Altered pharmacokinetics and excessive hypotensive effect of candesartan in a patient with the CYP2C91/3 genotype.
An 89-year-old man with severe hypertension (190/82 mm Hg) and chronic heart failure (New York Heart Association class II) despite treatment with benidipine, doxazosin mesylate (INN, doxazosin), and furosemide was given oral candesartan cilexetil (4 mg/d), an angiotensin II type 1 receptor blocker metabolized via cytochrome p450 (CYP) 2C9. Two days later, he started to have severe dizziness and returned to the hospital on the fourth day without taking any of his medications. The blood pressure 30 hours after the last dose of candesartan was 126/64 mm Hg. Polymorphism analysis revealed the heterozygous poor metabolizer genotype CYP2C9*1/*3. The area under the concentration-time curve and the mean residence time of candesartan were both increased 2.5-fold, and the oral clearance of candesartan was 48% lower than that of the average elderly Japanese patient with hypertension. These results suggest that the CYP2C9*1/*3 genotype could be associated with decreased clearance and increased plasma concentration of candesartan, potentially enhancing its hypotensive effect.
Department of Clinical Pharmacology and Therapeutics, Hospital Pharmacy and Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Shinya
S
Uchida
Hiroshi
H
Watanabe
Shinichiro
S
Nishio
Hisakuni
H
Hashimoto
Keisuke
K
Yamazaki
Hideharu
H
Hayashi
Kyoichi
K
Ohashi
D000368:Aged; D000369:Aged, 80 and over; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects* / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D005838:Genotype; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D008297:Male; D011110:Polymorphism, Genetic; D013777:Tetrazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C081643:candesartan