Objective—To evaluate the inhibitory potency of
ketoconazole (KTZ) on the metabolic activities of
isozymes of cytochrome P-450 (CYP) in dogs.
Animals—4 healthy 1-year-old male Beagles.
Procedure—Hepatic microsomes were harvested
from 4 dogs after euthanasia. To investigate the
effects of KTZ on CYP metabolic activities, 7-
ethoxyresorufin, tolbutamide, bufuralol, and midazolam
hydrochloride were used as specific substrates
for CYP1A1/2, CYP2C21, CYP2D15, and CYP3A12,
respectively. The concentrations of metabolites
formed by CYP were measured by high-performance
liquid chromatography, except for the resorufin concentrations
that were measured by a fluorometric
method. The reaction velocity-substrate concentration
data were analyzed to obtain kinetic variables, including
maximum reaction velocity, Michaelis-Menten
constant, and inhibitory constant (Ki).
Results—KTZ competitively inhibited 7-ethoxyresorufin
O-deethylation and midazolam 4-hydroxylation;
it noncompetitively inhibited tolbutamide
methylhydroxylation. Bufuralol 1'-hydroxylation was
inhibited slightly by KTZ. The mean Ki values of KTZ
were 10.6 ± 6.0, 17.0 ± 2.5, and 0.180 ± 0.131 µM for
7-ethoxyresorufin O-deethylation, tolbutamide
methylhydroxylation, and midazolam 4-hydroxylation,
Conclusion and Clinical Relevance—In dogs, KTZ
at a therapeutic dose may change the pharmacokinetics
of CYP3A12 substrates as a result of inhibition
of their biotransformation. Furthermore, no influence
of KTZ on the pharmacokinetics of CYP1A1/2,
CYP2C21, and CYP2D15 substrates are likely. In clinical
practice, adverse drug effects may develop when
KTZ is administered concomitantly with a drug that is
primarily metabolized by CYP3A12. (Am J Vet Res
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.