The role of human carboxylesterases in drug metabolism laizure et al 211. The biochemistry of drug metabolism an introduction. In this singlepass method, 14cenalapril was delivered. Intestinal wall is rich in esterases and lipases enzymes. Pharm00a14 discuss the roles of the plasma esterases on drugs used in anaesthesia 67% background plasma esterases are enzymes that hydrolyse ester bonds to form alcohol and carboxylic acid. Cossum department of pharmacological sciences, genentech, inc. Thus, various esterases, which include enzymes that have not been known to hydrolyze drugs, are involved in drug metabolism with different substrate specificity. Although humans do not have cess in plasma, other hydrolases can. The liver enzyme had a much lower affinity for cocaine than that of serum, indicating that a different form of esterase was present in liver. In addition, drugdrug interactions involving these enzymes will be described, and their role in the metabolism of commonly prescribed drugs will be used to illustrate the importance of carboxylesterase.
Bacterial flora present in the intestine and colon appear to play an important role in the reduction of many aromatic azo and nitro drug. Drug metabolism refers to the biochemical transformation of a compound into its more polar chemical form. Chapters 2 and 3 deal with the chemistry of drug biotransformation. New treatment strategies for heroin addiction are needed, and an alternative could be modulation of the enzymes involved in the heroin metabolism with the objective of reducing the rewarding effects of the drug. The term metabolism is commonly used probably because products of drug transformation are called metabolites. The chemistry of drug metabolism uk essays ukessays.
See atypical plasma cholinesterase red cell esterase. Conclusions wide variety of esterases present in humans different substrate specificity, localization, catalytic mechanism esterases can act as hydrolases and synthases gaining prominence in the field of drug metabolism interspecies and interindividual variability in esterase activity exists does this affect drug metabolism. Notable examples include opioid, amphetamine, nicotine, and cocaine metabolism by specific isozymes to varying degrees in different organs. Sulfation and glucuronidation are presystemic intestinal first pass metabolism. Abstract heroin is the main abused opioid, and is causing most drug use related deaths in the european union and in the usa. Moreover, a metabolism of toxic substances is also frequently investigated 4. The impact of carboxylesterases in drug metabolism and. List of drugs known to be metabolized by red blood cells rbc and the enzyme s responsible.
Ester protection can also introduce antimicrobial properties into previously nontoxic drugs through alterations in cell permeability or solubility. Further esterase studies should be conducted to promote our understanding in clinical pharmacotherapy and drug development. Changes in diet may lead to significant alterations in drug metabolism 18, 19. Both drugs can also be metabolized by nonspecific plasma esterases. Prasugrel, which contains one chiral center, is rapidlyhydrolyzed in vivo by esterases inthe intestine toa thiolactone, r959,which contains two chiral centers figure 15. Prodrug biochemical or chemical processes drug inactive active the definition of a prodrug is controversial in some circles. The two most significant forms of cess in humans for drug metabolism are ces1 and ces2 1, 2, 68. Plasma esterasedeficient mice are useful to evaluate the impact of plasma esterases on pk.
Presented data important for prediction of drug drug or drug food interactions as well as for individual variations in metabolism. However, a number of pathogenic and commensal microbial esterases have been found to possess significant substrate specificity and can play an unexpected role in drug metabolism. Found in cytosol of rbc metabolism of esmolol and possibly remifentanil not reduced in pt with pseudocholinesterase deficiency. Analytical methods for quantification of drug metabolites. Pharmacokinetics, metabolism, and pharmaceutics of drugs. The esterases exhibit specificities for certain substrates and inhibitors but a drug is often hydrolysed by more than one esterase at different sites.
Phase 2 drug metabolism enzymatic conjugation reaction in the intestine and liver to form mostly inactive polar metabolite that is excreted in urine or feces mostly in the cellular cytosol except glucuronidation enzyme, which is a microsomal enzyme. Abstract human esterases such as the human carboxylesterases hces are important for the catalytic ester hydrolysis of xenobiotics and they play an important role in the detoxification of drugs e. Esterases are a heterogenous group of enzymes which hydrolyse esters through the oxygen bridge to form alcohol and alkanoic acid inactivates ester drugs found in plasma, nmj, rbc, hepatic sinusoids high capacity pathway with high clearance. Prodrugs require conversion to active metabolite to produce their therapeutic effect phase 2 drug metabolism enzymatic conjugation reaction in the intestine and liver to form mostly inactive polar metabolite that is excreted in urine or feces. Major location of drug metabolizing enzymes dysfunction can lead to impaired drug metabolismdecreased enzyme activity first pass metabolism effected may inc 24 x bioavailiability results in exaggerated pharmacological responses and adverse effects. Pharm00a14 discuss the roles of the plasma esterases on. Key words red blood cell metabolism esterases cytochromes haemoglobin dehydrogenases proteases transferases.
Metabolism or biotransformation the conversion from one chemical form of a substance to another. Cholinesterases are primarily involved in drug hydrolysis in the plasma, arylesterases in the plasma and red blood cells, and carboxylesterases in the liver, gut and other tissues. Strategies for in vitro metabolic stability testing. Sex differences in drug metabolism by rodent liver are documented in the literature. It provides an invaluable introduction to the core areas of pharmacology and examines recent progress and advances in this fast moving field and its. Medch 527 12820 hydrolases esterases and epoxide hydrolases. Current developments in molecularbased studies into the structure and function of cholinesterases, carboxylesterases, and paraoxonases are described.
