CYP 2C8 Inhibitors
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Authored by: Aahynes 20:01, 22 February 2007 (PST) Certified by : Khlee3 13:49, 25 February 2007 (PST) |
Contents |
CYP-450 Background
Drug metabolism or biotransformation occurs by two primary categories: phase I and phase II reactions. The primary purpose of drug (xenobiotic) biotransformation is to convert exogenous lipophilic compounds to water-soluble metabolites. The water-soluble metabolites are subsequently ionized at physiologic pH allowing for excretion, which occurs primarily through the kidneys.[1]
Phase I reactions are nonsynthtic biotransformation reactions and include: oxidation, reduction, and hydrolysis. Phase II reactions are synthetic biotransformation reactions in that they link the parent drug or parent drug phase I metabolite with an endogenous substance. Phase II biotransformation reactions include: glucuronidation, sulfation, acetylation, methylation, gluathione conjugation, and conjugation with amino acids. Phase I reactions will be the focus of this page.[1]
Of the phase I drug metabolism pathways, the Cytochrome P-450 enzyme system (P450), located primarily in the hepatocytes, is the most important with the greatest diversity. P450 is a heme containing protein located in the phospholipid bilayer of the smooth endoplasmic reticulum of most of the organs in the body including kidneys, small intestine, skin, nasal mucosa, eyes lung, adrenals, pancreas, heart, brain, erythrocytes, platelets, and most abundantly in the liver. There are many forms (isozymes) of P450, with unique, as well as, some overlapping catalytic activity. Each isozyme is encoded by a separte gene. CYP families are named according to their amino acid sequence homology developed by Nebert and colleagues (e.g. CYP1, CYP2, CYP3, etc).[2] Furthermore, there are subfamilies designated based on their amino acid homology compared to others in the same family (e.g. CYP2A, CYP3A, etc.). Once more, individuals within a subfamily are also differentiated (e.g. CYP3A4, CYP2C9, etc.). There are currently 18 families and 42 subfamilies known within the human species.[1]
CYP 2C8 Background
CYP 2C8 is one of the more prevalent members of the Cytochrome-P450 enzyme family, accounting for approximatly 7% of CYP activity in the liver. It is similar in structure to CYP 2C8, with 70% sequence homology and 80% sequence similarity. However, only a handful of drugs are metabolized by both CYP 2C8 and CYP 2C9. CYP 2C8 shares more common substrates with the structurally dissimilar CYP 3A4 than it does with CYP 2C9. Molecules that are metabolized by CYP 2C8 tend to be large in size and either mildly acidic, basic, or neutral in nature. While this enzyme is found primarily in the liver, extrahepatic CYP 2C8 has been found in the kidney, intestine, adrenal gland, brain, mammary gland, ovary, and heart. CYP 2C8 may be an important factor in the pathology of cardiac diseases due to it's catalytic role in the conversion of arachidonate to vasoactive metabolites. A number of polymorphisms have been described for the CYP 2C8 enzyme. Most of these variations are rare, with the exception of CYP 2C8*2 (seen in 18% of patients of african descent) and CYP2C8*3 (seen in 23% of patients of caucasian descent). CYP 2C8*3 may be clinically relevant due to in vitro studies showing decreased metabolism of paclitaxel and arachidonic acid.[3]
Interaction Mechanism
Inhibition of CYP2C8 by drugs (see table below) can be reversible or irreversible. Reversible inhibitors can be sub-divided into competative, non-competative, and uncompetative and are dose and concentration dependent. Irreversible inhibitors can covalently bind to heme-prosthetic groups of CYP450 and are time and dose dependent.
Interaction Implications
To make the best clinical decision about the severity of the consequence of a CYP2C8 inhibtion reaction refer to the drug interaction chart for the inhibited drug, as well as the cited literature supporting the severity level.
Summary of CYP 2C8 Substrates, Inhibitors, and Inducers
| Substrates | Inhibitors | Inducers |
|---|---|---|
| amiodarone, amodiaquine, arachadonic acid, benzphetamine, cerivastatin, chloroquine, diazepam, diclofenac, fluvastatin, ibuprofen, isotretinoin, methadone, morphine, omeprazole, paclitaxel, repaglinide, retinoic acid, rosiglitazone, azarotenic acid, tolbutamide, troglitazone | anastrozole, diethyldithiocarbamate, gemfibrozil, montelukast, omeprazole | primidone, rifapentine |
References
- ↑ 1.0 1.1 1.2 1.3 Kashuba AD, Park JJ, Persky AM, Brouwer KL. Drug Metabolism, Transport, and the Influence of Hepatic Disease. In: Burton, ME, Schentag JJ, Shaw LM, Evans WE, editors. Applied Pharmacokinetics & Pharmacodynamics, Principle of Therapeutic Drug Monitoring, 4th edition. Philadelphia: Lippincott Williams & Wilkins; 2006. p. 121-158
- ↑ Nebert DW, Nelson DR, Coon MJ, et al. The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature. DNA Cell Biol 1991; 10:1-14
- ↑ Totah RA, Rettie AE, Totah RA, Rettie AE. Cytochrome P450 2C8: substrates, inhibitors, pharmacogenetics, and clinical relevance. Clinical Pharmacology & Therapeutics. 2005 May;77(5):341-52.
- ↑ Totah RA, Rettie AE, Totah RA, Rettie AE. Cytochrome P450 2C8: substrates, inhibitors, pharmacogenetics, and clinical relevance. Clinical Pharmacology & Therapeutics. 2005 May;77(5):341-52.
