What Exactly is Drug Metabolism?
Drug metabolism is the process by which drug molecules are chemically altered, usually to more polar metabolites with increased water solubility which facilitates elimination in urine or bile and/or increased access to excretory transporters. The liver is quantitatively and qualitatively the most important site of drug metabolism with smooth endoplasmic reticulum of the hepatocyte being the principal site of metabolism in the liver and enzymes being located within the microsomes.
An Endless Array of Drug Substrates
One of the most unique features of hepatic drug metabolizing pathways is their ability to cope with a seemingly endless array of drug substrates. Thus, many of the newer fully synthetic drugs that have no close structural counterparts in nature are successfully metabolized by the liver and irreversibly removed or ‘cleared’ from the body. This broad substrate recognition is achieved by the presence of multiple drug metabolizing enzymes in the hepatocyte, and many can metabolize multiple substrates.
The CYP Gene System
The largest family of membrane-bound, nonspecific, mixed-function enzymes is called the cytochrome P450 system (CYP) which are the predominant catalysts of phase I metabolism in the liver. CYP comprise a gene superfamily with 57 members in the human genome. A subset of approximately 15 CYP enzymes belonging to the CYP1, 2 and 3 gene families mediates 70–80% of all phase I-dependent metabolism of therapeutic drugs. Some important drug-metabolizing CYPs such as CYP3A4 are predominantly expressed in pericentral hepatocytes. In addition to cytochrome P450 enzymes, there are other enzymes in the liver which are involved in the drug metabolism which include, esterases and flavin-containing mono-oxygenases, etc.
Liver Blood Flow is Key
Several factors affect the drug metabolism in liver with most important factors being, hepatic blood ﬂow, which determines the rate at which drugs are delivered to the liver; binding to plasma proteins, as only unbound drug can be taken up by hepatocytes; afﬁnity for hepatocyte uptake transporters; and the intrinsic afﬁnity of hepatic enzymes for the drug as a substrate. The relative importance of these factors varies greatly for individual drugs, with hepatic blood ﬂow being the main determinant of the rate of metabolism for very high metabolic clearance drugs and the other factors assuming more importance for drugs with low metabolic clearance.
Inhibition and Interaction
At the level of hepatic drug metabolism, the two mechanisms of drug–drug interactions are induction and inhibition of drug metabolizing enzymes. Inductive drug–drug interactions occur when an inducing drug causes an increase in the metabolism of co-administered drugs with a resultant diminution in their therapeutic effect. The most important enzyme affected by this form of interaction is CYP3A4 because of the potential magnitude of its induction and the vast array of drugs metabolized by this P450 enzyme. Inhibition of metabolism by co-administered drugs is also a common cause of drug– drug interactions and occurs by two basic mechanisms. The most common mechanism of inhibition is simple competition between drugs for access to the catalytic pocket of the relevant drug-metabolizing enzyme. The second way in which drugs inhibit P450s, often referred to as ‘mechanism-based P450 inhibition’, involves the formation of a catalytically inactive, covalently bound complex between a metabolite of the substrate drug and the P450 enzyme.
Avoid Liver Toxicity with Pharmacogenetic Testing
Drug metabolism also contributes to both dose-related and idiosyncratic drug-induced hepatotoxicity. Paracetamol is a classic example of dose-related toxicity. In advanced liver disease, drug metabolism mediated by some P450 enzymes or enzyme subfamilies, particularly CYP1A, 2C19 and 3A. Pharmacogenetic testing with Rxight® is based on the analysis of over 50 alleles and 18 genes and is designed to determine how well you might metabolize an array of medications across over 50 pharmacological classes.