title: 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.
abstract: 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimomura
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 Japan.
authors.forename: Sena
authors.initials: S
authors.lastname: Andachi
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Aono
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kigure
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyajima
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hirota
authors.affiliation: Department of Pharmacy, Chemotherapy Research Institute, Kaken Hospital, 6-1-14 Konodai, Ichikawa, Chiba 272-0827 Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Imanaka
authors.affiliation: Department of Respiratory medicine, Chemotherapy Research Institute, Kaken Hospital, 6-1-14 Konodai, Ichikawa, Chiba 272-0827 Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Majima
authors.affiliation: Department of Respiratory medicine, Chemotherapy Research Institute, Kaken Hospital, 6-1-14 Konodai, Ichikawa, Chiba 272-0827 Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Masuyama
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670 Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Aoyama
keywords: 6 beta-hydroxycortisol to cortisol ratio; CYP3A4; Clarithromycin; Clinical efficacy; Mycobacterium avium complex; Rifampicin; Serum concentration
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