Category: Clinical Pharmacology
Purpose: Cytochrome P450 (CYP) is a phase I drug metabolizing enzyme that plays a key role in metabolism of various drugs. Previous studies have discovered and validated the endogenous metabolic markers for hepatic CYP3A activity. Among the different inhibitors of CYP3A activity, itraconazole and clarithromycin are classified as strong inhibitors with different mechanism of inhibition. In this study, we aimed to evaluate different inhibitory effect of itraconazole and clarithromycin on hepatic CYP3A activity using oral sildenafil as a probe drug and endogenous metabolic markers for CYP3A activity.
Methods: This study was an open-label, one-sequence, one-period parallel study. Thirty-two healthy male subjects were enrolled, and each of 16 subjects were randomly assigned to itraconazole and clarithromycin group. Both groups received a single dose of sildenafil 25 mg as a control and then administered either clarithromycin 250 mg or itraconazole 100 mg for four times to inhibit the CYP3A activity. The last dose of CYP3A inhibitor was concomitantly administered with sildenafil. For PK analysis, the serial blood samples were obtained at 0 (pre-dose), 0.17, 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 24 h after single administration of sildenafil and after last administration of CYP3A inhibitor with sildenafil. The additional 0 (pre-dose) h blood samples were obtained to analyze the plasma endogenous marker. To quantify the urinary endogenous marker, 12 h interval urine was collected before administration of sildenafil alone, and after administration of both sildenafil and CYP3A inhibitor. Plasma concentration of sildenafil and its metabolites were quantified using liquid chromatography-mass spectrometry. Urinary and plasma endogenous metabolic markers including 6β-OH-cortisol/cortisol, 6β-OH-cortisone/cortisone, and 4β-OH-cholesterol were quantified using gas chromatography-mass spectrometry.
Results: Thirty-one subjects completed all procedure, 1 subject allocated in clarithromycin group withdrew his consent. There was no statistically significant demographic difference, including age, weight, height, and body mass index between clarithromycin and itraconazole group. Administration of itraconazole and clarithromycin both similarly decreased apparent clearance (CL/F) and increased systemic exposure of orally administered sildenafil about two-fold. For clarithromycin group, the geometric mean ratio (GMR) (95% CI; confidence interval) of sildenafil for maximal observed concentration (Cmax) and area under the curve from time zero to the last observable concentration time (AUClast) was 1.86 (1.41 – 2.45) and 2.29 (1.93 – 2.71), respectively. The corresponding value for itraconazole group was 1.51 (1.24 – 1.83) and 2.51 (2.24 – 2.80), respectively. Pharmacokinetic of sildenafil supports that two inhibitors showed similar magnitude of inhibitory effect on total CYP3A activity. Urinary 6β-OH-cortisone/cortisone and plasma 4β-OH-cholesterol was significantly decreased to 0.51 and 0.80 fold, respectively, after administration of clarithromycin. However, both urinary and plasma metabolic markers were not significantly changed after administration of itraconazole. In addition, a significant correlation between sildenafil CL/F and endogenous metabolic markers for hepatic CYPA activity was observed after administration of clarithromycin but not after administration of itraconazole.
Conclusion: Administration of itraconazole and clarithromycin differently inhibited hepatic CYP3A activity; hepatic CYP3A activity was observed to be more effectively inhibit with clarithromycin than itraconazole. To avoid the possible DDI of the drugs that are mainly metabolized in liver, not only the pharmacokinetics but also the endogenous metabolic markers for hepatic CYP3A activity should be assessed.
Andrew HyoungJin Kim– Seoul, Seoul-t'ukpyolsi, Republic of Korea
Sumin Yoon– Seoul, Seoul-t'ukpyolsi, Republic of Korea
Jieon Lee– Seoul, Seoul-t'ukpyolsi, Republic of Korea
Yujin Lee– Seoul, Seoul-t'ukpyolsi, Republic of Korea
Sang Chun Ji– Seoul, Seoul-t'ukpyolsi, Republic of Korea
Seonghae Yoon– Seongnam-si, Kyonggi-do, Republic of Korea
SeungHwan Lee– Seoul, Seoul-t'ukpyolsi, Republic of Korea
Kyung-Sang Yu– Seoul, Seoul-t'ukpyolsi, Republic of Korea
In-Jin Jang– Seoul, Seoul-t'ukpyolsi, Republic of Korea
Joo-Youn Cho– Seoul National University, Seoul, Seoul-t'ukpyolsi, Republic of Korea