Enzymes and efflux transporters involved in the metabolism and distribution of neuropsychopharmacological compounds
Drugs | Enzymes and transporters | References |
---|---|---|
Acamprosate | Not metabolized | [1033] |
Agomelatine | CYP1A2, CYP2C19, CYP3A4 | [126, 721] |
Alprazolam | CYP3A4/5 | [24, 905] |
Amantadine | 90 % is excreted unchanged via the kidney | [38] |
Amisulpride | more than 90 % is excreted unchanged via the kidney | [1018] |
Amitriptyline | CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A3, UGT1A4, UGT2B10, P-gp (ABCB1) | [84, 150, 516, 878, 1187, 1215, 1216, 1293] |
Amitriptyline oxide | Flavin monooxygenase, CYP2C19, CYP2D6 | [150, 276] |
Amphetamine (dexamphetamine, lisdexamfetamine) | CYP2D6 | [55] |
Aripiprazole | CYP2D6, CYP3A4, P-gp (ABCB1) | [509, 639, 832, 1273] |
Asenapine | CYP1A2, UGT1A4 | [222, 1285] |
Atomoxetine | CYP2C19, CYP2D6, P-gp (ABCB1) | [217, 805, 1354] |
Benperidol | Unknown | [1068] |
Benserazide | Hydroxylation, COMT | [594] |
Biperiden | Unknown | [1146] |
Brexpiprazole | CYP3A4, CYP2D6 | [443] |
Brivaracetam | CYP2C8, renal elimination | [1042] |
Bromazepam | CYP2C19, CYP3A4 | [26, 877] |
Bromocriptine | CYP3A4 | [938] |
Bromperidol | CYP3A4 | [388, 1156, 1176, 1337] |
Brotizolam | CYP3A4 | [1193] |
Buprenorphine | CYP2C8, CYP3A4, UGT1A3, UGT2B7 | [129, 817] |
Bupropion | CYP2C19, CYP2B6, CR | [232, 514] |
Buspirone | CYP3A4 | [748] |
Cabergoline | Unknown, CYP3A4, P-gp (ABCB1) | [54, 278] |
Caffeine | CYP1A2, CYP2A6, xanthine oxidase, NAT | [15, 386, 475] |
Carbamazepine | CYP1A2, CYP2C8, CYP3A4/5, UGT2B7, P-gp (ABCB1), BCRP (ABCG2), epoxide hydrolase | [586, 618, 730, 906, 1214, 1280] |
Carbidopa | Loss of the functional hydrazine group, 1/3 not metabolized | [1030, 1261] |
Cariprazine | CYP2D6, CYP3A4 | [174, 840] |
Chlordiazepoxide | CYP3A4 | SPC |
Chlorpromazine | CYP1A2, CYP2D6, P-gp (ABCB1) | [1277, 1316] |
Chlorprothixene | Probably CYP2D6, CYP3A4 | |
Citalopram | CYP2C19,CYP2D6, CYP3A4, P-gp (ABCB1) | [158, 384, 1339] |
Clobazam (norclobazam) | CYP2C19, CYP3A4 | [271] |
Clomethiazol | CYP2A6, CYP3A4 | [189] |
Clomipramine | CYP1A2, CYP2C19, CYP2D6, CYP3A4, UGT2B10 | [412, 878] |
Clonazepam | CYP3A4 | [1070] |
Clorazepat | CYP2C19, CYP3A4 | |
Clozapine | CYP1A2, CYP2C19,CYP3A4, P-gp (ABCB1) | [568, 884, 1232, 1278] |
Cocain | Carboxylesterase 1 and 2, pseudocholinesterase, CYP3A4 | [776] |
Codeine | CYP2D6, CYP3A4, UGT2B4, UGT2B7 | [802, 878] |
Cyamemazine | CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 | [45] |
Dapoxetine | CYP2D6 | [1333] |
Desipramine | CYP2D6 | [412] |
Desvenlafaxine | CYP3A4, CYP2C19, UGT | [63] |
