In vivo inhibition profile of cytochrome P450TB (CYP2C9) by (+/-)-fluvastatin.
BACKGROUND
(+/-)-Fluvastatin is a synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that selectively and competitively inhibits P450TB (CYP2C9) in vitro. The potential for kinetic interactions in vivo between fluvastatin and P450TB substrates was therefore investigated in healthy volunteers.


METHODS
Diclofenac (25 mg orally) oxidation was used as a marker of P450TB activity on days 0, 1, and 8 of fluvastatin treatment (40 mg/day).


RESULTS
Diclofenac peak concentration (Cmax) increased over time (0.28 [SD, 0.12], 0.38 [0.20], and 0.45 [0.4] mg/L on days 0, 1, and 8, respectively). Oral clearance was reduced on days 1 and 8 (14% and 15%, respectively). A time-dependent decrease in urinary metabolic ratio (MR, 4'-hydroxydiclofenac/diclofenac) was noted (1.07 [0.34], 0.90 [0.23] and 0.70 [0.18] on days 0, 1, and 8, respectively [p < 0.0001]) for the first 4 hours. The interaction was clear in only some individuals; MR reduction was related to baseline MR and it was more pronounced in subjects with a higher baseline MR (p < 0.01). Fluvastatin Cmax (0.18 [0.11] and 0.32 [0.1] mg/L on days 1 and 8, respectively) and area under the curve (0.28 [0.12] and 0.43 [0.15] hr.mg/L on days 1 and 8, respectively; p < 0.001) increased over time. Diclofenac MR reduction was correlated with fluvastatin concentrations.


CONCLUSIONS
Interactions between fluvastatin and P450TB substrates (phenytoin, oral anticoagulants, oral hypoglycemic agents, and nonsteroidal antiinflammatory drugs) may occur, at least in some patients.
Transon
C
C
Division of Clinical Pharmacology, University Hospital, Geneva, Switzerland.
Leemann
T
T
Vogt
N
N
Dayer
P
P
D000328:Adult; D000924:Anticholesteremic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics; D065729:Cytochrome P-450 CYP2C9; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004008:Diclofenac / Q000378:metabolism* / Q000493:pharmacokinetics; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D005229:Fatty Acids, Monounsaturated / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000924:Anticholesteremic Agents; D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D004008:Diclofenac; D000077340:Fluvastatin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase