Effect of fluvastatin, lovastatin, nifedipine and verapamil on the systemic exposure of nateglinide in rabbits

Abstract

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.

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

“…Fluvastatin and nifedipine increase the systemic exposure of nateglinide, probably through the inhibition of the metabolism of nateglinide by CYP2C5 (human CYP2C9) (Kim et al, 2010).…”

Combination of fluvastatin and losartan relieves atherosclerosis and macrophage infiltration in atherosclerotic plaques in rabbits

“…The fluvastatin and losartan combination group (F+L) contained rabbits (n=9) that were provided with highcholesterol food and treated with a combination of fluvastatin (10 mg·kg -1 ·d -1 ) and losartan (25 mg·kg -1 ·d -1 ). Both drugs were administered in the food [11][12][13] . An additional 8 rabbits were provided with regular food to act as a negative control group for comparison with the occurrence of atherosclerotic plaques induced by high-cholesterol food.…”