薬物動態に基づく医薬品の安全性評価研究の推進

抄録

The objectives of pharmacokinetics and metabolic studies in drug safety evaluation is the drug absorption, the duration of drug exposure and the effects of multiple dose regimen on the pharmacokinetics in test animal species. There are many examples of drug to show little or no toxic event at extremely high dose level, which originate in low absorption or low bioavailability of the drug. A complicating situation can arise when the pharmacokinetic profile of the drug changes during repeated dosing due to such factors as enzyme induction, saturation of metabolism, accumulation of drug in the tissue, and renal excretion process. The toxic effect could also changed their pharmacokinetics during a toxicity testing. It is important to monitor a drug level during the toxicity testing. When toxicity cause depends on toxic metabolites or reactive intermediates, the plasma concentration of unchanged drug are difficult to correlate to the toxic efect. It is indispensable to evaluate the metabolic pathways and metabolic clearance of a durg under similar conditions of toxicity testing. These data may be useful for the interpretation of toxicological finding and their relevance to clinical safety evaluation.
Stereoselective pharmacokinetics and metabolic studies should be evaluated because of differences on the pharmacokinetics and metabolism of each enantiomer. Most of dihydropyridine calcium antagonists have one or more chiral centre, and the pharmacological activity between the enantiomers for these durg is known to be markedly different. The stereoselective pharmacokinetics of these drugs in animals, healthy subjects and patients should evaluated during the development process. Enantiomer-enantiomer interaction, enantiomeric inversion and the stereochemical aspects of pharmacokinetic drug interactions in these drugs should also be studied.