Oral absorption of CGS-20625, an insoluble drug, in dogs and man
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
Oral bioavailability of highly water-insoluble drugs is often quite limited and variable, requiring the development of improved formulations. Animal models are an essential aspect of the design and testing of such formulations designed to improve absorption in man. The present report compares the absorption of CGS-20625, an insoluble drug, in dog and man after oral administration of the drug as a powder, a solid dispersion capsule, and after gastric and duodenal administration in PEG 400 solution. CGS-20625 powder (20 mg) given orally exhibited slow, delayed absorption in both dog and man, with aC max of 0.26±0.07 μg/ml atT max of 3 hr in dog, and 0.01±0.004 μg/ml at 2 hr in man. Administration of CGS-20625 in PEG 400 solution improved absorption in dog and man, with aC max of 1.2±0.10 μg/ml atT max of 0.25 hr in dog, and aC max of 0.10±0.04 μg/ml at 0.5 hr in man.T max after administration of the hard gelatin capsule formulation was 0.9 and 1.0 hr in dog and man, withC max of 0.89±0.16 and 0.052±0.014 μg/ml, respectively. Absolute bioavailability of CGS-20625 powder in the dog was 0.67±0.21, whereas the bioavailabilities of the powder and the capsule relative to the PEG 400 solution were 0.84 and 1.1, respectively, in dog, and 0.41 and 0.85 respectively, in man. No significant benefits of duodenal administration were observed. Plasma levels were approximately 10-fold greater and oral clearance was approximately 5-fold less in the dog than in man. Furthermore, pharmacokinetic data were less variable and relative bioavailability was greater in dogs than in humans. Physiological factors in the gastrointestinal tract or greater first-pass metabolism in man may account for these species differences. The relative rate and extent of CGS-20625 absorption were similar between dog and man, in the order of powder
- W. A. Cressman and D. Sumner. The dog as a model for evaluation of nondisintegrating sustained-release tablets.J. Pharm. Sci. 60:132–134 (1971).
- T. T. Kararli and J. Stolzenbach. Rate-limiting steps in oral absorption of a leucotriene D4 antagonist in the beagle dog.J. Pharm. Sci. 81:875–878 (1992).
- E. Rosen, T. Ellison, P. Tannenbaum, S. M. Free, and A. P. Crosley, Jr. Comparative study in man and dog of the absorption and excretion of dextroamphetamine-14C sulfate in sustained-release and nonsustained-release dosage forms.J. Pharm. Sci. 56:365–369 (1967).
- J. B. Dressman. Comparison of canine and human gastrointestinal physiology.Pharm. Res. 3:123–131 (1986). CrossRef
- C. Y. Lui, G. L. Amidon, R. R. Berardi, D. Fleisher, C. A. Youngberg, and J. B. Dressman. Comparison of gastrointestinal pH in dogs and humans: Implications on the use of the beagle dog as a model for oral absorption in humans.J. Pharm. Sci. 75:271–274 (1986).
- L. A. Brunner and R. C. Luders. Determination of a potential anxiolytic drug (CGS 20625) in human plasma by high-performance liquid chromatography.J. Chromatog. 568:487–493 (1991).
- U.S. Pharmacopeia XXI.NF XVI, US Pharmacopeial Comvention Inc., Rockville, MD, 1985, p. 1243.
- Statistical Consultants, Inc. PCNONLIN and NONLIN: software for the statistical analysis of nonlinear models.Am. Statist. 40:52 (1986).
- J. G. Wagner.Fundamentals of Clinical Pharmacokinetics. Drug Intelligence Publications, Inc., Hamilton, IL, 1979, p. 71.
- J. C. K. Loo, and S. Riegelman. New method for calculating the intrinsic absorption rate of drugs.J. Pharm. Sci. 57:918–928 (1968).
- Oral absorption of CGS-20625, an insoluble drug, in dogs and man
Journal of Pharmacokinetics and Biopharmaceutics
Volume 23, Issue 1 , pp 11-23
- Cover Date
- Print ISSN
- Online ISSN
- Kluwer Academic Publishers-Plenum Publishers
- Additional Links
- insoluble drugs
- oral absorption
- animal model
- Industry Sectors
- Author Affiliations
- 1. Basic Pharmaceutics Research, Pharmaceuticals Division, Ciba-Geigy Corporation, 10502, Ardsley, New York
- 2. Bioanalytics and Pharmacokinetics, Pharmaceuticals Division, Ciba-Geigy Corporation, 10502, Ardsley, New York