Abstract
The cftrtm1Unc-knockout (CF-KO) mouse is being evaluated as a model of increased drug clearance noted clinically in patients with cystic fibrosis (CF). This study investigated whether CF-KO mice exhibited altered omeprazole pharmacokinetics compared with wild-type mice. Clinical observations have suggested reduced responses to omeprazole in CF children, which may reflect alterations in bioavailability or clearance. Omeprazole was dosed intravenously and orally in a crossover fashion to age-matched CF-KO and wild-type male and female mice. The mean terminal half-life of approximately 6 min was found across genotype and gender groups. Blood to plasma ratio estimates for omeprazole were similar across genders and genotypes with a mean value of 0.69. Omeprazole blood clearance (Clb) was significantly higher in both male (190 ml/min/kg) and female (168 ml/min/kg) CF-KO mice compared with wild-type controls of the same gender (73 ml/min/kg for males and 100 ml/min/kg for females). The distributional volume of omeprazole in CF-KO mice was also statistically higher than in control genotypes. Bioavailability estimates were similar between CF-KO and wild-type females but were unavailable for male mice, due to the large variability in plasma concentrations after oral administration and the difficulty estimating the area under the plasma curve when the terminal half-life suggested absorption rate-limited disposition. Potential mechanisms for the pharmacokinetic differences observed with omeprazole in CF-KO mice may be increased hepatic blood flow or an up-regulation of hepatic transporters. These results may provide support for using the CF-KO mouse as a model for the altered disposition of drugs in CF.
Footnotes
-
This study was funded in by the Cystic Fibrosis Foundation and an Under-graduate Research Fellowship in Pharmaceutics from the PhRMA Foundation.
-
ABBREVIATIONS: CF, cystic fibrosis; CF-KO, cftrtm1-UNC cystic fibrosis knockout mouse; Clb, blood clearance; CFTR, cystic fibrosis transmembrane conductance regulator protein; GERD, gastroesophageal reflux; AUC, area under the plasma concentration versus time curve; t1/2, half-life; Vd, volume of distribution; F, bioavailability; MDR-1, multidrug resistance protein-1; PSC-833, valspodar.
- Received March 10, 2004.
- Accepted May 28, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|