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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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Fig. 5.5 Metabolism of SM-10888, involving phase 1 and phase 2 metabolic processes.
5.4 Role of Lipophilicity in Drug Clearance 63
Fig. 5.6 Relationship between lipophilicity and renal clearance for SM-10888 and its metabolites. 5.4
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-
64 5 Clearance
Fig. 5.7 Relationship between lipophilicity and unbound renal (squares) and metabolic clearance (triangles) for a range of neutral drugs in man.
creasing log D and this becomes the major clearance route of lipophilic compounds. Noticeably, considering the logarithmic scale in Figure 5.7, overall clearance declines with decreasing lipophilicity. The lowest clearances, achieved by the combined renal and metabolic processes, are observed below log D74 values of 0 where metabolic clearance is negligible. This apparent advantage needs to be offset against the disadvantages of reliance on gastrointestinal absorption via the aqueous pore pathway that will tend to predominate for hydrophilic compounds. Moreover the actual potency of the compound is also normally affected by lipophilicity with potency tending to increase with increasing lipophilicity [5]. Furthermore as shown previously, volume of distribution also increases with increasing lipophilicity and hence tends to increase the elimination half-life (fy2 = 0.693 x Vd/Cl). Therefore the duration of the drug in the system is a fine balance between the relationship of lipophilicity and its effects on volume of distribution and clearance.
This balance is illustrated by reference to two р-adrenoceptor antagonists, atenolol and propranolol [6]. These have differing physicochemical properties. Atenolol is a hydrophilic compound which shows reduced absorption, low clearance predominantly by the renal route and a moderate volume of distribution. Note that absorption by the paracellular route is still high, due to the small size of this class of agent. In contrast, propranolol, a moderately lipophilic compound, shows high absorption, high clearance via metabolism and a large volume of distribution. Because of this balance of properties both compounds exhibit very similar elimination half-lives. These half-lives are sufficiently long for both drugs to be administered on twice daily
Tab. 5.1 Physicochemical, pharmacological and pharmacokinetic properties for atenolol and propranolol illustrating their interdependence.
Log Affinity Absorption Oral clearance Volume of Half-life
D7.4 (nM) (%) (unbound) mL min-1 kg-1 distribution (unbound) Lkg-1 (h)
Atenolol -1.9 100 50 4 0.8 3-5
Propranolol 1.1 4 100 700 51 3-5
Fig. 5.8 Analysis of marketed oral drugs and their lipophilic properties.
(b. d.) dosage regimens due to the relatively flat dose-response curves of this class of agent (Table 5.1).
Propranolol is considerably more potent (albeit less selective) than atenolol. Thus despite a much higher clearance than atenolol, both agents have a daily clinical dose size of around 25-100 mg.
Optimal properties may reside over a span of lipophilicities as illustrated by the р-adrenoreceptor antagonists. However analysis of over 200 marketed oral drugs illustrates the distribution shown in Figure 5.8, where most drugs reside in the “middle ground” of physiochemical properties with log D74 values in the range 0 to 3. This is probably a result of good fortune rather than design, but intuitively it fits with the idea of maximizing oral potency, absorption and duration by balancing intrinsic potency, dissolution, membrane transfer, distribution and metabolism.
1 Muller M, Jansen, PLM, Am. J. Physiol. 1997, 272, G1285-G1303.
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