Pharmacokinetic changes of drugs in a rat model of liver cirrhosis induced by dimethylnitrosamine, alone and in combination with diabetes mellitus induced by streptozotocin

Abstract

Rats with liver cirrhosis induced by N-dimethylnitrosamine (LC) and rats with LC with diabetes mellitus induced by streptozotocin (LCD) have been developed as animal models for human liver cirrhosis and liver cirrhosis with diabetes mellitus, respectively. Changes in the pharmacokinetics of drugs (mainly non-renal clearance, CL NR ) in LC and LCD rats reported in the literature compared with respective control rats were reviewed. This review mainly explains the changes in the CL NR s of drugs (which are mainly metabolized via hepatic microsomal cytochrome P450s, CYPs) in LC and LCD rats, in terms of the changes in in vitro hepatic intrinsic clearance (CL int ; mainly due to the changes in CYPs in the disease state), free (unbound) fraction of a drug in the plasma (f p ) and hepatic blood flow rate (Q H ) depending on the hepatic excretion ratio of the drug. Generally, changes in the CL NR s of drugs in LC and LCD rats could be well explained by the above-mentioned three factors. The mechanism of urinary excretion of drugs (such as glomerular filtration or renal active secretion or reabsorption) in LC and LCD rats is also discussed. The pharmacokinetics of the drugs reported in the LC and LCD rats were scarce in humans. Thus, the present rat data should be extrapolated carefully to humans.