Supplementary Tables

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-glycoprotein) on Drug

Disposition and Potential Clinical Implications: Update of the Literature

Clinical Pharmacokinetics

Stefan Wolking,1 Elke Schaeffeler,2,3 Holger Lerche,1 Matthias Schwab,2,4# Anne T. Nies2,3

1 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler Strasse 3, 72076 Tübingen, Germany2 Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, 70376 Stuttgart, Germany3 University of Tübingen, Germany 4 Department of Clinical Pharmacology, University Hospital Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany

#Corresponding authorEmail: Matthias.Schwab@ikp-stuttgart.deTel: +49 711 8101 3700Fax: +49 711 85 92 95

1

Supplementary Table 1 Extended list of effects of ABCB1 polymorphisms on pharmacokinetics

Drug Article

C1236T

G2677T/A

C3435T

Haplotypes

Other SN

Ps

No. of patients Ethnicity Parameters EffectAnalgeticFentanyl Kim et al. [1] X X 196 patients, post-op Korean D NSMethadone Levran et al. [2] X X X X 11,15,33

44,47,48109 former heroin addicts Jewish

ancestryD 1236TT/2677TT/3435TT: D

AnticancerDocetaxel Fajac et al. [3] X X X X 8,10 86 patients, breast cancer Mixed AUC 3435TT: AUC in premenopausal

womenKim et al. [4] X X X 216 patients, breast cancer Korean AUC, AE, OS 3435TT: OS, AUC for

docetaxel, neutropenia for docetaxel

Doxorubicin Lal et al. [5] X X X X 62 patients, advanced breast cancer

Asian CL, Cmax, AUC 1236CC/2677GG/3435CC: AUC, Cmax, CL

Voon et al. [6] X 51 151 patients, breast cancer Asian AUC, CL, Cmax, t1/2, OS, PFS, neutrophil count

2677T: CL; rs2235047G: neutrophils, OS

Erlotinib Fukudo et al. [7] X X X 88 patients, NSCLC Japanese C0, CL, response, AE

NS

Imatinib Gurney et al. [8] X X X 22 patients, gastrointestinal tumor

UK CL/F 1236TT, 2677TT, 3435TT: CL/F, toxicity-related dose reduction

Irinotecan Han et al. [9] X X X X 107 patients, NSCLC Korean AUC, CL 2677TT/3435TT: AUCZhou et al. [10] X X X 29 patients, nasopharyngeal

carcinomaAsian Cmax, AUC,

CL, t1/2

3435CC: Cmax

Paclitaxel de Graan et al. [11] X 261 cancer patients mainly Caucasian

CL, AUC, Cmax, C0, response, AE

NS

Fransson et al. [12] X X 33 patients, gynecological cancer

Caucasian CL 2677TT: CL

Green et al. [13] X X X 38 patients, ovarian cancer Caucasian AUC, Cmax, CL, AE

2677GA: CL

2

Jiko et al. [14] X X 16 patients, urogenital cancer

Japanese CL, C0/D NS

Nakajima et al. [15] X X X 8 Japanese AUC 3435T: AUCSissung et al. [16] X X X 26 patients, advanced solid

tumorsCaucasian AUC, t1/2, 2677T, 3435T: neutrophils

Sunitinib Mizuno et al. [17] X X X 19 patients, renal carcinoma Japanese AUC24, AUC4 NSVincristine Guilhaumou et al.

[18]X X X X 20 children, solid tumor Caucasian C, C

intracellular, AE

NS

Bicalutamide Kim et al. [19] X X X 27 healthy subjects Korean C NSAntiepilepticCarbamazepine Meng et al. [20] X X X X 84 patients, epilepsy Chinese C0 3435TT: C0

Ozgon et al. [21] X 97 patients Turkish C0/D, response NSPuranik et al. [22] X X X 41,45 90 patients, epilepsy Mixed CL, t1/2 1236T: CL (in African

