Role of Lipophilicity in Drug Clearance

Most of these steps result in a reduction in lipophilicity compared to the parent molecule. These reductions in lipophilicity lead to increased renal clearance and effectively permit the voiding of the dose from the body as illustrated in Figure 5.6.

This demonstrates the interaction between metabolic and renal clearance. Assuming that SM-10888 is the only pharmacologically active moiety, these processes govern the clearance of active drug and hence determine the required dose. In fact, only the formation of the N-glucuronide and the benzylic hydroxyl metabolites are of prime concern to the medicinal chemist. These represent the primary clearance routes of the compound and hence govern the rate of clearance and ultimately the dosage regimen needed to obtain a particular plasma concentration of the active compound, SM-10888 in this example.

Rather than looking at a metabolic pathway, similar models for the control of the mechanism of clearance by lipophilicity are demonstrated by considering drugs in general. Figure 5.7 illustrates free drug renal and metabolic clearance for a series of neutral compounds drawn from the literature [4].

For hydrophilic drugs (log D74 below 0) renal clearance is the predominant mechanism. For drugs with log D74 values above 0, renal clearance decreases with lipophilicity. In contrast to renal clearance, metabolic clearance increases with in-


Fig. 5.7 Relationship between lipophilicity and unbound renal (squares) and metabolic clearance (triangles) for a range of neutral drugs in man.

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