The disposition of intravenously (0.5 mg/kg) and orally (5 mg/kg) administered verapamil was studied in six dogs after 3 days' pre-treatment with verapamil alone (5 mg/kg, every 8 h) and during concomitant oral administration of cimetidine (16 mg/kg, every 8 h). Racemic verapamil and norverapamil, an active metabolite of verapamil, were measured by fluorescence high performance liquid chromatography using an achiral phenyl column. The isolated racemic verapamil was rechromatographed on an Ultron-OVM chiral column, which separated the two verapamil enantiomers. Cimetidine co-administration significantly reduced the systemic clearance of racemic verapamil as well as that of its enantiomers by 25-29%. The clearance of racemic verapamil administered orally as well as that of its enantiomers was also reduced by 28% during cimetidine coadministration. The decrease in verapamil metabolism by cimetidine appeared to be non-stereoselective. On the other hand, cimetidine co-administration had no significant effect on the apparent volume of distribution of racemic verapamil and its enantiomers or the plasma protein binding or the blood to plasma concentration ratio of racemic verapamil. In addition, the ratio of the area under the plasma concentration-time curve for norverapamil to that of verapamil was unaffected by cimetidine co-administration.(ABSTRACT TRUNCATED AT 250 WORDS)
The intravenous (0.5 mg/kg) and oral (5 mg/kg) dose kinetics of verapamil were studied in 6 dogs during steady-state oral verapamil dosing (5 mg/kg every 8 h for 3 days). Racemic verapamil and norverapamil, a metabolite of verapamil, were quantitated in plasma by HPLC-fluorescence detection. The verapamil peaks eluting off the column were collected and rechromatographed on an Ultron-OVM column, which resolved the two verapamil enantiomers. After intravenous administration, the systemic clearance and apparent volume of distribution of (-)-(S)-verapamil were nearly twice that of the (+)-(R)-isomer. There was no difference in the elimination half-lives between the two isomers. After oral administration, the oral clearance of (-)-(S)-verapamil was 20 times that of the (+)-(R)-isomer. The apparent bioavailability of (+)-(R)-verapamil was over 14 times that of (-)-(S)-verapamil. The plasma protein binding of the (+)-(R)-isomer was slightly higher by 5% than (-)-(S)-verapamil; however, this effect was not enough to account for the difference between the apparent volume of distribution of the enantiomers, indicating that the tissue binding of (-)-(S)-verapamil was greater than that of the (+)-(R)-isomer. This data on the disposition of the enantiomers of verapamil in the dog is similar to that reported for man and demonstrates that the dog may be an appropriate animal model for man in future studies on the disposition of the enantiomers of verapamil.
The IV and apparent steady-state kinetics of diltiazem HCI (DLT) and slow-absorption long-acting diltiazem (CD) given PO were investigated in cats. The effects of PO diltiazem on heart rate and PR interval were also studied. Plasma diltiazem concentrations were determined by ultraviolet highperformance liquid chromatography (UV-HPLC), using verapamil as the internal standard. Heart rate and PR interval determinations were evaluated over a 24-hour period for the PO formulations and compared with values under diltiazemfree conditions. The mean systemic clearance and apparent volume of distribution of IV diltiazem were 15.0 mL/min/ kg and 2.70 L/kg, respectively. The elimination half-life of iltiazem, the most widely used calcium-channel blocker D in humans in the United States, is effectively used for the treatment of angina pectoris, hypertension, and supraventricular tachyarrythmias.' Its application in veterinary medicine has primarily been in the treatment of hypertrophic cardiomyopathy in cats2 and supraventricular tachycardia in dogs.3 Diltiazem is beneficial to cats with hypertrophic cardiomyopathy by increasing ventricular filling and coronary perfusion, and decreasing heart rate and pulmonary congestion.* Although the pharmacokinetics of diltiazem have been extensively studied in humans and dogs, little is known about it in cats. Diltiazem dosing regimens in cats have been generally designed based on its kinetics in other species, most notably in humans. A major objective of this study was to define the pharmacokinetics of diltiazem administered IV and PO in cats. The kinetics, as well as the pharmacodynamic effects on heart rate (HR) and PR interval of 2 formulations of diltiazem PO, conventional diltiazem HCl (DLT) and a slow-absorption diltiazem (CD) formulation, were investigated. Because diltiazem is used clinically for long-term therapy, the dose kinetic PO and dynamic studies were carried out under apparent steady-state conditions. Materials and Methods ChemicalsConventional diltiazem HCI (Cardizem) and diltiazem CD (Cardizem CD) were obtained from Marion Merrell Dow (Kansas City, MO); 230 mg of diltiazem CD is equivalent to 100 mg of diltiazem free base. The doses of DLT and CD PO were individually weighed and put into gelatin capsules. Verapamil HCI was obtained from Sigma Chemical Co (St Louis, MO). Ammonium acetate, hexane, isoamyl alcohol, triethylamine, and heptanesulfonic acid were purchased from Fisher Scientific Co (Pittsburgh, PA). Glass-distilled acetonitrile and methanol were purchased from Burdick & Jackson Laboratories (Muskegon, MI). Glass-distilled water was used for all aqueous reagents. Experimental ProtocolsPharmacokinetics. The 6 female domestic short-hair cats (3 to 5 kg) used were cared for according to the principles outlined in the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The pharmacokinetics of diltiazem were evaluated under 3 different protocols:1. Single IV dose of DLT (0.1 mgkg).2. PO DLT (1 mgkg) after one day treatment with PO DL...
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