Effect of fluvastatin, lovastatin, nifedipine and verapamil on the systemic exposure of nateglinide in rabbits.
A diabetic patient may suffer simultaneously from cardiovascular disease; thus, lipid-lowering or anti-hypertensive agents could be given together with nateglinide. The pharmacokinetics of nateglinide were investigated in the presence and absence of HMG-CoA reductase inhibitors (fluvastatin, lovastatin) and calcium channel blockers (verapamil, nifedipine) in rabbits. A pharmacokinetic modeling approach was used to quantify the effects of the drugs that significantly influenced the pharmacokinetics of nateglinide. Fluvastatin and nifedipine shifted the time course of serum nateglinide concentrations upwards; there was no significant change with verapamil or lovastatin. The C(max) and AUC(inf) increased 1.5- (p<0.05) and 1.3-fold in the presence of fluvastatin and 1.8- (p<0.01) and 2.4-fold (p<0.01) in the presence of nifedipine, respectively. In a simultaneous nonlinear regression, fluvastatin and nifedipine decreased the elimination rate constant, by 76% and 32%, respectively. Fluvastatin and nifedipine increased the systemic exposure of nateglinide in rabbits, probably due to their inhibitory action on the metabolism of nateglinide by CYP2C5 (human CYP2C9). The concomitant use of fluvastatin and/or nifedipine with nateglinide is quite likely; therefore, the clinical consequences of long-term treatments must be considered.
Kim
Youngmin
Y
Daewon Foreign Language High School, Seoul, 143-713 Korea.
Park
Kyemyung
K
Kang
Wonku
W
D000818:Animals; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D003510:Cyclohexanes / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D065729:Cytochrome P-450 CYP2C9; D000072467:Cytochrome P450 Family 2; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004347:Drug Interactions; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D007211:Indoles / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D008148:Lovastatin / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D000077715:Nateglinide; D009543:Nifedipine / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D013255:Steroid 21-Hydroxylase / Q000378:metabolism; D014700:Verapamil / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology
D002121:Calcium Channel Blockers; D003510:Cyclohexanes; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D007211:Indoles; D000077715:Nateglinide; D010649:Phenylalanine; D000077340:Fluvastatin; D008148:Lovastatin; D014700:Verapamil; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C065407:CYP2C5 protein, Oryctolagus cuniculus; D000072467:Cytochrome P450 Family 2; D013255:Steroid 21-Hydroxylase; D009543:Nifedipine