Delayed de-induction of CYP2C9 compared to CYP3A after discontinuation of rifampicin: Report of two cases .
OBJECTIVE
Timely dose reduction of concomitant medications is important after withdrawal of rifampicin, a CYP inducer. However, little is known about the differences in the time course of deinduction for various CYP isoforms. To clarify the time courses of deinduction of CYP2C9 and -CYP3A activities after rifampicin withdrawal, we monitored these enzyme activities in 2 patients over time after discontinuing rifampicin.


METHODS
Two patients (aged 70 and 80 years) received warfarin and rifampicin for anticoagulation and antituberculosis therapy, respectively. Warfarin doses were increased due to rifampicin-induced CYP activity. Upon completion of antituberculosis therapy, rifampicin was discontinued and warfarin doses were titrated downward according to prothrombin time. We monitored CYP2C9 and CYP3A activities over their clinical courses by measuring the metabolic clearance of S-warfarin to S-7-hydroxywarfarin and that of cortisol to 6β-hydroxycortisol, respectively.


RESULTS
In both patients, the time courses of CYP2C9 deinduction appeared to be delayed compared to CYP3A.


CONCLUSIONS
Our findings suggest that a uniform dose reduction protocol for drugs metabolized by different CYP isoforms may be unsafe after rifampicin withdrawal. .
Soichi
S
Shibata
Harumi
H
Takahashi
Akiyasu
A
Baba
Kei
K
Takeshita
Koichiro
K
Atsuda
Hajime
H
Matsubara
Hirotoshi
H
Echizen
D000368:Aged; D000369:Aged, 80 and over; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000009:adverse effects*; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001777:Blood Coagulation / Q000187:drug effects; D065729:Cytochrome P-450 CYP2C9 / Q000096:biosynthesis*; D065698:Cytochrome P-450 CYP2C9 Inducers / Q000008:administration & dosage / Q000009:adverse effects*; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D065701:Cytochrome P-450 CYP3A Inducers / Q000008:administration & dosage / Q000009:adverse effects*; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D019338:Polypharmacy; D011517:Prothrombin Time; D012293:Rifampin / Q000008:administration & dosage / Q000009:adverse effects*; D013379:Substrate Specificity; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D000904:Antibiotics, Antitubercular; D000925:Anticoagulants; D065698:Cytochrome P-450 CYP2C9 Inducers; D065701:Cytochrome P-450 CYP3A Inducers; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D012293:Rifampin