Renal Clearance and Drug Design

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 D7 4 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. 

Copyright 2001 Wiley-VCH Verlag GmbH ISBNs 3-527-30197-6 (Hardcover) 3-527-60021-3 (Electronic) 

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