Effect of concomitant treatment with a CYP3A4 inhibitor and a calcium channel blocker.
OBJECTIVE
Grapefruit juice has been found to interact with calcium channel blockers (CCB). This interaction is due to certain nutrients found in grapefruit juice that block the activity of cytochrome P-450 (CYP) 3A4 in the small intestine and liver. Inhibition of CYP3A4 markedly increases bioavailability and increases the risk of an adverse drug reaction (ADR). Many drugs are known to have CYP3A4-blocking activity. This study was performed to investigate whether the concomitant use of a CYP3A4 inhibitor and a CCB in hypertensive patients results in an elevated incidence of ADRs.


METHODS
The study included data on 17,430 patients receiving a CCB. Data were obtained from an anti-hypertensive drug database developed by the RAD-AR Council, Japan. A nested case-control design was employed for this study. Cases are defined as patients experiencing an ADR during the follow-up period of 12 weeks. Four controls per case, matched for CCB use, were selected via incidence density sampling. An estimate of the association between the CYP3A4 inhibitor and the ADR was obtained via multivariate conditional logistic regression.


RESULTS
Univariate analysis revealed that the odds ratio for experiencing an ADR for the group treated concomitantly with a CCB and a CYP3A4 inhibitor was 1.35 (95% confidence intervals (95%CI), 1.02-1.78), compared with CCB monotherapy. The odds ratio based on multivariate analysis using the 1:4 matched dataset was 1.53 (95%CI, 0.95-2.47) after adjusting for possible confounding factors.


CONCLUSIONS
The concomitant treatment with a CYP3A4 inhibitor and a CCB increases the risk of an ADR by 53%, compared with CCB monotherapy.
Yoshida
Masanori
M
SciStat Inc. Chiba, Nagareyama, Japan.
Matsumoto
Takuyuki
T
Suzuki
Tatsuo
T
Kitamura
Shigeto
S
Mayama
Takashi
T
D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000369:Aged, 80 and over; D002121:Calcium Channel Blockers / Q000009:adverse effects* / Q000627:therapeutic use; D016022:Case-Control Studies; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D016208:Databases, Factual; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged
D002121:Calcium Channel Blockers; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human