Drug Metabolism
Phase I vs
Phase I vs. Phase II
Phase I reactions usually precede Phase II, though not necessarily. During these reactions, polar bodies are either introduced or unmasked, which results in (more) polar metabolites of the original chemicals. In the case of pharmaceutical drugs, Phase I reactions can lead either to activation or inactivation of the drug.
Phase I reactions (also termed nonsynthetic reactions) may occur by oxidation, reduction, hydrolysis, cyclization, and decyclization reactions. Oxidation involves the enzymatic addition of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver. These oxidative reactions typically involve a cytochrome P450 monooxygenase (often abbreviated CYP), NADPH and oxygen. The classes of pharmaceutical drugs that utilize this method for their metabolism include phenothiazines, paracetamol, and steroids. If the metabolites of phase I reactions are sufficiently polar, they may be readily excreted at this point. However, many phase I products are not eliminated rapidly and undergo a subsequent reaction in which an endogenous substrate combines with the newly incorporated functional group to form a highly polar conjugate.
A common Phase I oxidation involves conversion of a C-H bond to a C-OH. This reaction sometimes converts a pharmacologically inactive compound (a prodrug) to a pharmacologically active one. By the same token, Phase I can turn a nontoxic molecule into a poisonous one (toxification). A famous example is acetonitrile, CH3CN. Simple hydrolysis in the stomach transforms acetonitrile into acetate and ammonia, which are comparatively innocuous. But Phase I metabolism converts acetonitrile to HOCH2CN, which rapidly dissociates into formaldehyde and hydrogen cyanide, both of which are toxic.
Phase I metabolism of drug candidates can be simulated in the laboratory using non-enzyme catalysts. This example of a biomimetic reaction tends to give a mixture of products that often contains the Phase I metabolites, and Alpha Chimica's approach to preparing prospective drug candidates makes use of this in vitro chemistry.
Phase II reactions usually known as conjugation reactions (e.g., with glucuronic acid, sulfonates (commonly known as sulfation) , glutathione or amino acids) are usually detoxication in nature, and involve the interactions of the polar functional groups of phase I metabolites. Sites on drugs where conjugation reactions occur include carboxyl (-COOH), hydroxyl (-OH), amino (NH2), and sulfhydryl (-SH) groups. Products of conjugation reactions have increased molecular weight and are usually inactive unlike Phase I reactions which often produce active metabolites.
Sites
Quantitatively, the smooth endoplasmic reticulum of the liver cell is the principal organ of drug metabolism, although every biological tissue has some ability to metabolize drugs. Factors responsible for the liver's contribution to drug metabolism include that it is a large organ, that it is the first organ perfused by chemicals absorbed in the gut, and that there are very high concentrations of most drug-metabolizing enzyme systems relative to other organs. If a drug is taken into the GI tract, where it enters hepatic circulation through the portal vein, it becomes well-metabolized and is said to show the first pass effect.
Other sites of drug metabolism include epithelial cells of the gastrointestinal tract, lungs, kidneys, and the skin. These sites are usually responsible for localized toxicity reactions.
Major enzymes and pathways
Several major enzymes and pathways are involved in drug metabolism, and can be divided into Phase I and Phase II reactions:
Phase I
Oxidation
Cytochrome P450 monooxygenase system
Flavin-containing monooxygenase system
Alcohol dehydrogenase and aldehyde dehydrogenase
Monoamine oxidase
Co-oxidation by peroxidases
Reduction
NADPH-cytochrome P450 reductase
Reduced (ferrous) cytochrome P450
It should be noted that during reduction reactions, a chemical can enter futile cycling, in which it gains a free-radical electron, then promptly loses it to oxygen (to form a superoxide anion).
