PHASE I  neuropsych Rx above dotted lines in all sections rev 2/11/2011 SUBSTRATES OF P450 ENZYMES [NOTE: * = AN , **= THE ACTIVE METABOLITE] 1A2 2C9 2C19 2D6 2E1 3A4 AED , AED phenytoin, phenobarb, AED , valproate antidep antidep antidep antidep antidep SSRI: SSRI: fluoxetine SSRI: , escital, SSRI: fluoxetine, fluvoxamine., SSRI:citalopram, , , sertraline paroxetine (minor), sertraline (minor) SNRI: SNRI: SNRI: duloxetine; venlafaxODV* : [a 3°] : both 3° and 2° TRICYCLICS: 3° only TRICYCLICS: 3° only ATYPICAL: ATYPICAL: mirtazapine, ATYPICALS: mirtazapine, mCPP (toxic metabolite of traz/nefaz) /mCPP (toxic) antiΨ FGA: all antiΨ FGA: all antiΨ FGA: all antiΨ FGA: , SGA: , SGA: , SGA: aripirazole, , , * risperidone (lesser), benzo () benzo diazepam benzo diazepam/; clonaz/midaz/estaz/triaz/; cognition/DAT tacrine (not loraz/oxaz/)

hypnotic // stimulant , , dextromethorph substance caffeine substance THC subst stimulants above, opiods below substance etOH substance ; opiods below antimicrobial antimicrobial antimicrobial antimicrobial antimicrobial MISC:sulfamethoxazole, ANTIRETROVIRAL: ANTIRETROVIRAL: ritonavir dapsone ANTIFUNG: itracon/ketoconazole trimethoprim nelfinavir, ritonavir ANTIRETROVIRAL: indinavir, anesthetic nelfinavir, ritonavir, saquinavir asthma theophylline asthma zafirlukast MACROLIDE:clarithro/erythromycin; [also at 2E1 & 3A4?] not azithro/dirithro/spira/telithro CV CV ACEI: irbe/losartan CV CV ANITARRHYTH: procainamide CV ANTIARRHYTHMIC:

ANTICOAG: warfarin ANTICOAG: warfarin ANTICOAG: clopidogrel** ANTICOAG: ticlopidine β-BLOCK: β-BLOCK: at least atenolol, CA-CHAN BLOCK: all carvedilol, metoprolol, STATIN: fluvastatin STATIN: all except pravastatin, propranolol, timolol fluvastatin, and rosuvastatin diabetes , glyburide, GI PPI:all GI hormone levonorgestrel (in , hormone ethinyl estradiol, hormone Norplant, Mirena IUD) , medroxyprogesterone, norethindrone, (prednisone), progesterone

immune cyclosporine, tacrolimus musc rel: cyclobenezaprine oncol cyclophosphamide* oncol ** oncol tamoxifen*(?) pain acetaminophenNAPQI pain NSAID: celecoxib, pain pain acetaminoph pain acetaminophenNAPQI (N-acetyl-p-benzoquinone diclofenac, flurbiprofen, OPIOD: NAPQI OPIOD: imine, a toxic metabolite) ibuprofen, naproxen, hydrocodoneh'morphone**? piroxicam oxycodoneo'morphone** M1* tramadolM1* sex sildenafil, , vardenafil INHIBITORS OF P450 ENZYMES [EFFECTS HAPPEN QUICKLY: HOURS TO DAYS] 1A2 2C9 2C19 2D6 2E1 3A4 AED (valproate) AED carbamazepine, oxcarb, , (valproate) antidep antidep antidep antidep antidep SSRI fluoxetine (mod) SSRI fluoxetine SSRI fluoxetine SSRI fluoxetine (strong) SSRI fluoxetine (weak-mod?) fluvoxamine fluvoxamine fluvoxamine paroxetine (strong) fluvoxamine (sertraline ) sertraline (sertraline? (weak evid))

SNRI duloxetine

ATYP (strong) ATYP nefazodone (strong)

trazodone

TCA imip/clomip/desip TCA (mod) antiΨ FGAS: all (?) antiΨ FGAS: haloperidol cognition/DAT tacrine SGAS: asenapine, stimulant clozapine (moderate) substance caffeine substance disulfiram substance cocaine, methadone subst disulfiram [food] grapefruit juice (hepatic) [food] grapefruit juice (hepatic) [food] grapefruit juice (hepatic) [food] watercress [food] grapefruit juice (gut), starfruit antimicrob antimicrob antimicrob ANTI-TB: antimicrob antimicrob antimicrob ANTI-TB: isoniazid ANTIFUNG: ketoconazole ANTIFUNG: , ANTIFUNG: fluconazole, ANTIFUNG: ketoconazole, terbinaf. ANTI-TB: isoniazid ANTIFUNG: all azoles (eg ketoconazole) ketoconazole ketoconazole, etoconazole ANTIRETROVIR: ritonavir ANTIRETROVIR:atazan/nelfin/riton/ indinavir [OTHERS? UPDATE COMING!] FLUOROQUIN: ciproflox (strong), MISC: sulfamethoxazole FLUOROQUIN: norfloxacin others? [not gemi/levoflox] antihist MACROLIDE: all but azithro/diritho/spira