Americans)Seo et al. [23] X X X X 8 210 patients, epilepsy Japanese CL/F,

responder status

2677TT, 3435TT, 1236T/2677T/3435T: resistance

Zhu et al. [24] X X X 210 patients, epilepsy Chinese C0/D 3435CT: C0/DGabapentin Kang et al. [25] X 30 healthy subjects Korean Cmax, AUC, t1/2 NSLamotrigin Lovric et al. [26] X X X 222 patients, epilepsy Caucasian C0, C0/D 1236CC, 1236C/2677G/3435C:

C0/DPhenobarbital Basic et al. [27] X X 60 patients, generalized

epilepsyCaucasian CSF

concentration3435CT, 3435TT: CSF C

Phenytoin Ponnala et al. [28] X 127 patients, epilepsy Mixed C0 3435CC: lower C0

Valproate Turgut et al. [29] X 104 patients, bipolar disorder

Turkish C0 NS

AntiinfectiousAtazanavir Rodriguez-Novoa et

al. [30]X 74 HIV patients Caucasian C0 3435CC: C0

Rodriguez-Novoa et al. [31]

X 118 HIV patients Caucasian C0 3435T: C0

Atazanavir/Ritonavir

D’Avolio et al. [32] X X X 35 HIV patients Caucasian C0 2677GG: C0

Azithromycin He et al. [33] X X X 20 Healthy subjects Chinese Cmax 2677TT/3435TT: Cmax

Cloxacilline Yin et al. [34] X X X 18 healthy subjects Chinese CL, C0, Cmax 1236CC: C0 ,Cmax

Dicloxacilline Beringer et al. [35] X 11 patients, cystic fibrosis/ Caucasian CL 3435TT: CL

3

11 controlsPutnam et al. [36] X 18 healthy subjects Caucasian Cmax, AUC,

CLNS

Efavirenz Elens et al. [37] X 1 50 HIV patients Caucasian c.*193G: accumulation in peripheral mononuclear cells

Mukonzo et al. [38] X X X 12,20,21,23,26,28,30,36,38,53

121 healthy subjects African F c.*193G: F

Mukonzo et al. [39] X 53 99 HIV patients African CL/F, F, AUC c.*193G: FNgaimisi et al. [40] X 53 494 HIV patients African C0 c.*193G: C0

Efavirenz/ Lopinavir Winzer et al. [41] X 43/ 32 HIV patients Caucasian C12, C0 NSEfavirenz/ Nelfinavir

Fellay et al. [42] X 69/ 54 HIV patients Caucasian C0 3435TT: C0

Indinavir Curras et al. [43] X 21 HIV-infected children South American

C0, CL, C0/D 3435CC: C0/D

Solas et al. [44] X X X 28 HIV patients Caucasian C0, CL, absorption rate constant

3435CT vs CC: absorption rate constant

Lopinavir/ Atazanavir

Ma et al. [45] X X 103 HIV patients Mixed C0 NS

Lopinavir/ Ritonavir Estrela et al. [46] X X X X 113 HIV patients Brazilian C0 NSNelfinavir Colombo et al. [47] X X X X 28 HIV patients Caucasian cellular C,

AUC3435TT: cellular AUC

Saitoh et al. [48] X X X 23 152 HIV-infected children Mixed CL/F NSSaquinavir Frohlich et al. [49] X X 8 healthy subjects Caucasian AUC, Cmax,

tmax, t1/2, CLNS

Valacyclovir Zhang et al. [50] X X X X 200 healthy subjects Chinese AUC, Cmax NSAntipsychoticClozapine Consoli et al. [51] X X X 60 patients, psychosis Caucasian D, C0 2677GG, 3545CC: C0, DOlanzapine Ghotbi et al. [52] X X 121 schizophrenic patients Caucasian AUC NSLevisulpiride Cho et al. [53] X X X 58 healthy subjects Korean AUC, Cmax 2677TT, 3435TT: AUC, Cmax

Risperidone Gunes et al. [54] X X X X 46 patients, schizophrenia Caucasian C0/D 1236T/2677T/3435T: C0/D of 9'-hydroxyrisperidone