Dextroamphetamine | CPY2D6 | [55] |
Diacetylmorphine (heroin) | Carboxylesterase 2 and 1, UGT | [776, 802, 878] |
Diazepam | CYP2B6, CYP2C19, CYP3A4, UGT2B7, P-gp (ABCB1) | [387, 846, 1275] |
Dihydroergocryptine | CYP3A4 | [29, 274] |
Diphenhydramine | CYP2D6, UGT1A4, UGT2B10, P-gp (ABCB1) | [17, 846, 878] |
Disulfiram | CYP1A2, CYP2A6, CYP2B6, CYP2E1, CYP3A4 | [743] |
Donepezil | CYP2D6,CYP3A4, P-gp (ABCB1) | [863, 1242] |
Dothiepin = Dosulepin | CYP2C19,CYP2D6 | [1341] |
Doxepin | CYP2C9, CYP2C19, CYP2D6 | [488, 633] |
Doxylamine | Unknown | |
Dronabinol | CYP2C9, CYP3A4, UGT1A9, UGT1A7, UGT1A8, UGT1A10 | [119, 787, 878] |
Duloxetine | CYP1A2,CYP2D6, P-gp (ABCB1) | [726, 1024] |
Entacapone | UGT1A9 | [687] |
Escitalopram | CYP2C19,CYP2D6, CYP3A4, P-gp (ABCB1) | [166, 1207, 1268] |
Ethanol | Alcohol dehydrogenase, CYP2E1 | [193] |
Felbamate | Renal excretion | [995] |
Flunarizine | CYP2D6 | [841] |
Flunitrazepam | CYP2C19, CYP3A4 | [228, 392] |
Fluoxetine | CYP2B6, CYP2C9, CYP2C19, CYP2D6, P-gp (ABCB1) | [723, 1064] |
Flupenthixol | CYP2D6 | [254, 633] |
Fluphenazine | CYP2D6, P-gp (ABCB1) | [1352, 1353] |
Flurazepam | CYP2C19, CYP3A4 | [1061] |
Fluspirilen | Renal excretion, CYP3A4 | [1113] |
Fluvoxamine | CYP2D6, CYP1A2, P-gp (ABCB1) | [303, 611, 814] |
Gabapentin | Not metabolized, renal excretion | [123] |
Galantamine | CYP2D6, CYP3A4 | [58] |
Gammahydroxybutyric acid (GHB) | Beta-Oxidation | [710] |
Guanfacine | CYP3A4, epoxide hydratase, UGT | [623] |
Haloperidol | CYP2D6, CYP3A4, AKR, UGT, P-gp (ABCB1) | [73, 154, 1176, 1277] |
Heroin (diacetylmorphine) | Carboxylesterase 2 and 1, UGT | [776, 802, 878] |
Iloperidone | CYP2D6,CYP3A4 | [175] |
Imipramine | CYP1A2, CYP2C19, CYP2D6,CYP3A4, UGT1A4, UGT2B10 | [412, 744, 878] |
Lamotrigine | UGT1A4, UGT3B7, P-gp (ABCB1), BCRP (ABCG2) | [201, 1281] |
Levetiracetam | Not metabolized, P-gp (ABCB1) | [849] |
Levodopa | DDC,COMT, MAO | [1030] |
Levomepromazine | CYP3A | [61, 1315] |
Levomethadone | CYP2B6, CYP3A4, CYP2D6 | [249] |
Levomilnacipran | CYP3A4, P-gp (ABCB1) | [166, 901] |
Levosulpiride | P-gp (ABCB1) | [214] |
Lisdexamfetamine | Erythrocyte peptidase, CYP2D6 | [668] |
Lisuride | CYP3A4, CYP2D6 | [975] |
Lithium | No metabolism, renal clearance | [424, 1125] |
Lorazepam | UGT2B15 | [275, 334, 878] |
Loxapine | CYP3A4, CYP2D6, CYP1A2, CYP2C8, CYP2C19, FMO | [736] |
Lurasidone | CYP3A4 | [213] |
Maprotiline | CYP2D6, CYP1A2 | [140] |
Medazepam | CYP2B6, CYP2C19, CYP3A4 | SPC |
Melatonin | CYP1A2 | [489] |
Melperone | Unclear | [135] |
Memantine | Scarcely metabolized | [419] |
Methadone | CYP2B6,CYP3A4, CYP2D6, ABCB1 | [249, 718, 1082, 1203] |
