CYP3A4: Interactions/Inhibitions

1. CYP3A4: Interactions/Inhibitions SalimanJoyian, AlessiaForestieri, Janice Law, Amir Ali Imani PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. Cytochrome Oxidase • Member of cytochrome P450 superfamily of enzymes • Catalyze many reactions in drug metabolism • CYP3A4 involved in oxidation of largest range of substrates Williams P, Cosme J, Vinkovic D, Ward A, Angove H, Day P, Vonrhein C, Tickle I, Jhoti H. Crystal structures of human cytochrome P450 3A4 bound to metyrapone and progesterone. Science (2004) 30: 305

3. Function • Metabolism of xenobiotics leading to • Deactivation to facilitate excretion • Activation to reactive metabolites

4. Tissue Distribution • Localized in smooth endoplasmic reticulum • Predominately in liver and intestine Bailey D, Dresser G. Natural products and adverse drug interactions. Cmaj (2004) 10: 1531-1532

5. CYP3A4 Inducers CYP3A4 activity is known to be induced by a variety of drugs, including: • Rifampicin – an antibiotic • Phenobarbital, phenytoin – antiepileptic drugs • Carbamazepine – an anticonvulsant • Dexamethasone – a corticosteroid • Efavirenz, nevirapine– antiretroviral drugs • Polycyclic hydrocarbons

6. How do they affect CYP3A4 activity? The majority of drugs that induce CYP3A4 do so by activating the pregnane X receptor (PXR). This includes rifampicin, phenobarbital, and carbamazepine. Drugs that bind to another nuclear receptor, constitutive androstane receptor (CAR), are also known to induce CYP3A4 There are also other signalling molecules, such as HNFs, that are involved in CYP3A4 stimulation.

7. PXR Mechanism • Upon ligand binding, PXR dissociates from CCRP in the cytosol and migrates to the nucleus • It forms a heterodimer with 9-cis retinoic acid receptor (RXR) • Binds other coactivators • Bind to CYP3A4 promoter and increase its transcription Shukla SJ et al. Identification of clinically used drugs that activate pregnane X receptors. Drug Metab Dispos (2011) 39:151–159.

8. CYP3A4 Inhibition • CYP3A4 inhibition leads to potentially serious drug toxicity • Many drugs are moderate-to-potent inhibitors of CYP3A4 • Inhibitors also effect P-glycoprotein, resulting in additive effects

9. CYP3A4 Inhibition Clinal professionals should avoid using drugs which inhibit CYP3A4, particularly when combined with other drugs which are substrates Horn J, Hansten P. Get to Know an Enzyme: CYP3A4. Pharmacy Times (2008) [ePub]

10. Mechanisms of Inhibition of CYP3A4 • The mechanism whereby CYP3A4 is inhibited is characterised by nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)-, the factor of time and concentration-dependent enzyme inactivation • []- dependent-enzyme inactivation happens when some drugs are converted by CYP isoenzymes* to reactive metabolites which have the power to covalently bind irreversibly o CYP3A4, thereby reducing its activity • There are similarities in the structural designs of drugs that inactivate CYP3A4. These include: a tertiary amine function, furan ring, and acetylene function • Most often than not, the inhibiting pathway include the formation of reactive metabolites by CYP isoenzymes*, preponderance of CYP inducers and P-glycoprotein (P-gp) substrate, and the concluding clinical observances (PK) in patients • *An isoenzyme is defined as two or more enzymes with identical function but different structure

11. What Inhibits CYP3A4? Grapefruit Juice • Relatively recently (1998)*, researchers discovered that elements in grapefruit (and its accompanying juices) had powerful CYP3A4 inhibiting activities • Clinically this indicates that the metabolism of various drugs (ones that get processed by CYP3A4) is affected in the way that their levels increase in blood plasma in the body (hence an increase in bioavailability) • CYP3A4 not only mechanistically does this but it is in-fact very potent at it (leading to fatal outcomes in such cases as with drugs like astemizole or terfenadine) • The effects of grapefruit last from 3-7 days, with the greatest impact on the patient within 24 hours of consuming the drug • In many hospitals (including a handful in Toronto), the administrations have banned and do not distribute grapefruit to their patients in any format • What also inhibits CYP3A4? • Noni (M. citrifolia), a dietary supplement (typically consumed as a juice) also has inhibiting capacities • * As early as 1989, it was found that grapefruit juice affected drug absorption (papers published on Felodipine and Nifedipine in 1991 - the first reported food-drug interaction clinically). However it wasn’t until a few years later and several medical deaths that the 1998 studies were pursued.

12. What Inhibits CYP3A4? • Clinically important mechanism-based CYP3A4 inhibitors: antibacterials (e.g. clarithromycin, erythromycin and isoniazid), anticancer agents (e.g. tamoxifen and irinotecan), anti-HIV agents (e.g. ritonavir and delavirdine), antihypertensives (e.g. dihydralazine, verapamil and diltiazem), sex steroids and their receptor modulators (e.g. gestodene and raloxifene), and several herbal constituents (e.g. bergamottin and glabridin).

13. Summary • Metabolism through oxidation leading to activation and deactivation of xenobiotics • Found predominately in the liver and intestine (first pass elimination) • CYP3A4 is known to be induced by a wide variety of drugs • The most potent inducer is the antibiotic rifampicin • Rifampicin, as well as many other drugs that induce CYP3A4, stimulate its activity by activating pregnane X receptor (PXR). PXR which binds to other factors and overall promotes the transcription of CYP3A4. • CYP3A4 inhibition leads to potentially serious drug toxicity • Many drugs are moderate-to-potent inhibitors of CYP3A4 • Inhibitors also effect P-glycoprotein, resulting in additive effects • Grapefruit juice is a potent inhibitor of CYP3A4 and has many life implications on medical care (i.e. hospital use) • Significant mechanism inhibitors of CYP3A4 include: antibacterials, anticancer agents, anti-HIV agents, antihypertensives, sex steroids and their receptor modulators along with several herbal constituents • Most drugs that inhibit CYP3A4 usually have a tertiary amine function, furan ring, and acetylene function

14. References Bailey D, Dresser G. Natural products and adverse drug interactions. Cmaj (2004) 10: 1531-1532. Chen J, Zhao K, Chen C. The role of CYP3A4 in the biotransformation of bile acids and therapeutic implication for cholestasis. Ann Trans Med [ePub] Goodwin B, Hodgson E, Liddle C. The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. MolPharmacol (1999) 56:1329-39. Horn J, Hansten P. Get to Know an Enzyme: CYP3A4. Pharmacy Times (2008) [ePub] Shukla SJ et al. Identification of clinically used drugs that activate pregnane X receptors. Drug MetabDispos (2011) 39:151–159. Timsit YE, Negishi M. CAR and PXR: The xenobiotic-sening receptors. Steroids (2007) 72: 231-246. Williams P, Cosme J, Vinkovic D, Ward A, Angove H, Day P, Vonrhein C, Tickle I, Jhoti H. Crystal structures of human cytochrome P450 3A4 bound to metyrapone and progesterone. Science (2004) 30: 305. Zhou S. Potential strategies for minimizing mechanism-based inhibition of cytochrome P450 3A4. Curr Pharm Des (2008) 14: 990-1000. Zhou S, Yung Chan S, Cher Goh B, Chan E, Duan W, Huang M, McLeod H. Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs. ClinPharmackinet (2005) 44: 279-304.