The In Vitroin Vivo Prediction

The challenge is to predict systemic clearance, volume of distribution, and oral bioavailability in man from a combination of in vitro and in vivo preclinical data. If this prediction can become reliable, then Phase I studies become more confirmatory. The use of human hepatocytes and isolated enzymes can form a critical part of the in vitro database.

Clearance of almost all drugs is by renal, metabolic, and/or biliary mechanisms. There are rare exceptions, such as anaesthetic gases that are exhaled unchanged. However, here we shall concentrate on the typical situation.

Physicochemical properties, especially lipophili-city, frequently govern the clearance route; lipophi-licity is commonly measured as log D7.4, where this variable equals log10 ([drug in octanol]/[drug in buffer]) at pH = 7.4, in a closed system at equilibrium. Generally compounds with a log D7 4 value below 0 have significant renal clearance values, whereas compounds with log D7 4 values above 0 will principally undergo metabolism (Smith et al 1996). Molecular size also has some effect on these clearance routes. For example, compounds with molecular weights greater than 400 Da are often eliminated through the bile unchanged, whilst smaller lipophilic compounds will generally be metabolized.

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