Methylphenidate | Carboxylesterase 1 | [844] |
Mianserine | CYP2D6,CYP1A2, CYP3A4 | [664] |
Midazolam | CYP3A4, UGT1A4 | [372, 878] |
Milnacipran | CYP3A4,ABCB1, renal excretion | [166, 704, 904, 968] |
Mirtazapine | CYP3A4, CYP1A2, CYP2D6 | [712, 1150] |
Moclobemide | CYP2C19,CYP2D6 | [423] |
Modafinil | Amide hydrolysis, CYP3A4 | [1003, 1323, 1324] |
Morphine | CYP2C8, CYP3A4, UGT2B7 | [262, 620, 776] |
Nalmefene | UGT | [297] |
Naloxone | UGT2B7, AKR1C | [73, 878] |
Naltrexone | AKR1C4 | [73, 152] |
Nicotine | CYP2A6, UGT1A1, UGT1A2, UGT2B10 | [104] |
Nitrazepam | CYP3A4 | [1171] |
Nordazepam | CYP3A4, CYP2C19 | [887, 1171] |
Nortriptyline | CYP2D6, P-gp (ABCB1) | [675, 885, 1215, 1249] |
Olanzapine | UGT1A4, UGT2B10, Flavin monooxigenase, CYP1A2, CYP2D6, P-gp (ABCB1) | [176, 337, 878, 1277] |
Opipramol | CYP2D6 | SPC |
Oxazepam | UGT1A9, UGT2B7, UGT2B15 | [246, 878] |
Oxcarbazepine | AKR, UGT2B15, P-gp (ABCB1) | [73, 878, 1279] |
Paliperidone ( = 9-Hydroxyrisperidone) | 60 % excreted unmetabolized, CYP3A4, UGT, P-gp (ABCB1), BCRP (ABCG2) | [273, 303, 461, 1250, 1277, 1278] |
Paroxetine | CYP2D6, CYP3A4, P-gp (ABCB1) | [303, 351, 596, 1215, 1256] |
Perampanel | CYP3A4, CYP2B6, UGT1A1, UGT1A4 | [910] |
Perazine | CYP1A2, CYP2C9, CYP2C19, CYP3A4, Flavin monooxigenase | [1149, 1316] |
Pergolide | CYP3A4 | [1329] |
Perphenazine | CYP1A2, CYP2C19, CYP2D6, CYP3A4 | [16, 886] |
Phenobarbital | CYP2C19, UGT1A4 | [34] |
Phenytoin | CYP2C9, CYP2C19, UGT2B15 | [730] |
Pimozide | CYP1A2, CYP2D6, CYP3A4 | [285, 1011] |
Pipamperone | Unknown | |
Piribedil | Demethylation, p-hydroxylation, and N-oxidation | [279] |
Pramipexole | Not metabolized | [97] |
Prazepam | CYP2C19, CYP3A4 | SPC |
Pregabalin | Not metabolized, renal excretion | [123] |
Promazine | CYP1A2, CYP2A6, CYP2C19, CYP3A4 | [1318] |
Promethazine | CYP2D6 | [839] |
Quetiapine | CYP3A4, CYP2D6, ABCB1 | [65, 1277] |
Rasagiline | CYP1A2 | [458] |
Reboxetine | CYP3A4 | [510, 1299] |
Retigabine | NAT, UGT | [1197] |
Risperidone | CYP2D6,CYP3A4, P-gp (ABCB1), BCRP (ABCG2) | [303, 461, 1278, 1330] |
Rivastigmine | Cholinesterase | |
Ropinirole | CYP1A2 | [614] |
Rotigotine | CYP2C19, CYP1A1, CYP1A2, CYP2D6, CYP3A4, SULT1A1, SULT1A2, SULT1A3, SULT1B1, SULT1C4, SULT1E1, UGT | [187, 279, 335, 579] |
Rufinamide | Carboxylesterase | [936] |
Selegiline | CYP2B6 | [95] |
Sertindole | CYP2D6, CYP3A4 | [1322] |
Sertraline | CYP2B6, CYP2C19,CYP2C9, CYP2D6, CYP3A4, UGT1A1, P-gp (ABCB1) | [876, 1215, 1276] |
Sulpiride | Not metabolized, renal excretion, P-gp (ABCB1) | [214] |
Temazepam | CYP219, UGT2B7 | [622, 887] |
Tetrahydrocannabinol, THC | CYP2C9, CYP3A4 | [776, 1151] |
Thioridazine | CYP1A2,CYP2D6, CYP3A4 | [1184, 1294] |
Tianeptine | Beta oxidation | [449] |
Tiapride | Not metabolized | [865] |
Tolcapone | COMT, CYP2A6, CYP3A4, UGT | [687] |
Topiramate | UGT, P-gp (ABCB1) | [730] |
Tranylcypromine | MAO, unclear | [64] |
Trazodone | CYP3A4,CYP2D6 | [442, 1019] |
Triazolam | CYP3A4 | [439] |
Trifluoperazine | UGT1A4 | [878] |
Trimipramine | CYP2C19, CYP2D6,CYP2C9, CYP3A4, UGT2B10 | [319, 878] |
Valproic acid | UGT1A3, UGT1A6, UGT2B7, CYP2A6, CYP2B6, CYP2C9, CYP219, beta-oxidation | [878, 1169] |
Venlafaxine | CYP2C19, CYP2D6, CYP2C9, CYP3A4, P-gp (ABCB1) | [367, 606, 788] |
Vilazodone | CYP3A4, ABCB1 | [128, 166] |
Vortioxetine | CYP2D6,CYP3A4, CYP2A6, CYP2C9, P-gp (ABCB1) | [548] |
Zaleplone | Aldehyde oxidase, CYP3A4 | [993] |
Ziprasidone | CYP3A4, aldehyde oxidase | [93, 950] |
Zolpidem | CYP1A2, CYP2C9, CYP3A4 | [1269] |
Zopiclone | CYP2C8, CYP3A4 | [92, 1202] |
Zotepine | CYP1A2, CYP2D6, CYP3A4 | [1083] |
Zuclopenthixol | CYP2D6 | [559] |
Inhibitors of CYP enzymes involved in drug metabolism.
Inhibiting drugs | Inhibited enzymes | References |
---|---|---|
Amiodarone | CYP2C9, CYP2D6, CYP3A4 | [790] |
Amprenavir | CYP3A4 | [1313] |
Aprepitant | CYP3A4 | [749] |
Atazanavir | CYP3A4 | [1266] |
Boceprevir | CYP3A4 | [407] |
Bupropion | CYP2D6 | [663] |
Cimetidin | CYP1A2, CYP2D6, CYP3A4 | [769] |
Ciprofloxacin | CYP1A2, CYP3A4 | [76] |
Clarithromycin | CYP3A4 | [969] |
Clomethiazole | CYP2E1 | [296] |
Clopidogrel | CYP2B6 | [996] |
Crizotinib | CYP3A4 | [761] |
Diltiazem | CYP3A4 | [1154] |
Disulfiram | CYP2E1 | [619] |
Duloxetine | CYP2D6 | [1096] |
Enoxacin | CYP1A2 | [1112] |
Erythromycin | CYP3A4 | [883] |
Esomeprazole | CYP2C19 | [879] |
Felbamate | CYP2C19 | [981] |
Fluconazole | CYP2C9, CYP3A4 | [860] |
Fluoxetine and norfluoxetine | CYP2D6, CYP2C19, CYP3A4 | [572] |
Fluvoxamine | CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 | [572] |
Fosamprenavir | CYP3A4 | [1313] |
Gemfibrocil | CYP2C8 | [59] |
Grapefruit juice | CYP3A4 | [1128] |
Indinavir | CYP3A4 | [1270] |
Isoniazid | CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP3A4, MAO | [859] |
Itraconazol | CYP3A4 | [1173] |
Ketoconazol | CYP3A4 | [293] |
Levomepromazine | CYP2D6 | [1258] |
Melperone | CYP2D6 | [502] |
Metoclopramide | CYP2D6 | [724] |
Miconazol | CYP2C9, CYP3A4 | [860] |
Moclobemide | CYP2C19, CYP2D6, MAO-A | [215, 423, 485] |
Nelfinavir | CYP3A4 | [629] |
Norfloxacine | CYP1A2 | [385] |
Omeprazole | CYP2C19 | [1282] |
Paroxetine | CYP2D6 | [572] |
Perazine | CYP1A2 | [360, 1317] |
Phenylpropanolamin | CYP1A2 | [182] |
