Renal Clearance and Drug Design

Small molecules with relatively simple structures (molecular weights below 350) can successfully combine paracellular absorption and renal clearance. Table 6.1 lists examples of this. Noticeably the compounds are all peripherally acting G-protein-cou-pled receptor antagonists. When a compound has to cross membrane barriers to access an intracellular target (see Chapter 2, Section 2.10) or cross the blood-brain barrier, then these physicochemical properties are generally unsuitable. It is possible to design molecules of high metabolic stability that "defy" the general trends shown in Figure 5.7 of Chapter 5.

Fluconazole (Figure 6.5) is an example where knowledge of the relationship between physicochemical properties and drug disposition has allowed optimization of the drug's performance [3]. The project's goal was a superior compound to ketocona-zole, the first orally active azole antifungal drug. Ketoconazole (Figure 6.5) is cleared primarily by hepatic metabolism and shows irregular bioavailability, due partly to

Fig. 6.5 Structures of the antifungal agents, ketoconazole and fluconazole.

ketoconazole II fluconazole

Fig. 6.5 Structures of the antifungal agents, ketoconazole and fluconazole.

this, and also its poor aqueous solubility and consequent erratic dissolution. Ketoconazole is a neutral molecule with a log D74 value greater then 4.0. Its high lipophilicity leads to its dependence on metabolic clearance and its low solubility.

Synthesis was directed towards metabolic stability and this was found in the bis-triazole series of compounds. Metabolic stability is achieved by the relative resistance of the triazole moiety to oxidative attack, the presence of halogen functions on the phenyl grouping, another site of possible oxidative attack, and steric hindrance of the hydroxy function, a site for possible conjugation.

Due to the metabolic stability, low molecular weight and absence of ionization at physiological pH, fluconazole has to rely on renal clearance as its major clearance mechanism. The compound has a log P or D74 value of 0.5, which means following filtration at the glomerulus a substantial proportion (80 %) of the compound in the filtrate will undergo tubular reabsorption. The resultant low rate of renal clearance gives fluconazole a 30-h half-life in man and is consequently suitable for once-a-day administration.


1 Ullrich KJ, Biochim. Biophys. Acta 1994, 1197, 45-62.

2 Walker DK, Beaumont KC, Stopher DA, Smith, DA, Xenobiotica 1996, 26, 1101-1111.

3 Smith DA, Jones BC, Walker DK, Med. Res. Rev. 1996, 16, 243-266.

Pharmacokinetics and Metabolism in Drug Design 75 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)

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