Effects of lovastatin on the pharmacokinetics of nicardipine in rats.

It has been reported that both nicardipine and lovastatin are substrates of both the cytochrome P450 (CYP) 3A subfamily and P-glycoprotein (P-gp), and P-gp transport is unlikely to be a significant factor. Thus, the effects of oral lovastatin on the pharmacokinetics of intravenous and oral nicardipine were investigated in rats. Nicardipine was administered intravenously (4 mg/kg) and orally (12 mg/kg) with 0 (control), 0.3 and 1 mg/kg of oral lovastatin to rats. Lovastatin was administered 30 min before nicardipine administration. After intravenous administration of nicardipine with 0, 0.3 and 1 mg/kg of lovastatin, the total areas under the plasma concentration-time curve from time zero to infinity (AUCs) of nicardipine were not changed by lovastatin. However, after oral administration of nicardipine with 1 mg/kg of oral lovastatin, the AUC of nicardipine was significantly greater (by 67.4%), and the extent of absolute oral bioavailability (F) of nicardipine was increased (by 38.5%). The above data suggest that lovastatin did not considerably inhibit the metabolism of nicardipine via the hepatic CYP3A subfamily, but inhibited intestinal P-gp and/or the CYP3A subfamily.

Effects of naringin on the pharmacokinetics of verapamil and one of its metabolites, norverapamil, in rabbits.

It was reported that verapamil is metabolized via hepatic microsomal cytochrome P450 (CYP) 3A4 and that naringin (a component of grapefruit juice) inhibits CYP3A4 in humans. Hence, after oral administration of verapamil, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) of verapamil and the AUC(verapamil)/AUC(D-617 (a metabolite of verapamil)) ratio were significantly greater after oral grapefruit juice in humans. The aim of this study was to determine whether similar results could be obtained from rabbits. The pharmacokinetics of verapamil and one of its metabolites, norverapamil, were investigated after oral administration of verapamil at a dose of 9 mg/kg without or with oral naringin at a dose of 7.5 mg/kg in rabbits. With naringin, the AUC of verapamil was significantly greater (28.4 versus 18.4 microg min/ml). Although, the AUC values of norverapamil were not significantly different between groups without and with naringin, the AUC(verapamil)/AUC(norverapamil) ratio was considerably greater (1.49 versus 1.11) with naringin. The above data suggested that the metabolism of verapamil and the formation of norverapamil was inhibited by naringin possibly by inhibition of CYP3A in rabbits.

Transretinal electrical stimulation by an intrascleral multichannel electrode array in rabbit eyes.

BACKGROUND: A new method of stimulating the retina electrically, called suprachoroidal transretinal stimulation (STS), was shown to be effective in eliciting electrically evoked cortical potentials (EEPs) in Royal College of Surgeons (RCS) rats. Before extending this technique to patients, it is important to determine its safety and feasibility in eliciting EEPs from medium-size animal (rabbits). The purpose of this study was to determine the safety and efficacy of the surgical procedures used to implant an multichannel electrode array into a scleral pocket, and to determine whether the implanted electrodes can stimulate the retina effectively. METHODS: These acute experiments were conducted on six rabbits. An array of eight gold microelectrodes, embedded in polyimide, was implanted into a scleral pocket over the visual streak area. The size of the microarray was 2 x 4 x 0.180 mm. The reference electrode was implanted into the vitreous. The electrode array and reference electrodes were connected to a stimulator to deliver monophasic current pulses. Cortical responses were recorded with a stainless steel electrode implanted into each rabbit's skull over the visual cortex. After the experiment, the eyes and electrodes were examined histologically. RESULTS: The surgical procedures for electrode implantation were accomplished without serious complications. EEPs were recorded after monophasic electrical pulse stimulation from each electrode. The mean threshold for EEPs was 55.0+/-10.0 microA with a 0.5-ms duration inward current pulse. The charge delivered at threshold was about 27.5 nC, and the charge density was about 56.0 microC/cm2. Histopathological examination of the retinal tissue around the area of stimulation did not show damage at the light microscope level with the electrical parameters used. CONCLUSIONS: Our technique for STS with an intrascleral microelectrode array is safe in rabbit eyes, and EEPs were elicited by current densities that did not induce tissue damage. These results suggest that STS via intrascleral multichannel electrodes is a feasible method for stimulating the retina.

Pharmacokinetic changes of diltiazem and desacetyldiltiazem after oral administration of diltiazem in rabbits with diabetes mellitus induced by alloxan.

Physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics of drugs used to treat hypertension resulting from diabetic complications. Hence, the pharmacokinetics of diltiazem (DTZ) and its metabolite, desacetyldiltiazem (DAD), were investigated after oral administration of DTZ. DTZ, 20 mg/kg, was orally administered to control rabbits and rabbits with fifth day (experiment was performed at fifth day after first and second days intravenous administration of alloxan) and 13th day (experiment was performed at 13th day after first, second, sixth, and 10th days intravenous administration of alloxan) diabetes mellitus induced by alloxan. Impaired kidney and liver functions were observed in both diabetic groups based on plasma chemistry data and/or tissue microscopy. After oral administration of DTZ, the area under the plasma concentration-time curve from time zero to time infinity were 767, 1280 and 1550 ng h/ml for control rabbits and fifth and 13th days diabetes mellitus rabbits, respectively. The values in diabetes mellitus rabbits were significantly different as compared to control rabbits. The terminal half-lives of DTZ were significantly longer in fifth (13.4 h) and 13th (13.0 h) days diabetes mellitus rabbits than that in control rabbits (8.76 h). The renal clearances of DTZ in fifth (0.3161/h/kg) and 13th (0.2641/h/kg) days diabetes mellitus rabbits were significantly slower than that in control rabbits (0.5051/h/kg), and this could be due to impaired kidney function in the diabetes mellitus rabbits. However, other pharmacokinetic parameters of DAD were not significantly different among three groups of rabbits.