Jovanovic et al. [55] X X X 83 patients, psychosis Caucasian C0/D, side effects

2677TT, 3435TT: C0/D; 2677TT/3435TT: extrapyramidal side effects

4

Kastelic et al. [56] X X 59 patients, psychosis Caucasian C0, response NSXiang et al. [57] X X X 23 healthy subjects Chinese Cmax, tmax,

AUC, CL/F, t1/2

2677GA: tmax

Yasui-Furukori et al. [58]

X X X 85 schizophrenic patients Japanese C0 NS

Quetiapine Bakken et al. [59] X 289 schizophrenic patients Caucasian C0/D NSCardiacAmlodipine Kim et al. [60] X X X 26 healthy subjects Korean CL/F, AUC,

Cmax

2677TT/3435TT: AUC, Cmax, CL/F

Zuo et al. [61] X 60 patients; essential hypertension

Chinese CL/F, AUC 3435TT: CL/F

 Digoxin Aarnoudse et al. [62] X X X X 195 patients, digoxin user Caucasian C0 1236T, 2677T, 3435T, 1236T/2677T/3435T: C0

Gerloff et al. [63] X 50 healthy subjects Caucasian AUC4, Cmax, tmax

NS

Johne et al. [64] X X X 24 healthy subjects Caucasian AUC4, Cmax 3435TT: Cmax, AUC4; 2677G/3435T: AUC

Kurata et al. [65] X X X 15 healthy subjects Japanese CL, F 2677TT/3435TT: CL, FVerstuyft et al. [66] X X 32 healthy subjects Caucasian AUC4, AUC24 3435TT: AUC4, AUC24

Verstuyft et al. [67] X 12 healthy subjects Caucasian AUC4, AUC24, CL, Cmax

3435TT: AUC4, AUC24

Xu et al. [68] X X X X 23 20 healthy subjects Chinese AUC4, Cmax, tmax

1236TT/2677TT/3435TT: AUC4, Cmax, tmax

Losartan Yasar et al. [69] X 58 healthy subjects Turkish urine C NSTelmisartan Guo et al. [70] X 19 healthy subjects Chinese Cmax, tmax, t1/2,

AUC, CLNS

Verapamil Pan et al. [71] X X X 10 healthy subjects Korean AUC, Cmax, tmax NSZhao et al. [72] X X X 24 healthy subjects Chinese Cmax, CL, AUC 2677TT/3435TT: AUC

ImmunosuppressantsTacrolimus Anglicheau et al. [73] X X X X 8 81 renal recipients mainly

CaucasianD, C0/D 2677GG, 2677G/3435C: C0/D

Bonhomme-Faivre et al. [74]

X 42 liver recipients Caucasian C0/D 3545TT: C0/D 1-3 days post transplantation, not beyond

Cheung et al. [75] X X 103 renal recipients Chinese D, AUC12/D NSCho et al. [76] X X X X 70 renal recipients Korean C0 NS

5

Choi et al. [77] X X X X 29 healthy subjects Korean Cmax, AUC12, tmax, t1/2

NS

Diaz-Molina et al. [78]

X 65 cardiac recipients Caucasian D NS

Elens et al. [79] X X X 10,23 150 liver recipients Caucasian C0/D, C0, C liver

1199A, 1236CC, 2677GG: C liver

Fredericks et al. [80] X X X X 206 renal recipients Mixed C0/D 2677GG, 3435CC: C0/DGervasini et al. [81] X X X X 103 renal recipients Caucasian D, CL/F, C0 NSGomez-Bravo et al. [82]

X X X 98 liver recipients Caucasian C0, C0/D, D NS

Goto et al. [83] X X X 69 liver recipients Japanese C0/D NSGoto et al. [84] X X 181 liver recipients, 114

donorsJapanese C0/D NS

Haufroid et al. [85] X X X 19 renal transplant candidates

Mixed C0, AUC NS

Hawwa et al. [86] X X X 51 paediatric liver recipients Caucasian D G2677TT, 3435TT, 1236T/2677T/3435T: D

Hesselink et al. [87] X 136 renal recipients mainly Caucasian

D, C0, C0/D, acute rejection

NS

Hosohata et al. [88] X X X 63 living-donor liver recipients

Japanese C0/D NS

Jun et al. [89] X X 506 liver/ renal recipients, 62 donors

Korean C0 NS

Kuypers et al. [90] X X 95 renal recipients Caucasian C0/D, AUC12/D, nephrotoxicity, acute rejection, survival.

NS

Kuypers et al. [91] X X 304 renal recipients Caucasian D, AUC, C0 NSLi et al. [92] X X 73 liver recipients, 73

donorsChinese CL/F NS

Li et al. [93] X X 70 liver recipients, 70 donors

Chinese D, C0/D NS

López-Montenegro et al. [94]

X X 35 renal recipients Caucasian C0/D 3435CC: C0/D

MacPhee et al. [95] X 180 renal recipients Mixed C0/D 3435CC: C0/DMacPhee et al. [96] X 178 renal recipients Mixed C0, C0/D NS

6

Mai et al. [97] X X X 73 renal recipients Caucasian C0/D NSMin et al. [98] X X 62 renal recipients Japanese C0 NSMourad et al. [99] X X X 59 renal recipients mainly

CaucasianD, C0/D NS

Op den Buijsch et al. [100]

X X X X 63 renal recipients Caucasian D, C0/D, Cmax/D AUC12/D

NS

Provenzani et al. [101]

X X 32 liver recipients Caucasian D NS

Provenzani et al. [102]

X X 101 liver/ renal recipients Caucasian C0, D 2677T/A: D

Roy et al. [103] X X X 8,10 44 renal recipients mainly Caucasian

D, C0, C0/D -129C, 2677T, 3435T: C0/D when less than 3 copies of these SNPs

Shi et al. [104] X X 216 liver recipients Chinese D, C0/D, early renal injury

NS

Shilbayeh et al. [105] X 38 renal recipients Middle Eastern

t to attain target C

NS

Tada et al. [106] X 39 renal recipients Japanese D, AUC12/D, Cmax, tmax, t1/2, CL/F

NS

Tsuchiya et al. [107] X X 30 renal recipients Japanese D, AUC12/D, Cmax, Cmax/D, tmax, t1/2, CL/F

NS

Wang et al. [108] X X X X 91 lung recipients Caucasian C0/D 1236TT/2677TT/3435TT: C0/DWei-lin et al. [109] X 50 liver recipients, 50

donorsChinese C0/D 3435CC: C0/D

Zhang et al. [110] X 118 renal recipients Chinese D, C0, C0/D NSZheng et al. [111] X X 75 lung recipients mainly

CaucasianD, C0/D NS

Tacrolimus/ Sirolimus

Mourad et al. [112] X X X 24 renal recipients Caucasian D, C0, C0/D NS

Renders et al. [113] X X 134 renal recipients Caucasian D, C0, C0/D, AUC12, AUC24

NS

Everolimus Lemaitre et al. [114] X 59 cardiac recipients Caucasian CL, CL/F NSTacrolimus/ Cyclosporine

Bandur et al. [115] X X X X 407 Cy, 425 Tac renal recipients

Caucasian C0, C0/D, rejection

1236T/2677T/3435T: risk of rejection.

Haufroid et al. [116] X X X X 50 Cy, 50 Tac renal recipients

Caucasian D, C0, C0/D NS

7

Hesselink et al. [117] X 110 Cy, 64 Tac renal recipients

Mixed D, C0, C0/D NS

Loh et al. [118] X 64 Cy, 18 Tac renal recipients

Mixed Asian D, C0, C0/D, C2 NS

Onizuka et al. [119] X X X 21 Cy, 37 Tac patients after HCST

Japanese NS

Singh et al. [120] X X X X 225 Cy, 75 Tac renal recipients

South Asian C0/D 2677GG, 3435CC: C0/D

Cyclosporine Anglicheau et al. [121]

X X X X 8 106 renal recipients White C0/D, Cmax/D, AUC4/D, AUC12/D, t1/2

1236C: Cmax/D, AUC4/D

Azarpira et al. [122] X 88 liver recipients Iranian D, C0, C0/D 3435TT: C0/DBonhomme-Faivre et al. [123]

