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  • Author or Editor: Eiichi Kokue x
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Abstract

Objective—To evaluate the effect of oral administration of dexamethasone (DEX) at clinically relevant doses on metabolic activities of cytochrome P450 (CYP) isoenzymes in dogs and rats.

Animals—15 healthy 1-year-old male Beagles and 20 healthy 10-week-old male Wistar rats.

Procedure—Hepatic microsomes were harvested from dogs treated orally with DEX at 2.5 and 7.5 mg for 5 days and from rats treated orally with DEX at 0.75, 6, and 48 mg/kg for 5 days. 7-ethoxyresorufin, tolbutamide, bufuralol, and midazolam were used as CYP1A, CYP2C, CYP2D, and CYP3A substrates, respectively. Concentrations of metabolites formed by CYPs were measured by use of high-performance liquid chromatography, except for the resorufin concentrations measured by use of a fluorometric method. Reaction velocity-substrate concentration data were analyzed to obtain maximum reaction velocity (Vmax) and Michaelis-Menten constant (Km).

Results—Values of Vmax for midazolam 4-hydroxylation were significantly decreased by treatment with DEX at 2.5 and 7.5 mg in dogs, although values of Km were not affected. Values of Vmax for bufuralol 1'-hydroxylation were also decreased by treatment with DEX. In rats, values of Vmax for midazolam 4- hydroxylation were significantly decreased by treatment with DEX at 0.75 and 6 mg/kg but significantly increased at 48 mg/kg. Other reactions were not affected by treatment with DEX.

Conclusions and Clinical Relevance—Our results indicate that DEX downregulates the CYP3A subfamily when administered at clinically relevant doses to dogs. The effect of downregulation of CYP3A in dogs treated with DEX should be considered to avoid adverse effects from coadministration of drugs.

Full access
in American Journal of Veterinary Research

SUMMARY

Erythromycin (em) pharmacokinetic variables were studied after IV administration of the drug (10 mg/kg of body weight) to 1-, 6-, and 15-day-old pigs. With advancing age, from 1 day to 15 days after birth, half-life of em became shorter (3.0 hours to 1.4 hour), whereas apparent volume of distribution, total body clearance (CLt), and intrinsic clearance became greater: 0.68 to 3.28 (L/kg), 0.15 to 1.42 (L/h/kg), and 1.81 to 3.56 (L/h/kg), respectively. The percentage of plasma protein binding of em decreased from 91 to 56%, correlating well with volume of distribution and CLt values. The altered binding percentage depended on plasma α1-acid glycoprotein (agp) concentration, but not on albumin concentration. With advancing age, plasma agp concentration was markedly decreased from approximately 6,000 μg/ml to 700 μg/ml. Despite a twofold increase in intrinsic clearance with advancing age, CLt increased ninefold, implying that the decreased protein binding contributed to the increase of CLt more preferentially than did maturational development of elimination capacity. Therefore, the altered protein binding of em attributable to the change in plasma agp concentration could be a major causal factor of the age-related pharmacokinetic variables of em in pigs.

Free access
in American Journal of Veterinary Research