Posaconazole | CYP3A4 | [667] |
Propafenon | CYP1A2, CYP2D6 | [804] |
Quinidine | CYP2D6 | [142] |
Ritonavir | CYP2D6, CYP3A4 | [72, 629, 1270] |
Saquinavir | CYP3A4 | [72] |
Telaprevir | CYP3A4 | [394] |
Telithromycine | CYP3A4 | [601] |
Ticlopidine | CYP2B6, CYP2C19 | [996] |
Tranylcypromine | CYP2A6, MAO | [411] |
Valproate | CYP2C9 | [291, 460] |
Verapamil | CYP3A4 | [692] |
Voriconazol | CYP2B6, CYP2C9, CYP2C19, CYP3A4 | [179] |
Zileuton | CYP1A2 | [426] |
Inducers of enzymes and efflux transporters involved in drug metabolism and distribution.
Inducing drugs | Induced enzymes or ABC transporters | Comments | References |
---|---|---|---|
Bosentan | CYP3A4 | [764] | |
Carbamazepine | CYP1A2, CYP2B6, CYP2C9, CYP3A4, P-gp (ABCB1), UGT | Increase of CYP3A4 ativity within 3 weeks, induction of its own metabolism | [12, 266, 409, 882, 1122] |
Efavirenz | CYP2B6, CYP3A4 | [1004] | |
Ethanol | CYP2E1 | Induction may lead to metabolic tolerance | [590, 708] |
Isoniazide | CYP2E1 | Initial inhibition and then induction of CYP2E1 | [1069, 1343] |
Lamotrigine | UGT | [266] | |
Modafinil | CYP1A2, CYP2B6, CYP3A4 | [1002] | |
Oxybutynin | CYP3A4 | [452] | |
Phenobarbital | CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, UGT1A1 | [742] | |
Phenytoin | CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, UGT | [60, 266] | |
Primidon | CYP2C9, CYP2C19, CYP3A4 | [935] | |
Rifabutin | CYP3A4 | Induction of own metabolism | [1349] |
Rifampicin | CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4 | After induction by rifampicin, CYP2C19 and CYP3A4 activities remain elevated for 4 days after discontinuation and return to baseline levels within 8 days | [552, 742] |
Ritonavir | CYP2C9,CYP3A4 (high dose), UGT | [368] | |
Smoke | CYP1A2 | Maximal increase by 10 or more cigarettes per day, decrease of CYP1A2 activity within 3 days after smoking cessation | [342, 343] |
St. Johns wort | CYP3A4,CYP2C9, P-gp (ABCB1) | [466] |
Inducers of enzymes and efflux transporters involved in drug metabolism and distribution.
Drugs and active -metabolites | Therapeutic reference range | t1/2 (h) | Laboratory alert level | Level of recommendation to use TDM | Con-version factor, CF | Comments | References |
---|---|---|---|---|---|---|---|
Agomelatine | 7–300 ng/mL (1–2 h after 50 mg) | 1–2 h | 600 ng/mL | 4 | 4.11 | Because of rapid elimination, trough drug concentrations are not measurable under chronic treatment; determinations, preferentially of Cmax, should be restricted to specific indications | [126] |
Inducers of enzymes and efflux transporters involved in drug metabolism and distribution.
