CYTOCHROME P450\\CYTOCHROME P450 enzymes/metabolise drugs/more than 50 enzymes\6 metabolize 90 percent of drugs/CYP3A4 and CYPD2D6 are the most significant\\GENETIC VARIABILITY / Polymorphism/polymorphisms in enxymes may change response to prescribed drug CLASSES\BETA BLOCKERS\ANTI DEPRESSANTS/Cytohchrome P450\may be inhibited or induced by drug / this causes drug-drug interactions (unanticipated adverse reactions r therapeutic failures)WARFARINANTIDEPRESSANTS ANTIEPILEPTIC STATINS >>> CYTOCHROME P450 ENZYME******EVERYONE IS SUBJECTED DIFFERENT ENZYME POLYMORPHISM**********EVERYONE IS SUBJECTED DIFFERENT ENZYME POLYMORPHISM**********EVERYONE IS SUBJECTED DIFFERENT ENZYME POLYMORPHISM****\\Cytochrome P450 (CYP450)/enzyme for making:\CHOLESTEROL\STEROIDS\PROSTACYCLINS\THROMBOXANE A2/also detoxify foreign chemicals and metabolisms of drugs/they are bound to membranes inside cell (CYT)/contain heme pigment (CHROME and P)\absorbs light @ wavelength of 450 nm when exposed to carbon monoxide (WHAT DOES THIS MEAN?)/CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5\metabolize 90% of drugs\predominantly expressed in liver\small intestines as well/REDUCES BIOAVAILABILITY\lungs, placenta, kidneys as well\\PHARMOCOGENETICS/1 out of every 15 WHITE or BLACK persons may have exaggerated response to standard doses of BETA BLOCKERS\metoprolol [LOPRESSOR]\or no response to the analgesi tramadol (ULTRAM)\CYP450 MESSED UP METABOLISM due to polymorphism/A specific gene encodes each CYP450 enzyme\every person inherits one genetic allele from each parent/"WILD TYPE" or "VARIANT" (wild type most common)/"EXTENSIVE" metabolizer has received two copies of wild-type allels/POLYMORPHISM OCCURS WHEN VARIANT ALLELE REPLACES ONE OR BOTH WILD-TYPE ALLELS\VARIANT ALLELES usually encode a CYP450 that has reduced or no activity\Persons with two copies of variant alleles = "POOR" Metabolizers/those with one wild-type and one variant allele have reduced enzyme activity/Some persons inherit multiple copies of wild-type alleles\EXCESS ENZYME ACTIVITY/"ULTRARAPID" METABOLIZER\\CYP450 POLYMORPHISM/Responsible for observed variation in drug response in patients of dif ethnic origins\7% White ppl, 2-7% black ppl are POOR Metabolizers of drugs dependent on CYP2D6/CYP2D6 metabolizes many BETA blockers, antidepressants and opioids\1 in 5 Asian persons is a poor metabolizer of drugs dependent CYP2C19/Metabolizes PHENYTOIN (Dilantin), PHENOBARBITAL, OMEPRAZOLE (Prilosec), and other ###FIND OUT MORE###\\CLINICAL RECOMMENDATION/"Genotype testing may predict persons who are poor metabolizers or are nonresponsive to drugs metabolized by CYP450 enzymes"\Large prospectibve trials needed/"Genetic Variations in CYP450 metabolism should be considered when patients exhibit unusual sensitivity or resistance to drug effects at normal doses\Studies demonstrate a link between adverse effects and variant CYP450 alleles/"Patients should be monitored closely for the development of adverse drug effects or therapeutic failureswhen a potent CYP450 enzyme metabolized by one or more CYP450 enzyme"\Well-recognized cause of clinically significant drug interaction/"Severe toxicity can result if CYP450 enzyme-inhibiting drugs are added to the following medications: atypical, antipsychotics, benzodiazepines, cyclosporine (Sandimmune), slatins, or warfarin (Coumadin)\particularly true if substrate drug depends on only one CYP450 enzyme for metabolism/"Because they are known to cause cliniclly significant CYP450 drug interactions, always use caution when adding the following substances to medications that patients are taking: AMIODARONE (CORDARONE), ANTIEPILEPTIC DRUGS, ANTIDEPRESSANTS, ANTITUBERCULAR DRUGS, GRAPEFRUIT JUICE, MACROLIDE AND KETOLIDE ANTIBIOTICS, NONDIHYDROPINE, CALCIUM CHANNEL BLOCKERS, OR PROTEASE INHIBITERS"\Are either potent inhibiters or inducers of CYP450 enzymes\\DRUG INTERACTIONS/Many drug interaction result from alteration of CYP450 metabolism\terfenadine (Seldane), astemizole (Hismanal), gastrointestinal motility agent cisapride (Propulsid),/withdrawn from US Market because metabolic inhibition by other drugs (life-threatening arrhythmias)/Calcium channel blocker mibefradil (Posicor) also withdrawn '98 - potent enzyme inhibitor that resulted in toxic levels of other cardiovascular drugs/Drugs interact with CYP450 system in many ways+\can be metabolized by only one (metoprolol by CYP2D6)\multiple enzymes (e.g., warfarin [Coumadin] by CYP1A2, CYP2D6, CYP3A4)\drugs that cause CYP450 metabolic Dr.int. are INHIBITORS or INDUCERS/Inhibitors block metabolic activity of 1+ CYP450 enzymes/dose and ability to bind to enzyme affects the extent of metabolism/sertraline (Zoloft) is a mild inhibitor of CYP2D6 at 50 mg (200 mg = potent) - effects occur fastSIGNIFICANT CYTOCHROME P450 ENZYMES AND THEIR INHIBITORS, INDUCERS, AND SUBSTRATES\\\\\\\\\\\\ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \\ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \CYP1A2\ \Potent inhibitors\Amiodarone (Cordarone)\cimetidine (Tagamet)\ciprofloxacin (Cipro)\fluvoxamine (Luvox)\ \potent inducers\Carbamazepine (Tegretol)\phenobarbital\rifampin (Rifadin)\tobacco\ \substrates\Caffeine\clozapine (Clozaril)\teheophylline\ \ \ \CYP2C9\ \potent inhibitors\Amiodarone (Cordarone)\fluconazole (Diflucan)\metronidazole (Flagyl)\fluvoxamine (Luvox)\ritonavir (Norvir)\trimethoprim/sulfamethoxazole (Bactrim, Septra)\ \potent inducers\Carbamazepine (Tegretol)\phenobarbital\rifampin (Rifadin)\tobacco\ \substrates\Caffeine\clozapine (Clozaril)\teheophylline\ \ \ \CYP2C19\ \potent inhibitors\Fluvoxamine\isoniazid (INH)\ritonavir\ \potent inducers\Carbamazepine\phenytoin\rifampin\ \substrates\Omeprazole (Priolsec)\phenobarbital, phenytoin\ \ \ \CYP2D6\ \potent inhibitors\Amiodarone\cimetidine\diphenhydramine (Benadryl)\fluxetine\paroxetine (Paxil)\quinidine\ritonavir\terbinafine\ \potent inducers\No Significant inducers\ \substrates\Amitriptyline \carvedilol \codeine \donepezil (Aricept) \haloperidol (Haldol) \metaprolol (Lopressor) \paroxetine \risperidone (Risperdal) \tramadol (Ultram)\ \ \ \CYP3A4 and CYP3A5\ \potent inhibitors\Clarithromycin (Biaxin)\diltiazem (Cardizem)\erythromycin\grapefruit juice\itraconazole (Sapranox)\ketoconazole (Nizoral)\nefazodone (Serzone)\ritonavir\telithromycin (Ketek)\verapamil (Calan)\ \potent inducers\Carbamaepine\Hypercium perforatum (St. Jonh's wort)\phenobarbital\phenytoin\rifampin\ \substrates\Alprazolam (XANAX)\amlodipine (NORVASC)\atorvastatin (LIPITOR)\cyclosporine (SANDIMMUNE)\diazepam (VALIUM)\estradiol (ESTRACE)\simvasatin (ZOCOR)\sildenafil (VIAGRA)\verapamil zolpidem (AMBIEN)\\Drug can be metabolized by and inhibit same enzyme (e.g., erythromycin)\can also be metabolized by one enzyme and inhibit another enzyme (e.g., terbinafine [Lamisil])\intentionally combined to take advantage of CY450 Inhibition\Ritonavir (Norvir) - protease inhibitor and potent CYP3a4 inhibitor + lopinavir (Kaletra) to amp serum levels with human immunodeficiency virus\Inducers increa CYP450 enzyme activity by increasing enzyme synthesis\there is delay before enzyme activity increases - depending on half-life of drug induced\decrease contentration of drug metabolized by CYP2C9 can occur ~24hours~ after inducing of Rifadin - inducer w/ short half-life\can go up to one week after taking phenobarbital - inducer w/ long half-life\metabolized by same CYP450 enzyme that induces\Carbamazepine (Tegretol) - potent enzyme inducer - must start at low dose then increased at weekly intervals - half life gradually decreases over timeADVERSE DRUG EFFECTS\Standard doses may cause adverse effects related to elevated drug serum levels if one has poor metabolizer or CYP450 enzyme inhibitor added\effects are more likely if drug has narry saftey range or dependent on only 1 enzyme for metabolism\A woman was treated with Paxil for panic disorder\she developed hypertension\prescribed 50 mg daily of extended-release meoprolol (Toprol XL)\woman becomes symptomatically orthostatic ###FIND OUT MORE### \metoprolol is metabolized solely by CYP2D6, and present in higher serum levels because of paroxetine\Peak serum levels of Zocor (Metabolized solely by CYP3A4) can increase by a lot w/ those with poor metabolizers or w/ addition of potent inhbitor\e.g., verapamil [Calan], nefazodone [Serzone; brand not available in US]), increasing risk of myopathy + rhabdomyolysis at usual doses\Some drugs like dramadol or losartan (COZAAR) are not therapeutic until they are metabolized by active compounds\known as prodrugs - can cause exaggerated therapeutic effect or adverse effect when CYP450 inducer is added\if CYP450 inhibitor is combined with a prodrug, or a person has poor metabolizer of a prodrug, therapeutic failure is likely because of no production of the active drugGENOTYPE TESTING\Genotyping for CYP450 polymorphism has been for reasearch purposes or drug trails\FDA approved first genotype test for physicians to guide selection of medications metabolized by CYP450 enzymes\Amplichip CYP450 test is a DNA microarray that can detect 29 polymorphisms of CYP2D6 and two polymorphisms of CYP2C19 using blood sample\There is evidence ofa link between adverse effects and polymorphisms coding for reduced CYP450 activity, large prospective clinical trials are needed to determine whether use of genotyping in clinical practice is cost-effective and improves outcomes by preventing adverse drug effects or identifying poor responders