evaluation of other endogenous biomarkers for the assessment of CYP3A activity in healthy subjects.

Kasichayanula Sreeneeranj S Boulton David W DW Luo Wen-Lin WL Rodrigues A David AD Yang Zheng Z Goodenough Angela A Lee Michelle M Jemal Mohammed M LaCreta Frank F

British journal of clinical pharmacology 20141101 5

<h4>Aims</h4>This study aimed to assess changes in the plasma concentrationss of 4β-hydroxycholesterol (4βHC) against intravenous (i.v.) and oral midazolam (MDZ) pharmacokinetics (PK) after administration of a potent CYP3A inhibitor [ketoconazole (KETO)] and inducer [rifampicin (RIF)].<h4>Methods</h4>Thirty-two healthy subjects (HS) were allocated into three groups of 12 each in KETO and RIF and 10 in a placebo group (PLB). All HS were randomized to receive oral and i.v. MDZ on day 1 or 2 and on ...[more]

PMID: 24837659

Similar Datasets

Project description:Currently, there is considerable debate as to which method is more accurate for measuring the activity of CYP3A in vivo: cortisol 6beta-hydroxylation clearance (Cl(m(6beta))) or the urinary ratio of 6beta-OHF to F (6beta-OHF/F). Furthermore, the value of measuring endogenous levels of cortisol over a 24 h period (AUC(F)) needs to be confirmed. The aim of the present study was to determine which method was most effective at measuring changes in the in vivo activity of CYP3A: AUC(F), Cl(m(6beta)), or 6beta-OHF/F.A two phase, cross-over design was adopted in this study. A total of 24 subjects (12 males and 12 females) were randomly assigned to one of two groups: the test group subjects were given 250 mg clarithromycin tablets twice a day for a period of 4 d, whereas the control group received a placebo twice daily for a similar period. On d 5 of the study, the last dose of either clarithromycin or placebo was supplemented with an oral dose of 7.5 mg midazolam (MDZ); blood and urine samples were then collected at various times. All samples collected at the same sampling times on d 4 were used to evaluate the effects of MDZ administration on cortisol levels and metabolism. The ratio of 1-hydroxymidazolam (1-OHMDZ) concentration to MDZ concentration at 1 h (MR) was taken as a measure of the in vivo CYP3A activity. AUC(F), Cl(m(6beta)), and 6beta-OHF/F were also used as biomarkers for CYP3A activity.No correlations were found (either before or after inhibition) between CYP3A activity and any of the following measures: AUC(F), Cl(m(6beta)), or 6beta-OHF/F (r<0.4, P>0.05). After 4 d of clarithromycin administration, CYP3A activity (MR) decreased by 75% (P=0.000), whereas AUC(F) increased by 19% (P=0.040), and Cl(m(6beta)) and 6beta-OHF/F decreased by 54.2% (P=0.000) and 50% (P=0.003), respectively. No significant changes in AUC(F) (P=0.178), or in the amount of urinary 6beta-OHF (P=0.169), or in F (P=0.391) were found over a 24 h time period, either with or without MDZ administration.Although Cl(m(6beta)) and 6beta-OHF/F can reflect the decline in CYP3A activity, the impression they provide is neither accurate nor complete. AUC(F) is completely ineffective for evaluating variations in CYP3A activity. MDZ administration had no evident effects on either cortisol metabolism or excretion over a period of 24 h.

Dataset Information

Validation of 4?-hydroxycholesterol and evaluation of other endogenous biomarkers for the assessment of CYP3A activity in healthy subjects.

Publications

Validation of 4β-hydroxycholesterol and evaluation of other endogenous biomarkers for the assessment of CYP3A activity in healthy subjects.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets