The Disposition and Pharmacokinetics of the Oxidative Metabolism Substrates Midazolam, Phenytoin, and Theophylline in Greyhound Dogs
ACVIM 2008
Butch KuKanich; Michelle Hubin; Jon Nauss
Kansas State University, Department of Anatomy and Physiology
Manhattan, KS, USA

The purpose of the study was to assess the disposition and pharmacokinetics of midazolam, phenytoin, and theophylline in healthy Greyhound dogs. Midazolam is a CYP3A12 substrate in dogs, whereas the definitive mechanisms of metabolism for phenytoin and theophylline have not been identified in dogs. Phenytoin is a CYP2C9 and CYP2C19 substrate in humans and theophylline is primarily a CYP1A2 substrate in humans. There is evidence supporting the role of CYP1A in the metabolism of theophylline in dogs.

Six healthy Greyhound dogs, 3 male and 3 female, were used in the study which was approved by the Kansas State University Institutional Animal Care and Use Committee. On separate occasions, with at least a 7 day washout period, midazolam (0.25 mg/kg), phenytoin (11 mg/kg), and theophylline (7.88 mg/kg) administered as aminophylline, were administered IV. Blood samples were obtained at predetermined intervals for the determination of plasma drug concentrations with mass spectrometry (midazolam) or fluorescence polarization immunoassay (phenytoin, theophylline). The pharmacokinetics were estimated with noncompartmental analyses.

The half-life (t ½), clearance (Cl), and volume of distribution (Vd) for phenytoin, and theophylline were similar to values reported in dogs (see Table I). The Cl and Vd for midazolam appear to be different in Greyhounds. The results are suggestive that the disposition and pharmacokinetics phenytoin and theophylline are similar in Greyhound and non-Greyhound, non-Beagle dogs, but midazolam may be different. Further studies are indicated.

Table 1. Pharmacokinetic parameters of midazolam, phenytoin, and theophylline in Greyhound dogs. Pharmacokinetic parameters from previous studies in non-Greyhound dogs are included for comparison.

Parameter

Units

Breed

Midazolam

Phenytoin

Theophylline

Half-life

hr

Greyhound

1.2

5

9.3

Non-Greyhound

1.3 1

4.5 2

8.4 3

Clearance

mL/min/kg

Greyhound

10.2

2.4

1

Non-Greyhound

27 1

2.8 2

0.8 3

Volume of
Distribution

L/kg

Greyhound

1.0

1

0.75

Non-Greyhound

3.0 1

1 2

0.55 3

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Butch KuKanich, DVM, PhD, DACVCP
Kansas State University
Manhattan, KS


MAIN : SA Pharmacology : Disposition & Pharmacokinetics
Powered By VIN
SAID=27