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Methods and Principles in Medicinal Chemistry - Mannhold R.

Mannhold R., Kubinyi H., Timmerman H. Methods and Principles in Medicinal Chemistry - Wiley-VCH, 2001. - 155 p.
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Cls = Cli ■ Q/(Clj + Q)
9.5 Inter-Species Scaling for Clearance by Hepatic Uptake 1129
The equation can be solved for intrinsic clearance (Clj) based upon systemic clearance (Cls) obtained after i.v. administration and hepatic blood flow (Q) in the test species. Intrinsic clearance in man can then be estimated based upon relative in vitro microsomal stability and the equation solved to provide an estimate for human systemic clearance. Hence this approach combines allometry (by considering differences in organ blood flow) and species-specific differences in metabolic clearance.
The incorporation of in vitro metabolism data into allometric scaling of compounds cleared by hepatic metabolism has been extensively evaluated [18] and shown to accurately predict human clearance. In this review it is suggested that the utility of such methods are most appropriately applied in drug candidate selection, to confirm early estimates and to support early clinical studies.
The inclusion of relative metabolic stability in animal and human hepatocytes in allometric scaling for 10 metabolically cleared compounds has been detailed [19]. In this study, the correction for species differences in metabolic rate resulted in extrapolated human clearance values within two-fold of those observed. In contrast extrapolations based on simple allometry or incorporating a correction for brain weight gave up to 10-fold errors on the extrapolated values. Again in these approaches to scaling, differences in plasma protein binding can be incorporated using the equation:
Cli = Cliu- fu (9.4)
where fu is the fraction unbound in plasma of the relevant species. Extrapolation based on unbound drug clearance is generally the approach of choice for estimating metabolic clearance in man prior to progressing a compound into clinical trials [20].
A comparison of various inter-species scaling methods was conducted for the en-dothelin antagonist, bosentan [21]. This compound is eliminated mainly through metabolism. Simple, direct allometric scaling based on five animal species provided a relatively poor correlation coefficient (r2) of 0.525. Whilst the r2 value was greatly improved (0.895) by correcting for brain weight, this gave a relatively poor prediction of human clearance of 44 mL min-1 versus an actual value of 140 mL min-1. The best r2 value (0.976) was obtained by correcting for rates of metabolism in liver hepato-cytes from the various species and this also provided a relatively good prediction of human clearance at 100 mL min-1. Whilst the correlation coefficient was inferior when incorporating metabolic stability in liver microsomes (0.725) instead of hepa-tocytes, this also provided a good estimate of human clearance at 126 mL min-1. In this example no account was taken of plasma protein binding differences between species.
9.5 Inter-Species Scaling for Clearance by Hepatic Uptake
When transporter proteins are involved in the rate-determining step of compound clearance, there is clearly the potential for species differences to exist which are not related to allometry. Given the large (and growing) number of transporter proteins
130 9 Inter-Species Scaling
implicated in the removal of drugs from the systemic circulation (see Chapter 5) there exists the possibility for divergent substrate specificity in the various laboratory animal species and man.
Organic anions have frequently been implicated as substrates for transporters in the sinusoidal membrane of the liver. This was illustrated for a series of TxRAs, where hepatic uptake was identified as the rate-determining step in the clearance process [22]. A representative compound from this series, UK-147,535 (Figure 9.3), was progressed to clinical trials [23]. It is thus possible to contrast clearance of this compound between a number of species including man (Figure 9.4).
Fig. 9.4 Allometric relation-100 ship for clearance of UK-147,535 in various species.
As observed in Figure 9.4 the intrinsic clearance (as represented by oral unbound clearance Clou) of UK-147,535 shows an allometric relationship between the rat, dog and man. This would indicate that the transporter protein involved is conserved across these species and has similar affinity. However, marked reduction in clearance in the rabbit suggests the absence, or marked alteration, of the responsible protein in the hepatic sinusoidal membrane of this species. This finding may explain the common observation of reduced biliary excretion of acidic compounds in rabbits compared to other species [24, 25].
It remains to be established whether other transporter proteins for other drug classes (e. g. cations) are conserved between species. Active transport processes are believed to be involved in the renal and hepatic clearance of the zwitterionic throm-
Fig. 9.5 Structure of the thrombin inhibitor, napsagatran.
9.6 Elimination Half-life 1131
bin inhibitor, napsagatran (Figure 9.5). Allometric scaling based on pharmacokinetic data from the rat, rabbit, monkey and dog overestimated total clearance, non-renal clearance and volume of distribution in man by 3-, 7- and 2-fold respectively. As napsagatran is not metabolized in vitro or in vivo, this would suggest that species differences in the transport proteins involved in the clearance of napsagatran, especially the protein responsible for hepatic uptake across the sinusoidal membrane, compromise the kinetic extrapolations from animals to man. Notably, amongst the individual species investigated, the monkey was most predictive of human clearance and volume of distribution [26].
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