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

• Published in: Biological & pharmaceutical bulletin 2006, Vol.29(8), pp.1692-1699
• Main Authors: Mano, Yasunari, Tsukada, Hirotaka, Kurihara, Takeshi, Nomura, Masaaki, Yokogawa, Koichi, Miyamoto, Ken-ichi
• Format: Article
• Language: English
• Subjects: Animals; Carbon Tetrachloride - toxicity; Chronic Disease; chronic hepatic failure; disposition kinetics; dosage design; Liver - blood supply; Liver - metabolism; Liver Failure - metabolism; low/high-hepatic extraction drug; Male; Protein Binding; Rats; Rats, Wistar; Serum Albumin - metabolism; serum albumin concentration
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.29.1692

We have previously reported good correlations among serum aminotransferase (AST) activity, metabolic enzyme activity of CYPs, and total clearance (CLtot) of probe drugs in rats with acute hepatic failure induced by CCl4. 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 CCl4 (1 ml/kg, s.c., 3 times/week) and used at 48 h 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 (CLint), and the unbound fraction of drugs in plasma (fp) 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, CLtot was obtained. As a result of having evaluated this model using administration of cyclosporin, there was a statistically significant relationship between predicted CLtot and observed CLtot. 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.