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

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.

-c02h

Fig. 9.5 Structure of the thrombin inhibitor, napsagatran.

-c02h

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