Mechanisms of Hepatic Transport of Drugs: Implications for Cholestatic Drug Reactions

Abstract

Hepatocellular and canalicular transport proteins are major determinants of the hepatic uptake and biliary excretion of xenobiotics and their metabolites. Recent advances in molecular cloning have resulted in the characterization of many of these transport systems. These advances have enabled the identification of a number of drugs that are substrates for the transporters, and it has facilitated studies of mechanisms of drug-induced cholestasis. This review summarizes the normal function of hepatobiliary transporters and their alteration by drugs or other foreign compounds. Although most of these investigations have been performed in animal models of drug-induced cholestasis, the application to human forms of drug-induced cholestasis is also discussed when possible. One important finding is that genetic polymorphisms can result in changes in drug transporter expression and function that could increase susceptibility to cholestatic drug reactions.

Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone

“…Alternative or additional effects of troglitazone include inhibition of a key bile transporter, bile salt export protein [45,46]. This inhibition can therefore contribute substantially to the cholestasis that was often seen.…”

“…Attributes unique to troglitazone include the presence of a pro-oxidant phenoxyl radical-forming chroman ring. Finally, inhibition of bile salt export protein has been demonstrated only with troglitazone [45].…”

Troglitazone and liver injury

“…93 For example, rifampicin inhibits Bsep in experimental studies 94 but ameliorates pruritus (induced by bile acids) in patients with cholestasis. 93,95 This effect is achieved through the stimulation of CYP3A4 activity by rifampicin. 96 In turn, 6-␣ hydroxylation of bile acids by CYP3A4 and subsequent conjugation at C6 by UDP-glucuronosyltransferase increases the renal clearance of bile acids.…”

Pain Management in the Cirrhotic Patient: The Clinical Challenge

“…2 In patients with severe cholestasis, the clearance of drugs with high biliary elimination, such as buprenorphine, may also be compromised because of dysfunction of basolateral and/or apical transmembrane transport systems in hepatocytes, requiring dose reduction or avoidance of use of the drug. 4,6,7 dosing of analgesic drugs with a predominant renal elimination may require adjustment in patients with liver disease (Table 1). Cirrhotic patients often have impaired renal function despite a normal serum creatinine level because of poor nutrition and reduced muscle mass resulting in less creatinine production.…”