TDM

Enzymes and efflux transporters involved in the metabolism and distribution of neuropsychopharmacological compounds


DrugsEnzymes and transportersReferences
AcamprosateNot metabolized[1033]
AgomelatineCYP1A2, CYP2C19, CYP3A4[126, 721]
AlprazolamCYP3A4/5[24, 905]
Amantadine90 % is excreted unchanged via the kidney[38]
Amisulpridemore than 90 % is excreted unchanged via the kidney[1018]
AmitriptylineCYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A3, UGT1A4, UGT2B10, P-gp (ABCB1)[84, 150, 516, 878, 1187, 1215, 1216, 1293]
Amitriptyline oxideFlavin monooxygenase, CYP2C19, CYP2D6[150, 276]
Amphetamine (dexamphetamine, lisdexamfetamine)CYP2D6[55]
AripiprazoleCYP2D6, CYP3A4, P-gp (ABCB1)[509, 639, 832, 1273]
AsenapineCYP1A2, UGT1A4[222, 1285]
AtomoxetineCYP2C19, CYP2D6, P-gp (ABCB1)[217, 805, 1354]
BenperidolUnknown[1068]
BenserazideHydroxylation, COMT[594]
BiperidenUnknown[1146]
BrexpiprazoleCYP3A4, CYP2D6[443]
BrivaracetamCYP2C8, renal elimination[1042]
BromazepamCYP2C19, CYP3A4[26, 877]
BromocriptineCYP3A4[938]
BromperidolCYP3A4[388, 1156, 1176, 1337]
BrotizolamCYP3A4[1193]
BuprenorphineCYP2C8, CYP3A4, UGT1A3, UGT2B7[129, 817]
BupropionCYP2C19, CYP2B6, CR[232, 514]
BuspironeCYP3A4[748]
CabergolineUnknown, CYP3A4, P-gp (ABCB1)[54, 278]
CaffeineCYP1A2, CYP2A6, xanthine oxidase, NAT[15, 386, 475]
CarbamazepineCYP1A2, CYP2C8, CYP3A4/5, UGT2B7, P-gp (ABCB1), BCRP (ABCG2), epoxide hydrolase[586, 618, 730, 906, 1214, 1280]
CarbidopaLoss of the functional hydrazine group, 1/3 not metabolized[1030, 1261]
CariprazineCYP2D6, CYP3A4[174, 840]
ChlordiazepoxideCYP3A4SPC
ChlorpromazineCYP1A2, CYP2D6, P-gp (ABCB1)[1277, 1316]
ChlorprothixeneProbably CYP2D6, CYP3A4 
CitalopramCYP2C19,CYP2D6, CYP3A4, P-gp (ABCB1)[158, 384, 1339]
Clobazam (norclobazam)CYP2C19, CYP3A4[271]
ClomethiazolCYP2A6, CYP3A4[189]
ClomipramineCYP1A2, CYP2C19, CYP2D6, CYP3A4, UGT2B10[412, 878]
ClonazepamCYP3A4[1070]
ClorazepatCYP2C19, CYP3A4 
ClozapineCYP1A2, CYP2C19,CYP3A4, P-gp (ABCB1)[568, 884, 1232, 1278]
CocainCarboxylesterase 1 and 2, pseudocholinesterase, CYP3A4[776]
CodeineCYP2D6, CYP3A4, UGT2B4, UGT2B7[802, 878]
CyamemazineCYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4[45]
DapoxetineCYP2D6[1333]
DesipramineCYP2D6[412]
DesvenlafaxineCYP3A4, CYP2C19, UGT[63]
DextroamphetamineCPY2D6[55]
Diacetylmorphine (heroin)Carboxylesterase 2 and 1, UGT[776, 802, 878]
DiazepamCYP2B6, CYP2C19, CYP3A4, UGT2B7, P-gp (ABCB1)[387, 846, 1275]
DihydroergocryptineCYP3A4[29, 274]
DiphenhydramineCYP2D6, UGT1A4, UGT2B10, P-gp (ABCB1)[17, 846, 878]
DisulfiramCYP1A2, CYP2A6, CYP2B6, CYP2E1, CYP3A4[743]
DonepezilCYP2D6,CYP3A4, P-gp (ABCB1)[863, 1242]
Dothiepin = DosulepinCYP2C19,CYP2D6[1341]
DoxepinCYP2C9, CYP2C19, CYP2D6[488, 633]
DoxylamineUnknown 
DronabinolCYP2C9, CYP3A4, UGT1A9, UGT1A7, UGT1A8, UGT1A10[119, 787, 878]
DuloxetineCYP1A2,CYP2D6, P-gp (ABCB1)[726, 1024]
EntacaponeUGT1A9[687]
EscitalopramCYP2C19,CYP2D6, CYP3A4, P-gp (ABCB1)[166, 1207, 1268]
EthanolAlcohol dehydrogenase, CYP2E1[193]
FelbamateRenal excretion[995]
FlunarizineCYP2D6[841]
FlunitrazepamCYP2C19, CYP3A4[228, 392]
FluoxetineCYP2B6, CYP2C9, CYP2C19, CYP2D6, P-gp (ABCB1)[723, 1064]
FlupenthixolCYP2D6[254, 633]
FluphenazineCYP2D6, P-gp (ABCB1)[1352, 1353]
FlurazepamCYP2C19, CYP3A4[1061]
FluspirilenRenal excretion, CYP3A4[1113]
FluvoxamineCYP2D6, CYP1A2, P-gp (ABCB1)[303, 611, 814]
GabapentinNot metabolized, renal excretion[123]
GalantamineCYP2D6, CYP3A4[58]
Gammahydroxybutyric acid (GHB)Beta-Oxidation[710]
GuanfacineCYP3A4, epoxide hydratase, UGT[623]
HaloperidolCYP2D6, CYP3A4, AKR, UGT, P-gp (ABCB1)[73, 154, 1176, 1277]
Heroin (diacetylmorphine)Carboxylesterase 2 and 1, UGT[776, 802, 878]
IloperidoneCYP2D6,CYP3A4[175]
ImipramineCYP1A2, CYP2C19, CYP2D6,CYP3A4, UGT1A4, UGT2B10[412, 744, 878]
LamotrigineUGT1A4, UGT3B7, P-gp (ABCB1), BCRP (ABCG2)[201, 1281]
LevetiracetamNot metabolized, P-gp (ABCB1)[849]
LevodopaDDC,COMT, MAO[1030]
LevomepromazineCYP3A[61, 1315]
LevomethadoneCYP2B6, CYP3A4, CYP2D6[249]
LevomilnacipranCYP3A4, P-gp (ABCB1)[166, 901]
LevosulpirideP-gp (ABCB1)[214]
LisdexamfetamineErythrocyte peptidase, CYP2D6[668]
LisurideCYP3A4, CYP2D6[975]
LithiumNo metabolism, renal clearance[424, 1125]
LorazepamUGT2B15[275, 334, 878]
LoxapineCYP3A4, CYP2D6, CYP1A2, CYP2C8, CYP2C19, FMO[736]
LurasidoneCYP3A4[213]
MaprotilineCYP2D6, CYP1A2[140]
MedazepamCYP2B6, CYP2C19, CYP3A4SPC
MelatoninCYP1A2[489]
MelperoneUnclear[135]
MemantineScarcely metabolized[419]
MethadoneCYP2B6,CYP3A4, CYP2D6, ABCB1[249, 718, 1082, 1203]
MethylphenidateCarboxylesterase 1[844]
MianserineCYP2D6,CYP1A2, CYP3A4[664]
MidazolamCYP3A4, UGT1A4[372, 878]
MilnacipranCYP3A4,ABCB1, renal excretion[166, 704, 904, 968]
MirtazapineCYP3A4, CYP1A2, CYP2D6[712, 1150]
MoclobemideCYP2C19,CYP2D6[423]
ModafinilAmide hydrolysis, CYP3A4[1003, 1323, 1324]
MorphineCYP2C8, CYP3A4, UGT2B7[262, 620, 776]
NalmefeneUGT[297]
NaloxoneUGT2B7, AKR1C[73, 878]
NaltrexoneAKR1C4[73, 152]
NicotineCYP2A6, UGT1A1, UGT1A2, UGT2B10[104]
NitrazepamCYP3A4[1171]
NordazepamCYP3A4, CYP2C19[887, 1171]
NortriptylineCYP2D6, P-gp (ABCB1)[675, 885, 1215, 1249]
OlanzapineUGT1A4, UGT2B10, Flavin monooxigenase, CYP1A2, CYP2D6, P-gp (ABCB1)[176, 337, 878, 1277]
OpipramolCYP2D6SPC
OxazepamUGT1A9, UGT2B7, UGT2B15[246, 878]
OxcarbazepineAKR, 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]
ParoxetineCYP2D6, CYP3A4, P-gp (ABCB1)[303, 351, 596, 1215, 1256]
PerampanelCYP3A4, CYP2B6, UGT1A1, UGT1A4[910]
PerazineCYP1A2, CYP2C9, CYP2C19, CYP3A4, Flavin monooxigenase[1149, 1316]
PergolideCYP3A4[1329]
PerphenazineCYP1A2, CYP2C19, CYP2D6, CYP3A4[16, 886]
PhenobarbitalCYP2C19, UGT1A4[34]
PhenytoinCYP2C9, CYP2C19, UGT2B15[730]
PimozideCYP1A2, CYP2D6, CYP3A4[285, 1011]
PipamperoneUnknown 
PiribedilDemethylation, p-hydroxylation, and N-oxidation[279]
PramipexoleNot metabolized[97]
PrazepamCYP2C19, CYP3A4SPC
PregabalinNot metabolized, renal excretion[123]
PromazineCYP1A2, CYP2A6, CYP2C19, CYP3A4[1318]
PromethazineCYP2D6[839]
QuetiapineCYP3A4, CYP2D6, ABCB1[65, 1277]
RasagilineCYP1A2[458]
ReboxetineCYP3A4[510, 1299]
RetigabineNAT, UGT[1197]
RisperidoneCYP2D6,CYP3A4, P-gp (ABCB1), BCRP (ABCG2)[303, 461, 1278, 1330]