CV CV CV CV ANTIARR: amiod, quinidine CV ANTIARRH: quinidine STATIN ANTICOAG: ticlopidine : fluvastatin ANTICOAG: ticlopidine β-BLOCK: lipohilics: β-BLOCK: lipohilics:

propranolol//timolol propranolol/pindolol/timolol CA-CHAN BLOCK: CA-CHAN BLOCK: , GI cimetidine GI cimetidine; PPIS: all GI cimetidine; PPIS: all GI cimetidine GI cimetidine pain NSAID: ibuprofen pain OPIOD: methadone

INDUCERS OF P450 ENZYMES [EFFECTS HAPPEN SLOWLY: DAYS TO WEEKS!] 1A2 2C9 2C19 2D6 2E1 3A AED carbamazepine AED carbamazepine, AED carbamazepine, AED carbamazepine, , phenytoin oxcarb (weak), phenytoin phenytoin, topiramate BARBIT: BARBIT: , BARBIT: phenobarbital BARBIT: all primidone, [2D6 not inducable in humans] antidep St. John’s wort antidep St. John’s wort antidep St. John’s wort

stimulant modafanil (weak) stimulant modafanil substance subst ethanol, substance methadone (early in Tx), smoked tobacco smoked tobacco smoked tobacco (<1A2)

[food]charbroiled/grilled meats, [food] fasting ↑ amts of cruciferous vegetable [condition] chronic antimicrob ANTI-TB:rifampin antimicrob ANTI-TB:rifampin antimicrob ANTI-TB:rifampin antimicrob ANTI-TB:rifampin/rifabutin alcoholism ANTIRETROVIRAL: , nevirapine CV ANTICOAG: warfarin diabetes diabetes insulin (moderate) [2D6 not inducable in humans] diabetes: pioglitazone GI PPI: (weak) hormone hormone:GLUCOCORTICOID:all? prednisone (weak) (includes prednisone (weak)),

medroxyprogesterone (weak)

PHASE II METABOLISM (mostly UGTs) ! CAVEATS Mostly glucuronidation (conjugation→more hydrophilic/excretable) NOTE! Not everything is significant; not all potentially significant interactions are via UGTs (uridine 5’-diphosphate glucuronosyltransferases); also acetylation listed; there are many other things that influence Rx levels. Examples follow.

SUBSTRATES OF PHASE II ENZYMES There are things NOT on the tables • all P450 enzymes (eg, 2B6 likely plays role in methadone metabolism) AED [UGT 1A4 &/or 2B7], valproate [multiple UGTs] • interactions of "lesser" significance (but these could matter, for example in the case of inhibition of a major pathway or induction of a minor pathway) antiΨ FGA: haloperidol • not all specialty Rx! Not comprehensive for HIV, oncology, rheumatology... SGA: asenapine [UGT 1A4], olanzapine [UGT 1A4], paliperidone • most “natural remedies” (eg, : may inhibit 1A2, 2C19, 2E1, 3A4?...There are multiple ingredients and different formulations...) benzo [acetylated]; , , temazepam [glucuronidated] Multiple sources of unpredictability subst [UGT 2B7], naltrexone, opiods below • may or may not reach clinical significance in general, or in a given individual • if multiple metabolic pathways, alternate pathway may “pick up the slack” [non-Rx] bilirubin • Pts with genetic variants of metabolic enzymes may have ↑’d or ↓’d sensitivity: antimicrob MACROLIDE:erythromycin enzyme variants associated populations ANTIRETROVIRAL:zidovudine 2C9/2C19 poor metabolizers Asians (<30%) African-Americans (<20%) pain acetaminophen & NAPQI (toxic metabolite); NSAIDS:some...; 2D6 ultrafast metabolizers Ethiopians (25%) OPIODS: , hydromorphone, morphine, tramadol Ex: need more fluoxetine Saudis (25%) INHIBITORS OF PHASE II ENZYMES poor metabolizers Chinese-Asians (<50%!) AED valproate [UGT 1A4] Ex: sensitive to fluoxetine African-Americans (<34%) [Absent in ~ 1/15 overall?] antidep sertraline [UGT 1A4] 3A4 miscellaneous (there is variation) [non-Rx] milk thistle There are other types of drug-drug interactions! antimicrob MACROLIDE: erythromycin • non-P450 metabolic (eg, beta-oxidation) gout probenecid • other pharmacokinetic: absorption (pH, P-gp), distribution (protein binding!) • pharmacodynamic (eg, additive effects, contradictory effects) INDUCERS OF PHASE II ENZYMES • idiosyncratic (eg, Li + FGAs → "NMS-like syndrome") AED carbamazepine [UGT 1A4], oxcarbazepine, phenytoin BARBITS: phenobarbital Many conditions/situations that can affect blood levels • hepatic/renal disease substance smoked tobacco • habitus, pregnancy... • is the Pt taking the Rx? taking too much Rx? antimicrob: ANTI-TB:rifampin hormone: ethinyl estradiol [UGT 1A4], progestins? ? FOR MORE INFO  metabolism effects of a given Rx: 1) Lexi-Comp (free via UW's link to UpToDate, pay for PDA access) 2) Micromedex (free via UW, PDA via browser if with UW) 3) the "Flockhart tables" at medicine.iupui.edu/clinpharm/ddis  interaction lookups: Lexi Interact, MicroMedex, ePocrates, Medscape For HIV Rx: depts.washington.edu/madclin/pharmacy/drugs/index.html www.hiv-druginteractions.org  latest version of ddiPad: will soon be available at ddipad.com!