Hydrolysis
Esterases and amidases
Epoxide hydrolase
Phase II
Methylation
methyltransferase
Sulphation
Glutathione S-transferases
Sulfotransferases
Acetylation
N-acetyltransferases
Amino acid N-acyl transferases
Glucuronidation
UDP-glucuronosyltransferases
Mercapturic acid biosynthesis
Factors that affect Drug Metabolism
The duration and intensity of pharmacological action of most lipophilic drugs are determined by the rate they are metabolized to inactive products. The Cytochrome P450 monooxygenase system is the most important pathway in this regard. In general, anything that increases the rate of metabolism (e.g., enzyme induction) of a pharmacologically active metabolite will decrease the duration and intensity of the drug action. The opposite is also true (e.g., enzyme inhibition).
Various physiological and pathological factors can also affect drug metabolism. Physiological factors that can influence drug metabolism include age, individual variation (e.g., pharmacogenetics), enterohepatic circulation, nutrition, intestinal flora, or sex differences.
In general, drugs are metabolized more slowly in fetal, neonatal and elderly humans and animals than in adults.
Genetic variation (polymorphism) accounts for some of the variability in the effect of drugs. With N-acetyltransferases (involved in Phase II reactions), individual variation creates a group of people who acetylate slowly (slow acetylators) and those who acetylate quickly, split roughly 50:50 in the population of Canada. This variation may have dramatic consequences, as the slow acetylators are more prone to dose-dependent toxicity.
Cytochrome P450 monooxygenase system enzymes can also vary across individuals, with deficiencies occurring in 1 - 30% of people, depending on their ethnic background.
Pathological factors can also influence drug metabolism, including liver, kidney, or heart diseases.
In silico modelling and simulation methods allow drug metabolism to be predicted in virtual patient populations prior to performing clinical studies in human subjects. This can be used to identify individuals most at risk from adverse reaction.
See also
Drug design
Xenobiotic metabolism
Active metabolite
Drug reaction testing
SPORCalc, an example process for exploring drug metabolism databases
Simcyp Simulator
Simulations Plus
References
^ Bernardin Akagah; Anh Tuan Lormier; Alain Fournet; Bruno Figadere (2008). "Oxidation of antiparasitic 2-substituted quinolines using metalloporphyrin catalysts: scale-up of a biomimetic reaction for metabolite production of drug candidates". Organic & Biomolecular Chemistry 6 (24): 44947. PMID 19039354.
^ Amin Rostami-Hodjegan; Geoffrey Tucker (2007). "Simulation and prediction of in vivo drug metabolism in human populations from in vitro data". Nature Reviews Drug Discovery 6 (2): 1408. doi:10.1038/nrd2173. PMID 17268485.
^ James Smith; Viktor Stein (2009). "SPORCalc: A development of a database analysis that provides putative metabolic enzyme reactions for ligand-based drug design". Computational Biology and Chemistry 33 (2): 149159. doi:10.1016/j.compbiolchem.2008.11.002. PMID 19157988.
Basic and Clinical Pharmacology (9th Edition; Katzung): 1.4. Drug Biotransformation
External links
University of Minnesota Biocatalysis/Biodegradation Database
Drug Metabolism Database
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Medication > Pharmacology
Pharmacokinetics
ADME: Absorption Distribution Metabolism Excretion (Clearance)
Loading dose Volume of distribution (Initial) Rate of infusion
Compartment Bioequivalence Bioavailability
Onset of action Biological half-life Plasma protein binding
Phase 1 reaction Phase 2 reaction
Therapeutic index (LD50/ED50)
Pharmacodynamics
Toxicity (Neurotoxicology) Dose-response relationship (Efficacy, Potency)
Antimicrobial pharmacodynamics: Minimum inhibitory concentration/Bacteriostatic Minimum bactericidal concentration/Bactericide
Agonism and antagonism
Agonist: Inverse agonist Irreversible agonist Partial agonist Superagonist Physiological agonist
Antagonist: Competitive antagonist Irreversible antagonist Physiological antagonist
Other: Binding Affinity Binding selectivity Functional selectivity
Other
Drug tolerance: Tachyphylaxis
Drug resistance: Antibiotic resistance Multiple drug resistance
Related fields/subfields
Pharmacogenetics Pharmacogenomics Neuropsychopharmacology (Neuropharmacology, Psychopharmacology)
Categories: Pharmacokinetics | Hepatology | Metabolism
Drug Metabolism
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