Hepatic Drug-Metabolizing Enzyme Induction and Implications for Preclinical and Clinical Risk Assessment

Abstract

Hepatic drug metabolizing enzyme (DME) induction complicates the development of new drugs owing to altered efficacy of concomitant treatments, reduction in exposure resulting from autoinduction, and potential generation of toxic metabolites. Risk assessment of DME induction during clinical evaluation is confounded by several uncertainties pertaining to hazard identification and dose response analysis. Hepatic DME induction rarely leads to clinical evidence of altered metabolism and toxicity in the patient, which typically occur only if the DME induction is relatively severe. High drug doses are associated with a greater likelihood of hepatic DME induction and downstream effects; therefore, drugs of low potency requiring higher dosing tend to lead to a greater risk of drug-drug interactions. Vigilance in clinical trials for increased or diminished drug effect and, specifically, pharmacokinetic studies in the presence of other drugs and concomitant diseases are necessary for a drug risk assessment profile.Efforts to remove hepatic DME-inducing drugs from development can be facilitated with current in vitro and in vivo assessments and will improve with the development of newer technologies. A carefully tailored case-by-case approach will lead to the development of efficacious drugs with an acceptable risk/benefit profile available to patients.

High Daily Dose and Being a Substrate of Cytochrome P450 Enzymes Are Two Important Predictors of Drug-Induced Liver Injury

“…Inhibitory effects usually occur immediately; however, induction of P450 enzymes is usually both time-and dose-dependent (Markowitz et al, 2003), which will lead to a delay before enzyme activity increases depending on the duration of exposure and half-life of the inducer in the liver. Consequently, induction of hepatic P450 enzymes rarely leads to altered metabolism and toxicity in the patient, which typically occurs only if the induction is very extensive (Mohutsky et al, 2010). For example, three drugs were recorded by the U.S. FDA as potent P450 inducers (i.e., carbamazepine, phenytoin, and rifampin; (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ ucm093664.htm).…”

Noscapine recirculates enterohepatically and induces self-clearance

“…Often, in cases where drugs are co-administered with xenobiotics, accelerated clearance of the drugs is observed due to drug-drug/herb interactions (Mohutsky et al, 2010). If one of the co-administered drugs is an inhibitor of the particular CYP enzyme responsible for metabolism of the other drug, it may lead to an increase in the exposure of the latter.…”

“…If one of the co-administered drugs is an inhibitor of the particular CYP enzyme responsible for metabolism of the other drug, it may lead to an increase in the exposure of the latter. Drug-drug interactions may also occur if one drug induces the CYP enzyme responsible for clearance of another drug, leading to therapeutic failure (Mohutsky et al, 2010). There also exists a possibility of auto-induction of the metabolizing enzymes by the drug administered.…”

Agents and drugs: precautions in patients with cirrhosis

“…Here, biotransformation takes place by the action of multiple drug-metabolizing enzymes including microsomal cytochrome P450 isoenzymes, mixed-function monooxygenases, glutathione-S-transferases, and UDPglucuronosyltransferases, to name but a few. Some of these can be induced through variable mechanisms which may lead to large interindividual variability in pharmacokinetics and susceptibility for drug-related liver damage [2]. Obviously, the capacity to handle drugs can be hampered with a reduced compartment of metabolically active liver cells such as in severe acute or chronic liver injury.…”

“…In addition, patients with hepatic dysfunction may also be more sensitive to the effects, both desired and adverse, of several drugs, and tolerate an event of drug-induced liver injury (DILI) less well than individuals without pre-existing liver diseases. However, only few methods are available for the assessment of the metabolic function of the liver, and among those that are established, all capture only a proportion of the liver's function [2]. Avoiding known hepatotoxins and adjustment of dosage of drugs without intrinsic hepatotoxicity in patients with liver dysfunction may therefore be required to avoid excessive accumulation of the drug, active drug metabolite(s) thereof, and subsequent adverse effects, either hepatic or extrahepatic.…”