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Cisplatin is a platinum-containing cytotoxic drug indicated for the treatment of solid tumors in veterinary and human patients. Several of the algorithms used to standardize the doses of cytotoxic drugs utilize allometry, or the nonproportional relationships between anatomical and physiological variables, but the underlying basis for these relationships is poorly understood. The objective of this proof of concept study was to determine whether allometric equations explain the relationships between body weight, kidney weight, renal physiology, and clearance of a model, renally cleared anticancer agent in dogs. Postmortem body, kidney, and heart weights were collected from 364 dogs (127 juveniles and 237 adults, including 51 dogs ≥ 8 years of age). Renal physiological and cisplatin pharmacokinetic studies were conducted in ten intact male dogs including two juvenile and eight adult dogs (4-55 kg). Glomerular filtration rate (GFR), effective renal plasma flow, effective renal blood flow, renal cisplatin clearance, and total cisplatin clearance were allometrically related to body weight with powers of 0.75, 0.59, 0.61, 0.71, and 0.70, respectively. The similar values of these diverse mass exponents suggest a common underlying basis for the allometry of kidney size, renal physiology, and renal drug handling., (© 2015 John Wiley & Sons Ltd.)

A pharmacokinetic study was conducted to compare the oral bioavailability of tepoxalin and its pharmacologically active acid metabolite in fasted dogs and dogs fed either a low-fat or high-fat commercial diet. Using a cross-over design, six beagles were administered tepoxalin (10 mg/kg) intravenously (i.v.) and orally (p.o.) after being fed one of three diets (fasted, low-fat, or high-fat). Thereafter, blood samples were collected at frequent intervals, concentrations of tepoxalin and acid metabolite in plasma were determined by high performance liquid chromatography, and pharmacokinetic parameters were estimated. After i.v. dosing, the mean (+/-SD) half-life of elimination (t(1/2(beta))) was 2.45 +/- 1.47 h. After p.o. administration, plasma concentrations of acid metabolite were consistently higher than corresponding concentrations of the parent tepoxalin, indicating that tepoxalin is subject to a substantial first-pass effect. Mean (+/-SD) peak concentrations of tepoxalin were significantly higher after feeding of low-fat (1.08 +/- 0.37 microg/mL) and high-fat (1.19 +/- 0.29 microg/mL) diets than in fasted dogs (0.53 +/- 0.20 microg/mL), suggesting that feeding improves oral bioavailability.

To investigate the effect of chloramphenicol, a cytochrome P-450 inhibitor, on the pharmacokinetics of propofol, either chloramphenicol (50 mg/kg of body weight, IV) or saline solution was administered IV to 5 Greyhounds in randomized manner, with at least 2 weeks between trials. Thirty minutes after either chloramphenicol or saline treatment, a bolus dose of propofol (10 mg/kg, IV) was administered, followed by a 2-hour infusion of propofol (0.4 mg/kg/min, IV). Samples for determination of blood propofol concentration were collected sequentially over a 6-hour period during each trial. After termination of propofol infusion, the time to spontaneous head lift, extubation, sternal recumbency, and standing was recorded. Blood propofol concentration was determined by use of high-performance liquid chromatography. Concentration-time data were fitted to a two-compartment open pharmacokinetic model and pharmacokinetic variables were determined, using a microcomputer program for modeling and simulation of concentration-time data. The effect of chloramphenicol on the pharmacokinetics of propofol and recovery time were evaluated, using paired t-tests and Wilcoxon's test for parameters that are not normally distributed (t1/2(beta), Vd(ss), ClB). Significant (P < 0.05) effects of chloramphenicol pretreatment included increased t1/2(beta) (by 209%), and decreased ClB (by 45%), and prolonged recovery indices (by 768 to 946%). These results indicate that cytochrome P-450 metabolic pathways have an important role in propofol clearance and propofol anesthetic recovery in Greyhounds.