Drug metabolites can have the same, increased or decreased activity compared to parent compound. Esterases are a heterogenous group of enzymes which hydrolyse esters through the oxygen bridge to form alcohol and alkanoic acid inactivates ester drugs. Both liver and serum enzymatically formed ecgonine methyl ester from cocaine. Hepatic metabolism continues to be the most important route of metabolism for foreign ingested chemicals xenobiotics and drugs. Insufficient studies have been conducted either in young or elderly volunteers to determine in a consistent manner the effects of diet and food on drug metabolism. Phase 1 metabolism involves chemical reactions such as oxidation most common, reduction and hydrolysis.
Interestingly, cess could serve as both drugs and drug targets 9. Degradation through the hoffman elimination produces laudanosine and pentamethylenediacrylate. Discuss the roles of plasma esterases on drugs used in anaesthesia. For instance, a drug containing a benzene group may undergo phase i reactions e. Presented data important for prediction of drugdrug or drugfood interactions as well as for individual variations in metabolism. It is also becoming increasingly clear that brain metabolism has a more prominent role than previously thought.
Identification and modulation of esterases involved in. An esterase is a hydrolase enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis a wide range of different esterases exist that differ in their substrate specificity, their protein structure, and their biological function ec classificationlist of enzymes. Esterases for enalapril hydrolysis are concentrated in the. This article reports on a symposium sponsored by the american society for pharmacology and experimental therapeutics and held at the april 2001 experimental biology meeting. Intestinal mucosa, kidney, lungs, skin and adrenals intestinal mucosa. Provides a timely update to a key textbook on human drug metabolism the third edition of this comprehensive book covers basic concepts of teaching drug metabolism, starting from extreme clinical consequences to systems and mechanisms and toxicity. I know there are no k types, but on a aba retired q, theres a question about a pt was given sux and then had no twitches 20 min later. Conjugation with small, endogenous substance, often takes advantage of functional group added in. The pharmacogenetics of drugmetabolizing enzymes is a prominent focus of this field, because genetic makeup is responsible for a significant portion of druginduced toxicity. There are three possible results of phase 1 metabolism. In glutathione conjugation, the drug is the electrophile i. More generally, xenobiotic metabolism from the greek xenos stranger and biotic related to living beings is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organisms normal biochemistry, such as any drug. Ces1 is currently being developed by the us military for prophylactic use against chemical weapons of organophosphates nerve agents such as sarin, soman, tabun and vx gas 9.
Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and. Heroin is the main abused opioid, and is causing most drug use related deaths. Hydrolasefold proteins ces1 ces2 ephx1 ephx2 sercys and asp proteases literature testa, b. Esterases in this hydrolysis reaction, youre adding a water to an ester for esterases or an amide for amidases initially creating a tetrahedral. Contribution of human esterases to the metabolism of. Prodrugs are inactive drugs that undergo a chemical or biochemical conversion to the active drug. Serum esterases involved in drug hydrolysis are mainly cholinesterase ec. This biotransformation can be deterred by replacing the hydrogen at the paraposition and using fluorine as a.
In early discovery, drug metabolism input provides a basis for choosing chemical structures and lead compounds with desirable drug metabolism and pharmacokinetic dmpk or safety profiles 5, 6. Perfusion of substrate via only the hepatic artery with simultaneous substratefree perfusion of portal vein or hepatic vein hepatic artery portal veinhepatic artery hepatic vein was used to examine the enzymic distribution of carboxylesterases towards the hydrolysis of enalapril to enalaprilat in the perfused rat liver preparation. Drug metabolism is often considered during drug design. In this paper we report a difference in the activities of the esterases asaesterase i. The role of human carboxylesterases in drug metabolism. Non organ dependent drug metabolism with generally inactive metabolites. In the first chapter, the principles underlying drug absorption, distribution, metabolism and elimination are described, with drug metabolism highlighted within the context of these fundamental processes. Substrate drugs may be prodrugs activated by hydrolysis or active compounds that are inactivated by hydrolysis. Acetylsalicylic acid asa, the most used drug worldwide, is hydrolyzed to salicylic acid and acetate by esterases present in tissues of several species including humans. Druginduced competitors for the enzyme etomidate ester local anaesthetics methotrexate esmolol ceaccp atypical plasma cholinesterase.
Biotransformation of drugs in human skin drug metabolism. Role of the red blood cell in drug metabolism wiley online library. Although it is the largest organ of the human body, skin is often not considered in discussions of drug metabolism. Addition or unmasking of functional, polar moiety oxidation p450 or fmo hydrolysis esterases most typical is hydroxyl group created or exposed dealkylations phase 2. However, there is growing evidence that most common drugmetabolizing enzymes are expressed in the skin. Plasma esterasepseudo cholinesterase student doctor network. Identification and modulation of esterases involved in the. Rifampin and rifabutin and their metabolism by human liver esterases. Enzymes of drug metabolism during delirium oxford academic.
Rifampin and rifabutin and their metabolism by human liver. Evidence for expression of cytochromes p450, flavin monooxygenases, glutathione s transferases, n acetyltransferases, and sulfotransferases in human. Carboxylesterase is one of the major esterases involved in drug metabolism and xenobiotic biotransformation of drugs with esters, amide and thioester functional groups. Vecuronium is quickly absorbed by the liver and mostly excreted in the bile as unchanged drug. In other words, the metabolites are pharmacologically inactive. Therefore, carboxylesterases play critical roles in drug metabolism, and pesticide detoxification 10,11,12,14,15,16,17. Request pdf contribution of human esterases to the metabolism of selected drugs of abuse human esterases such as the human carboxylesterases hces are important for the catalytic ester.
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