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36 Barratt MD, Cell Biol. Toxicol. 2000, 16, 1-13.
37 Hall AH, Toxicol. Lett. 1998, 102-103, 623-626.
38 Maran U, Karelson M, Katritzky AR, Quant. Struct. Activity Rel. 1999, 18, 3-10.
39 Vracko M, Novic M, Zupan J, Anal. Chim. Acta 1999, 384, 319-332.
40 Yang RSH, Thomas RS, Gustafson DL, Campain J, Benjamin SA, Verhaar HJM, Mumtaz MM, Environ. Health Perspect. 1998, 106 (Suppl.), 1385-1393.
122 | References
41 Cronin MTD, Pharm. Pharmacol. Commun. 1998, 4, 157-163.
42 Olson H, Betton G, Stritar J, Robinsin D, Toxicol. Lett. 1998, 102-103, 535-538.
43 Sina JF, Ann. Rep. Med. Chem. 1998, 33, 283-291.
44 Todd MD, Ulrich RG, Curr. Opin. Drug Discov. Dev. 1999, 2, 58-68.
45 Nuwaysir EF, Bittner M, Barrett JC, Afshari CA, Mol. Carcinogen. 1999, 24, 153-159.
46 Kitteringham NR, Powell H, Clement YN, Dodd CC, Tettey JNA, Pirmo-hamed M, Smith DA, McLellan LI,
Park BK, Hepatology 2000, 32, 321-333.
46 Burczynski ME, McMillian M, Ciervo J, Li L, Parker JB, Dunn RT, Hicken S, Farr S, Johnson MD, Toxicol. Sci. 2000, 58, 399-415.
47 Smith DA, Eur. J. Pharm. Sci. 2000, 11, 185-189.
Pharmacokinetics and Metabolism in Drug Design 123 Edited by D. A. Smith, H. van de Waterbeemd, D. K. Walker, R. Mannhold, H. Kubinyi, H. Timmerman I
Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-30197-6 (Hardcover); 3-527-60021-3 (Electronic)
BW Body weight
CYP2C9 Cytochrome P450 2C9 enzyme
GFR Glomerular filtration rate
MLP Maximum life span potential
P450 Cytochrome P450
TxRAs Thromboxane receptor antagonists
Maximum plasma concentration observed
Intrinsic clearance of unbound (free) drug
Oral unbound clearance (i.e. oral clearance correct for free fraction)
Fraction of plasma-bound drug
Fraction of drug unbound (to plasma proteins)
Fraction of unbound drug in tissues Natural logarithm Organ blood flow
Ratio of binding proteins in extracellular fluid (except plasma) to binding proteins in plasma Correlation coefficient Elimination half-life Volume of distribution Volume of extracellular fluid Volume of plasma Volume of remaining fluid
124 | 9 Inter-Species Scaling
9.1 Objectives of Inter-Species Scaling
Within the drug discovery setting, one of the principal aims of pharmacokinetic studies is to be able to estimate the likely pharmacokinetic behaviour of a new chemical entity in man. Only by doing this is it possible to establish whether a realistic dosing regimen may be achieved, in terms of both size and frequency of administration. Ultimately these factors will contribute to whether or not the compound can be used practically in the clinical setting and can thus be a successful drug. It is therefore important that pharmacokinetic data derived from laboratory animals can be extrapolated to man. Such extrapolations are at best only an estimate, but can provide valuable information to guide drug discovery programmes. Understanding the physiological processes which underlie the pharmacokinetic behaviour of a molecule will allow a more rational estimation of the profile in man.
When considering the likely pharmacokinetic profile of a novel compound in man, it is important to recognize the variability that may be encountered in the clinical setting. Animal pharmacokinetic studies are generally conducted in inbred animal colonies that tend to show minimal inter-subject variability. The human population contains a diverse genetic mix, without the additional variability introduced by age, disease states, environmental factors and co-medications. Hence any estimate of pharmacokinetic behaviour in man must be tempered by the expected inherent variability. For compounds with high metabolic clearance (e. g. midazolam), inter-individual variability in metabolic clearance can lead to greater than 10-fold variation in oral clearance and hence systemic exposure .
9.2 Allometric Scaling
Much of the inter-species variation in pharmacokinetic properties can be explained as a consequence of body size (allometry). Consequently it is possible to scale pharmacokinetic parameters to the organism’s individual anatomy, biochemistry and/or physiology in such a manner that differences between species are nullified. Several excellent reviews on allometric scaling are available in the literature [2-7]. Allometric relationships can be described by an equation of the general form:
Pharmacokinetic parameter = A • BW“ (9.1)
Where A is the coefficient (i.e. the intercept on the у-axis of logarithmically transformed data), BW is the body weight and a is the power function (slope of the line).
Volume of Distribution
When considering volume of distribution, an allometric relationship is not surprising as this value will be dependent upon the relative affinity for tissue compared to
9.2 Allometric Scaling 125
Fig. 9.1 Allometric relationship between body weight and volume of distribution of fluconazole.