CYP 3A4 Inhibitors
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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]
CYP3A4 Background
CYP3A4 represents 30% of the total hepatic P450 content and 70% of intestinal P450 content. CYP3A4 is responsible for the metabolism of 60% of all the drugs on the market including 38 different medication classes. To name a few, CYP3A4 metabolizes members of the psychotropics, antiarrhythmics, calcium antagonists, opioid analgesics, antihistamines, benzodiazepines, antimicrobial agents, antiretroviral agents, immunosuppressants, antiulcer agents, and anticonvulsants.[1] CYP3A4 has low intraindividual variability (<15%) over a short term period (<= 3 months) in activity, which should not markedly affect drug metabolism. However, there is a large interpatient variability (5-20 fold) in CYP3A4 activity due to both genetic (90%) and nongenetic (10%) factors.[3][4]
Interaction Mechanism
Inhibition of CYP3A4 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
Medications that inhibit CYP3A4 interact with medications whose primary biotransformation occurs via CYP3A4 resulting in increased plasma concentrations of the inhibited drug. The clinical consequence of such drug interactions are many and specific to the interacting drug combination. Typically, the main concern with metabolic pathway inhibition is substrate drug toxicity, which is the most common clinical manifestation found with interactions of this nature. Inhibition of CYP3A4 will result in higher plasma concentrations of the CYP3A4 substrate. Generally, the higher a drug's presystemic metabolism (high extraction ratio) and as such, the lower it's bioavailability, the greater the impact inhibition will have on the overall increase in plasma concentration. On the contrary, another consequence of metabolic inhibition is reduced efficacy for pro-drugs requiring conversion to active metabolites (e.g. cyclophosphamide).[1]
To make the best clinical decision about the severity of the consequence of a CYP3A4 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 3A4 Substrates, Inhibitors, and Inducers
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 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
- ↑ Kashuba AD, Bertino JS Jr, Rocci ML Jr, et al. Quantification of 3-month intraindividual variability and the influence of sex and menstrual cycle phase on CYP3A4 activity as measured by phenotyping with intravenous midazolam. Clin Pharmacol Ther 1998; 64:269-277
- ↑ Wilkinson GR. Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans. J Pharmacokinet Biopharm 1996;24:475-490
