Effects of Fluvastatin on the Pharmacokinetics of Repaglinide: Possible Role of CYP3A4 and P-glycoprotein Inhibition by Fluvastatin

The purpose of this study was to investigate the effects of fluvastatin on the pharmacokinetics of repaglinide in rats. The effect of fluvastatin on P-glycoprotein and CYP3A4 activity was evaluated. The pharmacokinetic parameters and blood glucose concentrations were also determined after oral and intravenous administration of repaglinide to rats in the presence and absence of fluvastatin. Fluvastatin inhibited CYP3A4 activity in a concentration-dependent manner with a 50% inhibition concentration(IC50) of 4.1 microM and P-gp activity. Compared to the oral control group, fluvastatin significantly increased the AUC and the peak plasma level of repaglinide by 45.9% and 22.7%, respectively. Fluvastatin significantly decreased the total body clearance (TBC) of repaglinide compared to the control. Fluvastatin also significantly increased the absolute bioavailability (BA) of repaglinide by 46.1% compared to the control group. Moreover, the relative BA of repaglinide was 1.14- to 1.46-fold greater than that of the control. Compared to the i.v. control, fluvastatin significantly increased the AUC0-infinity of i.v. administered repaglinide. The blood glucose concentrations showed significant differences compared to the oral controls. Fluvastatin enhanced the oral BA of repaglinide, which may be mainly attributable to the inhibition of the CYP3A4-mediated metabolism of repaglinide in the small intestine and/or liver, to the inhibition of the P-gp efflux transporter in the small intestine and/or to the reduction of TBC of repaglinide by fluvastatin. The study has raised the awareness of potential interactions during concomitant use of repaglinide with fluvastatin. Therefore, the concurrent use of repaglinide and fluvastatin may require close monitoring for potential drug interactions.

Clinical observation of acute drug intoxications / 영남의대학술지

Clinical observations were made on 349 cases of acute drug intoxication who were visited to emergency room of Yeungnam University Hospital during recent 7 years from January 1984 to December 1990. The following results were obtained. 1) Total number of cases of acute drug intoxication was 349 which was 0.39% of the total patients of the emergency room during the same period. 2) The ratio of male to female was 1.1:1. The age incidence was highest in the third decade (26.7%). The monthly incidence was highest in May. Higher frequency was observed in summer season. 3) The most common drug of the intoxication was pesticides and herbicides (71.9%), the remainders were miscellaneous drugs (11.2%), sedatives (7.7%), rodenticides (6.3%) and unknown drug (3.2%) in orders. 4) The most common cause of drug intoxication was suicide (69.1%) and the others were accident, unknown cause, intention in orders. 5) Main clinical manifestations were the impairment of consciousness, nausea, vomiting and convulsion. Physical examination revealed increased pulses, increased blood pressure, miosis of the pupil and sweating. Above symptoms and signs were more prominent in pesticide intoxication. Leukocytosis, glycosuria and abnormal LFT were common findings in acute intoxications. 6) The complications were developed in 18.3% among 349 cases and the most common complication was respiratory failure, pneumonia, cardiovascular collapse and pulmonary edema in orders. 7) Overall mortality rate was 8.3% of total cases and mortality rate was highest in herbicide intoxication (22.2%).