Serum concentrations of clarithromycin and rifampicin in pulmonary Mycobacterium avium complex disease: long-term changes due to drug interactions and their association with clinical outcomes.

Autor:	Shimomura H; Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 Japan., Andachi S; Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 Japan., Aono T; Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 Japan., Kigure A; Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 Japan., Yamamoto Y; Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 Japan., Miyajima A; Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 Japan., Hirota T; Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 Japan., Imanaka K; Department of Pharmacy, Chemotherapy Research Institute, Kaken Hospital, 6-1-14 Konodai, Ichikawa, Chiba 272-0827 Japan., Majima T; Department of Respiratory medicine, Chemotherapy Research Institute, Kaken Hospital, 6-1-14 Konodai, Ichikawa, Chiba 272-0827 Japan., Masuyama H; Department of Respiratory medicine, Chemotherapy Research Institute, Kaken Hospital, 6-1-14 Konodai, Ichikawa, Chiba 272-0827 Japan., Tatsumi K; Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670 Japan., Aoyama T; Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 Japan.
Jazyk:	angličtina
Zdroj:	Journal of pharmaceutical health care and sciences [J Pharm Health Care Sci] 2015 Nov 14; Vol. 1, pp. 32. Date of Electronic Publication: 2015 Nov 14 (Print Publication: 2015).
DOI:	10.1186/s40780-015-0029-0
Abstrakt:	Background: Concomitant use of clarithromycin (CAM) and rifampicin (RFP) for the treatment of pulmonary Mycobacterium avium complex (MAC) disease affects the systemic concentrations of both drugs due to CYP3A4-related interactions. To date, however, there has been no report that investigates the long-term relationship between the drug concentrations, CYP3A4 activity, and clinical outcomes. Our aim was to investigate the time course of the drug levels in long-term treatment of subjects with pulmonary MAC disease, and examine the correlation of these concentrations with CYP3A4 activity and clinical outcomes. Methods: Urine and blood samples from nine outpatients with pulmonary MAC disease were collected on days 1, 15, and 29 (for four subjects, sample collections were continued on days 57, 85, 113, 141, 169, 225, 281, 337, and 365). Serum drug concentrations and urinary levels of endogenous cortisol (F) and 6 beta-hydroxycortisol (6βOHF), the metabolite of F by CYP3A4, were measured, and evaluated 6βOHF/F ratio as a CYP3A4 activity marker. In addition, the clinical outcomes of 4 subjects were evaluated based on examination of sputum cultures and chest images. Results: The mean 6βOHF/F ratio increased from 2.63 ± 0.85 (n = 9) on the first day to 6.96 ± 1.35 on day 15 and maintained a level more than double initial value thereafter. The serum CAM concentration decreased dramatically from an initial 2.28 ± 0.61 μg/mL to 0.73 ± 0.23 μg/mL on day 15. In contrast, the serum concentration of 14-hydroxy-CAM (M-5), the major metabolite of CAM, increased 2.4-fold by day 15. Thereafter, both CAM and M-5 concentrations remained constant until day 365. The explanation for the low levels of serum CAM in pulmonary MAC disease patients is that RFP-mediated CYP3A4 induction reached a maximum by day 15 and remained high thereafter. Sputum cultures of three of four subjects converted to negative, but relapse occurred in all three cases. Conclusions: Our study demonstrated that serum CAM concentrations in pulmonary MAC disease patients were continuously low because of RFP-mediated CYP3A4 induction, which may be responsible for the unsatisfactory clinical outcomes.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu