Pharmacokinetic and Pharmacodynamic Properties of Conventional and CD‐Formulated Diltiazem in Cats

Abstract

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...

Calcium Channel Blockers in Veterinary Medicine

“…Bioavailability was reported to be 71% for conventional diltiazem and 36% for the extended release form of diltiazem. 62 The difference in bioavailability of conventional diltiazem in the cat in comparison to the dog is thought to be due to reduced hepatic 1st-pass metabolism in the cat.…”

Determination of plasma protein binding of diltiazem in horses by ultrafiltration

“…The results of our study showed that the extent of PB of diltiazem in horses is slightly higher than PB reported for humans (77-86%), dogs (70.2 ± 1.0%), rats (81.6 ± 0.6%), and monkeys (52.4 ± 3.8%) Piepho et al, 1982;Hermann & Morselli, 1985;Pool, 1996). In cats, PB ranges between 45% and 65%, and is higher after IV administration (65%) compared with PO administration (45-60%) (Johnson et al, 1996). Although PB in humans was unrelated to plasma diltiazem concentrations ranging from 30-2060 ng/mL , we found that PB is concentration-dependent in horses, suggesting a potential saturation of PB sites at higher plasma drug concentrations.…”

“…, 1982; Hermann & Morselli, 1985; Pool, 1996). In cats, PB ranges between 45% and 65%, and is higher after IV administration (65%) compared with PO administration (45–60%) (Johnson et al. , 1996).…”

Analysis of diltiazem in Lipoderm® transdermal gel using reversed-phase high-performance liquid chromatography applied to homogenization and stability studies

“…There is also evidence of significant pharmacokinetic differences between felines and humans. These include significant differences in bioavailability, clearance, and volume of distribution [3]. Current treatment regimens include multiple day dosing or the use of sustained release preparations in order to maintain therapeutic plasma concentrations [4].…”