Development of Dosage Design of Hepatic Metabolizing Drugs Using Serum Albumin Level in Chronic Hepatic Failure(Biopharmacy)

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We have previously reported good correlations among serum aminotransferase (AST) activity, metabolic enzyme activity of CYPs, and total clearance (CL_<tot>) of probe drugs in rats with acute hepatic failure induced by CCl_<4・> In this study, we searched for new biochemical indicators that correlate with hepatic function and tried to simulate appropriate drug dosage in chronic hepatic failure. Model rats were prepared by administration of CCl_4 (1ml/kg, s.c., 3 times/week) and used at 48h after the last administration. Serum albumin concentration was time-dependently decreased and correlated well with 3 major biologic determinants of drug clearance, hepatic blood flow (HBF), intrinsic clearance (CL_<int>), and the unbound fraction of drugs in plasma (f_p) after intravenous administration of cyclophospamide, tolbutamide, zonisamide, and chlorzoxazone (as probe drugs for low hepatic extraction) and propanolol and lidocaine (as high-hepatic extraction drugs). By calculating these parameters based on prediction equations by the level of albumin, CL_<tot> was obtained. As a result of having evaluated this model using administration of cyclosporin, there was a statistically significant relationship between predicted CL_<tot> and observed CL_<tot>. In conclusion, the value of serum albumin level is a useful parameter that correlates well with chronic hepatic function. We have shown that this quantitative administering design using serum albumin level can predict appropriate dosages of hepatic metabolizing drugs in chronic hepatic failure.
公益社団法人日本薬学会の論文
2006-08-01

Development of Dosage Design of Hepatic Metabolizing Drugs Using Serum Albumin Level in Chronic Hepatic Failure(Biopharmacy)

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