RivastigmineCholinesterase 
RopiniroleCYP1A2[614]
RotigotineCYP2C19, CYP1A1, CYP1A2, CYP2D6, CYP3A4, SULT1A1, SULT1A2, SULT1A3, SULT1B1, SULT1C4, SULT1E1, UGT[187, 279, 335, 579]
RufinamideCarboxylesterase[936]
SelegilineCYP2B6[95]
SertindoleCYP2D6, CYP3A4[1322]
SertralineCYP2B6, CYP2C19,CYP2C9, CYP2D6, CYP3A4, UGT1A1, P-gp (ABCB1)[876, 1215, 1276]
SulpirideNot metabolized, renal excretion, P-gp (ABCB1)[214]
TemazepamCYP219, UGT2B7[622, 887]
Tetrahydrocannabinol, THCCYP2C9, CYP3A4[776, 1151]
ThioridazineCYP1A2,CYP2D6, CYP3A4[1184, 1294]
TianeptineBeta oxidation[449]
TiaprideNot metabolized[865]
TolcaponeCOMT, CYP2A6, CYP3A4, UGT[687]
TopiramateUGT, P-gp (ABCB1)[730]
TranylcypromineMAO, unclear[64]
TrazodoneCYP3A4,CYP2D6[442, 1019]
TriazolamCYP3A4[439]
TrifluoperazineUGT1A4[878]
TrimipramineCYP2C19, CYP2D6,CYP2C9, CYP3A4, UGT2B10[319, 878]
Valproic acidUGT1A3, UGT1A6, UGT2B7, CYP2A6, CYP2B6, CYP2C9, CYP219, beta-oxidation[878, 1169]
VenlafaxineCYP2C19, CYP2D6, CYP2C9, CYP3A4, P-gp (ABCB1)[367, 606, 788]
VilazodoneCYP3A4, ABCB1[128, 166]
VortioxetineCYP2D6,CYP3A4, CYP2A6, CYP2C9, P-gp (ABCB1)[548]
ZaleploneAldehyde oxidase, CYP3A4[993]
ZiprasidoneCYP3A4, aldehyde oxidase[93, 950]
ZolpidemCYP1A2, CYP2C9, CYP3A4[1269]
ZopicloneCYP2C8, CYP3A4[92, 1202]
ZotepineCYP1A2, CYP2D6, CYP3A4[1083]
ZuclopenthixolCYP2D6[559]
Inhibitors of CYP enzymes involved in drug metabolism.


Inhibiting drugsInhibited enzymesReferences
AmiodaroneCYP2C9, CYP2D6, CYP3A4[790]
AmprenavirCYP3A4[1313]
AprepitantCYP3A4[749]
AtazanavirCYP3A4[1266]
BoceprevirCYP3A4[407]
BupropionCYP2D6[663]
CimetidinCYP1A2, CYP2D6, CYP3A4[769]
CiprofloxacinCYP1A2, CYP3A4[76]
ClarithromycinCYP3A4[969]
ClomethiazoleCYP2E1[296]
ClopidogrelCYP2B6[996]
CrizotinibCYP3A4[761]
DiltiazemCYP3A4[1154]
DisulfiramCYP2E1[619]
DuloxetineCYP2D6[1096]
EnoxacinCYP1A2[1112]
ErythromycinCYP3A4[883]
EsomeprazoleCYP2C19[879]
FelbamateCYP2C19[981]
FluconazoleCYP2C9, CYP3A4[860]
Fluoxetine and norfluoxetineCYP2D6, CYP2C19, CYP3A4[572]
FluvoxamineCYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4[572]
FosamprenavirCYP3A4[1313]
GemfibrocilCYP2C8[59]
Grapefruit juiceCYP3A4[1128]
IndinavirCYP3A4[1270]
IsoniazidCYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP3A4, MAO[859]
ItraconazolCYP3A4[1173]
KetoconazolCYP3A4[293]
LevomepromazineCYP2D6[1258]
MelperoneCYP2D6[502]
MetoclopramideCYP2D6[724]
MiconazolCYP2C9, CYP3A4[860]
MoclobemideCYP2C19, CYP2D6, MAO-A[215, 423, 485]
NelfinavirCYP3A4[629]
NorfloxacineCYP1A2[385]
OmeprazoleCYP2C19[1282]
ParoxetineCYP2D6[572]
PerazineCYP1A2[360, 1317]
PhenylpropanolaminCYP1A2[182]
PosaconazoleCYP3A4[667]
PropafenonCYP1A2, CYP2D6[804]
QuinidineCYP2D6[142]
RitonavirCYP2D6, CYP3A4[72, 629, 1270]
SaquinavirCYP3A4[72]
TelaprevirCYP3A4[394]
TelithromycineCYP3A4[601]
TiclopidineCYP2B6, CYP2C19[996]
TranylcypromineCYP2A6, MAO[411]
ValproateCYP2C9[291, 460]
VerapamilCYP3A4[692]
VoriconazolCYP2B6, CYP2C9, CYP2C19, CYP3A4[179]
ZileutonCYP1A2[426]
Inducers of enzymes and efflux transporters involved in drug metabolism and distribution.


Inducing drugsInduced enzymes or ABC transportersCommentsReferences
BosentanCYP3A4 [764]
CarbamazepineCYP1A2, CYP2B6, CYP2C9, CYP3A4, P-gp (ABCB1), UGTIncrease of CYP3A4 ativity within 3 weeks, induction of its own metabolism[12, 266, 409, 882, 1122]
EfavirenzCYP2B6, CYP3A4 [1004]
EthanolCYP2E1Induction may lead to metabolic tolerance[590, 708]
IsoniazideCYP2E1Initial inhibition and then induction of CYP2E1[1069, 1343]
LamotrigineUGT [266]
ModafinilCYP1A2, CYP2B6, CYP3A4 [1002]
OxybutyninCYP3A4 [452]
PhenobarbitalCYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, UGT1A1 [742]
PhenytoinCYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, UGT [60, 266]
PrimidonCYP2C9, CYP2C19, CYP3A4 [935]
RifabutinCYP3A4Induction of own metabolism[1349]
RifampicinCYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4After induction by rifampicin, CYP2C19 and CYP3A4 activities remain elevated for 4 days after discontinuation and return to baseline levels within 8 days[552, 742]
RitonavirCYP2C9,CYP3A4 (high dose), UGT [368]
SmokeCYP1A2Maximal increase by 10 or more cigarettes per day, decrease of CYP1A2 activity within 3 days after smoking cessation[342, 343]
St. Johns wortCYP3A4,CYP2C9, P-gp (ABCB1) [466]
Inducers of enzymes and efflux transporters involved in drug metabolism and distribution.


Drugs and active -metabolitesTherapeutic reference ranget1/2
(h)
Laboratory alert levelLevel of recommendation to use TDM
Con-version factor, CFCommentsReferences
Agomelatine7–300 ng/mL
(1–2 h after 50 mg)
1–2 h600 ng/mL44.11Because 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 metabolitesCL/F±SD
[mL/min]
F
[%]
t1/2
[h]
Δt
[h]
DRC meanDRC lowDRC highCommetsReferences
Agomelatine1,100±50031.522.781.524.04Trough 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 drugsMetabolitesMetabolite-to-parent compound ratiosMajor CYP enzymes involvedCommentsReferences
AmitriptylineNortriptyline0.2–1.8 (n = 83)CYP2C19[984]
AripiprazoleDehydroaripiprazole0.3–0.5 (n = 283)CYP3A4Similar ratio for oral and long-acting injectable form[509, 637, 751, 815]
BromperidolReduced bromperidol0.11–0.51 (n = 31)CYP3A4[1108, 1156]
BuprenorphineN-Desmethylbuprenorphine1.58–2.36 (n = 29)CYP3A4[772]
Bupropion6-Hydroxybuspirone11.2-21.0 (n=10)CYP2B6Bupropion is unstable at room temperature[259, 260, 421, 570] [621]
Buspirone6-Hydroxybuspirone25–53 (n = 20)CYP3A4[298]
CarbamazepineCarbamazepine-10,11-epoxide0.07–0.25 (n = 14)CYP3A4[577]
CariprazineN,N-Didesmethyl-cariprazine3 – 6 (n=38)CYP3A4[174, 840]
CitalopramN-Desmethylcitalopram0.31–0.60 (n = 2 330)CYP2C19[988]
ClobazamN-Desmethylclobazam2-10 (n > 150)CYP3A4[271, 661]
ClomipramineN-Desmethylclomipramine0.8–2.6 (n = 115)CYP1A2, CYP2C19[984]
Typical indications for measuring drug concentrations in blood of psychiatric or neurologic patients.


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)
Specific indications for TDM
  • 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