Abstract
Purpose. To conduct a retrospective evaluation of using dog as ananimal model to study the fraction of oral dose absorbed (F) of 43drugs in humans and to briefly discuss potential factors that mighthave contributed to the observed differences in absorption.
Methods. Mean human and dog absorption data obtained under fastedstate of 43 drugs with markedly different physicochemical andpharmacological properties and with mean F values ranging from 0.015 to1.0 were obtained from the literature. Correlation of F values betweenhumans and dogs was studied. Based on the same references, additionalF data for humans and rats were also obtained for 18 drugs.
Results. Among the 43 drugs studied, 22 drugs were virtuallycompletely absorbed in both dogs and humans. However, the overallcorrelation was relatively poor (r2 = 0.5123) as compared to the earlier ratvs. human study on 64 drugs (r2 = 0.975). Several drugs showed muchbetter absorption in dogs than in humans. Marked differences in thenonliner absorption profiles between the two species were found forsome drugs. Also, some drugs had much longer Tmax values andprolonged absorption in humans than in dogs that might be theoreticallypredicted. Data on 18 drugs further support great similarity in F betweenhumans and rats reported earlier from our laboratory.
Conclusions. Although dog has been commonly employed as ananimal model for studying oral absorption in drug discovery anddevelopment, the present study suggests that one may need to exercise cautionin the interpretation of data obtained. Exact reasons for the observedinterspecies differences in oral absorption remain to be explored.
Similar content being viewed by others
REFERENCES
W. L. Chiou, and A. Barve. Linear correlation of the fraction of oral dose absorbed of 64 drugs between humans and rats. Pharm. Res. 15:1792-1795 (1998).
Physicians' Desk Reference, 51th edition, pp. 1187-1190, Medical Economics company, Montvale, NJ, 1997.
L. F. Lacey, E. K. Hussey, and P. A. Fowler. Single dose pharmacokinetics of sumatriptan in healthy volunteers. Eur. J. Clin. Pharmacol. 47:543-548 (1995)
M. Gibaldi and D. Perrier. Pharmacokinetics, 2nd ed., Marcel Dekker, Inc., New York and Basel, 1982
H. C. Krasny, P. D. Miranda, M. R. Blum, and G. B. Elion. Pharmacokinetics and bioavailability of acyclovir in the dog. J. Pharmacol. Exp. Ther. 216:281-288 (1981).
F. H. Hsu, T. Prueksaritanont, M. G. Lee, and W. L. Chiou. The phenomenon and cause of dose-dependent oral absorption of chlorothiazide in rats: Extrapolation to human data based on the body surface area concept. J. Pharmacokin. Biopharm. 15:369-383 (1987).
D. E. Reserarits and T. R. Bates. Apparent dose-dependent absorption of chlorothiazide in dogs. J. Pharmacokin. Biopharm. 7:463-470 (1979).
H. A. Ahr, M. Boberg, E. Brendel, H. P. Krause, and W. Steinke. Pharmacokinetics of miglitol: Absorption, distribution, metabolism, and excretion following administration to rats, dogs, and man. Arneim.-Forsch. 47:734-745 (1997).
K. Balon, B. U. Riebesehl, and B. W. Muller. Drug liposome partitioning as a tool for the prediction of human passive intestinal absorption. Pharm. Res. 16:882-888 (1999).
Y. L. He, S. Murby, G. Warhurst, L. Gifford, D. Walker, J. Ayrton, R. Eastmond, and M. Rowland. Species differences in size discrimination in the paracellular pathway reflected by oral bioavailability of poly(ethylene glycol) and D-peptides. J. Pharm. Sci. 87:626-633 (1998).
