Metabolism and Excretion of Drugs

⇒Both metabolism and excretion can be viewed as processes responsible for elimination of drug (parent and metabolite) from the body. Drug metabolism changes the chemical structure of a drug to produce a drug metabolite, which is frequently but not universally less pharmacologically active. Metabolism also renders the drug compound more water soluble and therefore more easily excreted.

Drug excreation

⇒Drug metabolism reactions are carried out by enzyme systems that evolved over time to protect the body from exogenous chemicals. The enzyme systems for this purpose for the most part can be grouped into two categories: phase I oxidative or reductive enzymes and phase II conjugative enzymes. Enzymes within these categories exhibit some limited specificity in relation to the substrates acted upon; a given enzyme may interact with only a limited number of drugs.Some nonspecific hydrolytic enzymes, such as esterases and amidases, have not received much research attention. The focus of this discussion therefore is on phase I and phase II reactions and the enzymes that carry out these                                                                             processes.

MEtabolism of drugs

⇒The cytochrome P450 (CYP450) enzyme superfamily is the primary phase I enzyme system involved in the oxidative metabolism of drugs and other chemicals.These enzymes also are responsible for all or part of the metabolism and synthesis of a number of endogenous compounds,such as steroid hormones and prostaglandins. 

⇉Substrate Specificity of the CYP Enzymes፦

                                                                 CYP3A4 is thought to be the most predominant CYP isoform involved in human drug metabolism, both in terms of the amount of enzyme in the liver and the variety of drugs that are substrates for this enzyme isoform.

⇒This isoform may account for more than 50% of all CYP-mediated drug oxidation reactions,and CYP3A4 is likely to be involved in the greatest number of drug–drug interactions. The active site of CYP3A4 is thought to be large relative to other isoforms, as evidenced by its ability to accept substrates up to a molecular weight of 1200 (e.g., cyclosporine). 

⇒This active site size allows drugs with substantial variation in molecular structure to bind within the active site.However,the fact that two drugs are metabolized predominantly by CYP3A4 does not mean that coadministration will result in a drug–drug interaction, since drugs can bind in different regions of the CYP3A4 active site, and these binding regions may be distinct.In fact,it is believed that two drugs (substrates) can occupy the active site simultaneously,with both available for metabolism by the enzyme.

✱Regulation of the CYP Enzymes ፦

CYP450 enzymes can be regulated by the presence of other drugs or by disease states.This regulation can either decrease or increase enzyme function, depending on the modulating agent. These phenomena are commonly referred to as enzyme inhibition and enzyme induction,respectively.

1.Enzyme Inhibition፦

                                Enzyme inhibition is the most frequently observed result of CYP modulation and is the primary mechanism for drug–drug pharmacokinetic interactions. The most common type of inhibition is simple competitive inhibition, wherein two drugs are vying for the same active site and the drug with the highest affinity for the site wins out.

=A second type of CYP enzyme inhibition is mechanism-based inactivation (or suicide inactivation).In this type of inhibition, the effector compound (i.e., the inhibitor) is itself metabolized by the enzyme to form a reactive species that binds irreversibly to the enzyme and prevents any further metabolism by the enzyme. 

                     

 2.Enzyme Induction ፦          

                                   Induction of drug-metabolizing activity can be due either to synthesis of new enzyme protein or to a decrease in the proteolytic degradation of the enzyme.Increased enzyme synthesis is the result of an increase in messenger RNA (mRNA) production (transcription) or in the translation of mRNA into protein. Regardless of the mechanism,the net result of enzyme induction is the increased turnover (metabolism) of substrate.

☆CONJUGATIVE ENZYMES: PHASE II REACTIONS ፦

⇒Phase II conjugative enzymes metabolize drugs by attaching (conjugating) a more polar molecule to the original drug molecule to increase water solubility, thereby permitting more rapid drug excretion.This conjugation can occur following a phase I reaction involving the molecule, but prior metabolism is not required. The phase II enzymes typically consist of multiple isoforms, analogous to the CYPs, but to date are less well defined.

 

✱Glucuronosyl Transferases፦

⇒Glucuronosyl transferases (UGTs) conjugate the drug molecule with a glucuronic acid moiety,usually through establishment of an ether, ester, or amide bond. 

Glucuronosyl Transferases 

⇒Typically this conjugate is inactive, but sometimes it is active. For example, UGT-mediated conjugation of morphine at the 6- position results in the formation of morphine-6-glucuronide,which is 50 times as potent an analgesic as morphine.

✱N-Acetyltransferases፦

⇒As their name implies, the N-acetyltransferase (NAT) enzymes catalyze to a drug molecule the conjugation of an acetyl moiety derived from acetyl coenzyme A. 

N-Acetyltransfrases

⇒The net result of this conjugation is an increase in water solubility and increased elimination of the compound.The NATs identified to date and involved in human drug metabolism include NAT-1 and NAT-2.Little overlap in substrate specificities of the two isoforms appears to exist.