Drugs and metabolites | CL/F±SD [mL/min] | F [%] | t1/2 [h] | Δt [h] | DRC mean | DRC low | DRC high | Commets | References |
---|---|---|---|---|---|---|---|---|---|
Agomelatine | 1,100±500 | 3 | 1.5 | 2 | 2.78 | 1.52 | 4.04 | Trough level at t=24 h are not measurable because of rapid elimination, CL affected by CYP1A2 | [126, 1110] |
Metabolite-to-parent compound ratios (MPR) for neuropsychopharmacological drugs. MPR ranges are mean ratios – SD to mean ratios + SD under steady-state and for trough levels.
Parent drugs | Metabolites | Metabolite-to-parent compound ratios | Major CYP enzymes involved | Comments | References |
---|---|---|---|---|---|
Amitriptyline | Nortriptyline | 0.2–1.8 (n = 83) | CYP2C19 | [984] | |
Aripiprazole | Dehydroaripiprazole | 0.3–0.5 (n = 283) | CYP3A4 | Similar ratio for oral and long-acting injectable form | [509, 637, 751, 815] |
Bromperidol | Reduced bromperidol | 0.11–0.51 (n = 31) | CYP3A4 | [1108, 1156] | |
Buprenorphine | N-Desmethylbuprenorphine | 1.58–2.36 (n = 29) | CYP3A4 | [772] | |
Bupropion | 6-Hydroxybuspirone | 11.2-21.0 (n=10) | CYP2B6 | Bupropion is unstable at room temperature | [259, 260, 421, 570] [621] |
Buspirone | 6-Hydroxybuspirone | 25–53 (n = 20) | CYP3A4 | [298] | |
Carbamazepine | Carbamazepine-10,11-epoxide | 0.07–0.25 (n = 14) | CYP3A4 | [577] | |
Cariprazine | N,N-Didesmethyl-cariprazine | 3 – 6 (n=38) | CYP3A4 | [174, 840] | |
Citalopram | N-Desmethylcitalopram | 0.31–0.60 (n = 2 330) | CYP2C19 | [988] | |
Clobazam | N-Desmethylclobazam | 2-10 (n > 150) | CYP3A4 | [271, 661] | |
Clomipramine | N-Desmethylclomipramine | 0.8–2.6 (n = 115) | CYP1A2, CYP2C19 | [984] |
Typical indications for measuring drug concentrations in blood of psychiatric or neurologic patients.
Obligatory TDM
Obligatory TDM
- Dose optimization after initial prescription or after dose change for drugs with a high level of recommendation to use TDM (see Table 4 )
- Drugs for which TDM is mandatory for safety reasons (e. g., lithium or carbamazepine)
- Uncertain adherence to medication
- Relapse prevention because of uncertain adherence to medication
- Lack of clinical improvement under recommended doses
- Relapse under maintenance treatment
- Determination of optimal individual drug concentration when the patient has attained the desired clinical outcome
- Recurrence of symptoms under adequate doses
- Clinical improvement and adverse effects under recommended doses
- Combination treatment with a drug known for its interaction potential or suspected drug interaction
- Use of counterfeit medications by the patient
- Presence of a genetic peculiarity concerning drug metabolism (genetic deficiency, gene multiplication)
- Patient with differential ethnicity
- Patient with abnormally high or low body weight
- Pregnant or breast feeding patient
- Children or adolescent patient
- Elderly patient (> 65 y)
- Patient with intellectual disability
- Forensic psychiatric patient
- Court case related to neuropsychiatric medications
- Patient with pharmacokinetically relevant comorbidity (hepatic or renal insufficiency, cardiovascular disease)
- Patient with acute or chronic inflammations or infections and treated with CYP1A2 dependent drugs
- Patient with restrictive gastrointestinal resection or bariatric surgery
- Problem occurring after switching from an original preparation to a generic form (and vice versa)
- Use of over the counter (OTC) drugs by the patient
- Pharmacovigilance programs