Drug metabolism is an immense area of study where drugs undergo a range of enzymemediated chemical reactions, such as oxidation, reduction, hydrolysis, hydration, conjugation, and migration. Drug metabolizing enzymes and biotransformation reactions. The cytochrome p450 family accounts for over 80% of drug oxidation. From the department of pharmacology, vanderbilt university, nashville. Abstraction of a single electron on either n, p or s results in the formation of charged. There are three possible results of phase 1 metabolism. Contains hepatic drug metabolising enzymes cytochrome p450 referred to as cyp 1, 2.
Drug metabolism and pharmacokinetics dmpk is an official online journal of the japanese society for the study of xenobiotics jssx, and it replaces the jssxs former journal, xenobiotic metabolism and disposition. Drugs can be metabolized by oxidation, reduction, hydrolysis, hydration, conjugation, condensation, or isomerization. Phase 1 metabolism involves chemical reactions such as oxidation most common, reduction and hydrolysis. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. Induction of drug metabolism many currently used drugs are well known to induce their own metabolism or the metabolism of other drugs.
The plasma halflife of a drug is the most clinically useful indexofdrugmetabolizing capacity but it is not necessarily the most appropriate. Chapters 2 and 3 deal with the chemistry of drug biotransformation. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. Occurs in the smooth endoplasmic reticulum ser of the liver cells 2. Xenobiotic metabolism, which includes drug metabolism. The structural features and functional activity of these enzymes comprise the bioinorganic. Introduction to phase i and ii metabolisms phase i. Electrochemistry combined with mass spectrometry ecms is an emerging analytical technique in the imitation of oxidative drug metabolism at the early stages of new drug development. Quantum mechanicsmolecular mechanics modeling of drug.
The liver expresses p450 monooxygenase systems for drug metabolism and detoxification. Just as there are differences in the enzymes involved in the oxidation of the two different types of tertiary amines to their n oxides, it might be expected that there will be differences in the effect such a group has on the overall. Drugs need to reach the sites of action to elicit their pharmacological effects after administration into the body. For instance, a drug containing a benzene group may undergo phase i reactions e. Cellular location of drug metabolizing enzymes reduction. The two reactions are catalyzed by nadphdependent microsomal electron transfer chains. Regulation of gene expression, enzyme activities, and impact of genetic variation. Among these, the most important as far as xenobiotic metabolism is concerned are the cytochromes p450 ec 1. Noxidation, nmethylation and nconjugation reactions of.
Drug metabolism and pharmacokinetics journal elsevier. Drug metabolism university of california, san diego. A common feature of drug metabolized by cyp2d6 is the presence of at least one basic nitrogen atom at a distance of. Learn vocabulary, terms, and more with flashcards, games, and other study tools. Identification of the cytochrome p450 enzymes involved in. In other words, the metabolites are pharmacologically inactive. Phase i of drug metabolism results in the oxidation of the parent drug and usually. In vivo and in vitro studies have demonstrated that voriconazole is extensively metabolized, with the major circulating metabolite resulting from n oxidation. Drug metabolism is often considered during drug design. Tertiary amine drugs are converted into dealkylated and noxide metabolites by liver microsomal enzymes. The enzymes involved in metabolism are present in many tissues but generally are more concentrated in the liver. Metabolism chemical transformaion of xenobiotics occurs in mostly in liver enzymatic prosesses convertion into more hydrophil. Phase i metabolism is characterized as a functionalization reaction, where they add or reveal a functional group by oxidation, reduction, or hydrolysis, hence, leading to increase in overall. Article pdf available in the japanese journal of pharmacology 842.
Cytochrome p450 cytochrome p450 reductase nadph molecular oxygen the cycle involves four steps. Cigarette smoking can cause increased elimination of theophylline and other compounds. Voriconazole is a triazole antifungal agent with potent activity against a broad spectrum of clinically significant pathogens. Ndealkylation reactions are relatively common in that many drugs which. Prodrugs are inactive drugs that undergo a chemical or biochemical conversion to the active drug. The in vivo metabolism of compounds which contain n oxide groups, either aliphatic or heteroaromatic tertiary amines, has not been extensively studied.
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. Drug metabolites can have the same, increased or decreased activity compared to parent compound. Noxidation, nmethylation and nconjugation reactions of nicotine are metabolic transformations that result in the formation of the corresponding quaternary ammonium product, which is usually more polar in nature and more water soluble than the parent base. A drug may inhibit one isoenzyme while being itself a substrate of another isoenzyme e. 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. These reactions include hydrolysis, reduction, and oxidation. Noxide formation and related reactions in drug metabolism. Tertiary amine drugs are converted into dealkylated and n oxide metabolites by liver microsomal enzymes. The journal will accept original submissions in english on the understanding that the work is unpublished and is not being considered for publication elsewhere. Adverse reactions during salicylazosulfapyridine therapy and the relation with drug metabolism and acetylator phenotype.
Oxidation of ranitidine by isozymes of flavincontaining monooxygenase and cytochrome p450. The major family of enzymes associated with these metabolic reactions is the cytochrome p450 family. This biotransformation can be deterred by replacing the hydrogen at the paraposition and using fluorine as a. Plasma bombesin concentrations in patients with extensive small cell carcinoma of the lung.
Assessment of the drug metabolism capacity of the liver. Theoretical considerations anumberoffactors must be taken into account in assessing the effects ofliver disease on drug metabolism. Metabolism is considered one of the main reasons for. Here, we present the benefits of electrochemical oxidation by squarewave potential pulses for the oxidation of lidocaine, a test drug compound, on a platinum electrode. Nadph donates an electron to the cytochrome p450 reductase, which in turn. Introduction the cytochromes p450 cyps play an important role in drug metabolism. In the present study, we report on the human cytochrome p450 enzymes responsible for the generation of this. In addition to n oxidation of tertiary amines, n dealkylation of n. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and. Chemistry of drug metabolism drug metabolism is a chemical process, where enzymes play a crucial role in the conversion of one chemical species to another. Many findings suggest that n oxides play an important role in the metabolism of drugs. Sult1 and 2 are most important in the metabolism of drugs. Excess nicotinamide, a form of vitamin b3, is metabolized through two enzymatic systems and eventually excreted from the body.
In vitro metabolism studies in human and animal tissue. The production of the fluoride ion during biological oxidation of aryl fluorides has been observed in several systems. The enzymecatalyzed reactions of phase i metabolism bind oxygen, hydrogen, water, or amino acids to the lipophilic drug molecule to expose or introduce a hydroxyl oh, amino nh 2, sulfhydryl sh, or carboxyl cooh polar functional group, and thus, result in a modest increase in the parent drugs water solubility. Isoform subfamily is indicated by capital letter e.
Metabolism and detoxification protect liver from injury by drugs and toxic metabolites. The term metabolism is commonly used probably because products of drug transformation are called metabolites. The second enzymatic system oxidizes nicotinamide to nicotinamide n oxide. The first system starts with the methylation of nicotinamide by nicotinamide n methyltransferase, which can subsequently be oxidized by aldehyde oxidase. In addition to the pharmacologically active n oxides of natural origin, many others have been prepared synthetically. Glutathione can exist in a reduced form gsh or can be oxidized to a. Metabolism or biotransformation the conversion from one chemical form of a substance to another. Some examples are the anticonvulsant medications phenobarbital and carbamazepine, and even st.
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