J. Dreyfuss, J. M. Shaw, and J. J. Ross. Absorption of the β-adrenergic-blocking agent, nadolol, by mice, rats, hamsters, rabbits, dogs, monkeys, and man: An unusual species difference. Xenobiotica 8:503-508 (1978)
L. Z. Benet. Pharmacokinetics/pharmacodynamics of furosemide in man: A review. J. Pharmacokin. Biopharm. 7:1-27 (1979)
J. McAinsh and B. F. Holmes. Pharmacokinetic studies with atenolol in the dog. Biopharm. Drug Dispos. 4:249-261 (1983).
T. R. Marten, G. R. Bourne, G. S. Miles, B. Shuker, H. D. Rankine, and V. N. Dutka. The metabolism of ICI 118,587, a partial agoinst of ?1-adrenoceptors, in mice, rats, rabbits, dogs, and humans. Drug Metab. Dispos 12:652-660 (1984)
U. Fagerholm, M. Johansson, and H. Lennernäs. Comparison between permeability coefficients in rat and human jejunum. Pharm. Res. 13:1336-1342 (1996)
T. T. Kararli. Comparison of the gastrointestinal anatomy, physiology and biochemistry of humans and commonly used laboratory animals. Biopharm. Drug Dispos. 16:351-380 (1995).
J. B. Dressman. Comparison of canine and human gastrointestinal physiology. Pharm. Res. 3:123-131 (1986).
J. H. Lin. Species similarities and differences in pharmacokinetics. Drug. Metab. Dispos. 23:1008-1021 (1995).
T. Prueksaritanont and W. L. Chiou. Absorption of iothalamate after oral administration: A preliminary study in humans and interspecies differences. Biopharm. Drug Dispos. 8:99-101 (1987).
W. L. Chiou. New perspectives on the theory of permeability and resistance in the study of drug transport and absorption. J. Pharmacokin. Biopharm. 24:433-442 (1996).
J. A. Scatina, D. R. Hicks, M. Kraml, and M. N. Cayen. Metabolic disposition and pharmacokinetics of pelrinone, a new cardiotonic drug, in laboratory animals and man. Eur. J. Drug Metab. Pharmacokin. 15:37-48 (1990).
F. L. S. Tse. Pharmacokinetics in drug discovery and development. Chapter 12 in “Pharmacokinetics: Regulatory, Industrial, Academic Perspectives”, 2nd Ed., edited by P. G. Welling and F. L. S. Tse. Marcel Dekker, Inc., New York, NY, 1995.
E. H. Ulm. Enalapril maleate (MK-421), a potent, nonsulfhydryl angiotensin-converting enzyme inhibitor: Absorption, disposition and metabolism in man. Drug. Metab. Rev. 14:99-110 (1983).
D. I. Friedman and G. L. Amidon. Passive and carrier-mediated intestinal absorption components of two angiotensin converting enzyme (ACE) inhibitor prodrugs in rats: Enalapril and fosinopril. Pharm. Res. 6:1043-1047 (1989).
D. C. Garg, D. J. Weidler, and F. N. Eshelman. Ranitidine bioavailability and kinetics in normal male subjects. Clin. Pharmacol. Ther. 33:445-452 (1983).
P. J. Eddershaw, A. P. Chadwick, D. M. Higton, S. H. Fenwick, P. Linacre, W. N. Jenner, J. A. Bell, and G. R. Manchee. Absorption and disposition of ranitidine hydrochloride in rat and dog. Xenobiotica 26:947-956 (1996).
C. M. Dixon, D. A. Saynor, P. D. Andrew, J. Oxford, A. Bradbury, and M. H. Tarbit. Disposition of sumatriptan in laboratory animals and humans. Drug Metab. Dispos. 21:761-769 (1993).
J. D. Fitzgerald, R. Ruffin, K. G. Smedstad, R. Roberts, and J. McAinsh. Studies on the pharmacokinetics and pharmacodynamics of atenolol in man. Eur. J. Clin. Pharmacol. 13:81-89 (1978).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Chiou, W.L., Jeong, H.Y., Chung, S.M. et al. Evaluation of Using Dog as an Animal Model to Study the Fraction of Oral Dose Absorbed of 43 Drugs in Humans. Pharm Res 17, 135–140 (2000). https://doi.org/10.1023/A:1007552927404
Issue Date:
DOI: https://doi.org/10.1023/A:1007552927404