RATIONALIZATION OF TWO DOSAGE FORMS OF A MODEL COMPOUND ALPRAZOLAM, BASED ON PHARMACO- METABONOMIC CRITERION

摘要

Differences in metabolic patterns as result of genotype variations or environmental factors have been known to alter drug efficacies and adverse reactions of drug molecules and attempts are being made to individualize drug dosages. Important amongst these are differences in drug effects due to pre-systemic metabolism arising out of different routes of administration particularly for those drugs which are subject to significant degree of first pass metabolism. For such compounds assessment of pre-systemic metabolism is difficult and subject to assumptions which are not always valid.(eg. approximate amounts of hepatic blood flow, 100% absorption, the entire amount of drug being metabolized in the liver etc). Here through pharmaco-metabonomic studies and comparison of responses we have rationalized doses and estimated the effect of differences in metabolism (effect of pre-systemic metabolism ) on two dosage forms of a model compound alprazolam which to a significant degree is metabolized in the liver. We find that differences in metabolic pathways have significant effects on drug responses and conclude that rationalization of doses can be used to design more individualized, effective and safer dosage forms particularly in cases where genomic and metabolic factors show greater risk of adverse effects and for drugs with narrow therapeutic margins