X 44 liver recipients Caucasian D, C2, C2/D 3435TT: D, C2/D

Bouamar et al. [124] X X X 171 renal recipients Mixed C0, C2, rejection, renal function

NS

Chowbay et al. [125] X X X X 14 cardial recipients Mixed Asian C0, Cmax, AUC4, AUC12

1236T/2677T/3435T: AUC4, AUC12, Cmax, C0

Crettol et al. [126] X X X X 10,23 73 renal/ lung recipients Caucasian D, C0, C0/D, intracellular concentration

3435T: 1.7-fold intracellular C; 1199A: 1.8-fold intracellular C

Fanta et al. [127] X X X X 23 104 renal recipients mainly Finnish

D, CL, F 1236CC, 2677GG, 1199G/1236C/2677G/3435C: pre-hepatic ER, F

Foote et al. [128] X X 75 renal recipients Caucasian AUC4/D, C0 3435T: AUC4/DGarcia et al. [129] X X X 68 renal recipients Caucasian C0, AE 3435: nephrotoxicityHesselink et al. [130] X 151 cardial/ renal recipients Mainly

WhiteCL/F NS

Hu et al. [131] X 106 renal recipients Chinese D, C0, C0/D 3435C: C0/DKuzuya et al. [132] X X X 8 97 renal recipients Japanese AUC2 NSMai et al. [133] X X X 98 renal recipients Caucasian C0, C2, AUC12 NSMin et al. [134] X X X 16 healthy subjects mainly

African American

tmax, Cmax, t1/2, AUC, CL/F

NS

Press et al. X X X X 8 33 renal recipients mainly Caucasian

CL/F, AUC NS

Qiu et al. [135] X X X X 103 renal recipients Chinese C0/D, C2/D 1236CC, 1236C/2677A/3435C:

8

C0/DTaegtmeyer et al. [136]

X X X X 337 cardial recipients Caucasian C0 1236CC, 12677GG, 3435CC: C0

Wang et al. [137] X X X X 112 renal recipients Chinese C0/D 2677TT, 1236T/2677T/3435C: C0/D

Yates et al. [138] X 18 renal recipients Mixed Cmax/D, AUC/D, tmax, CL/F

3435T: CL/F

Methotrexate Kim et al. [139] X 20 patients after HCST Korean CL 3435CC,CT: CLBudesonide Dilger et al. [140] X X 21 patients, primary biliary

cirrhosisCaucasian AUC, Cmax NS

Prednisolone Miura et al. [141] X X X 95 renal recipients Japanese Cmax, AUC24 NSPlatelet InhibitionClopidogrel Frelinger et al. [142] X 160 healthy subjects,

homozygous CYP2C19Mixed AUC, Cmax NS

Taubert et al. [143] X 60 patients, coronary artery disease

Caucasian AUC, Cmax 3435TT: Cmax, AUC

Karazniewicz-Lada [144]

X 42 patients undergoing coronary angiography

Caucasian AUC, Cmax 3435TT: Cmax, AUC

StatinsFluvastatin/ Pravastatin/ Lovastatin/ Rosuvastatin

Keskitalo et al. [145] X X X X 20 healthy subjects Caucasian AUC NS

MiscellaneousFexofenadine Drescher et al. [146] X 20 healthy subjects Caucasian AUCinf, Cmax NS

Kim 2001 [147] X X X X 50 healthy subjects Caucasian and African-American

AUC, C0 1236C/2677G/3435C: AUC

Lansoprazole Kodaira et al. [148] X 15 healthy subjects Japanese Cmax 3435TT: Cmax

Loperamide Pauli-Magnus et al. [149]

X 16 healthy subjects Caucasian AUC, tmax NS

Skarke et al. [150] X X X 21 healthy subjects Caucasian AUC6 NSRebamipide Cho et al. [151] X X 30 healthy subjects Korean AUC, Cmax NS

“X” denotes that this variant was tested. “Other SNPs” are found in supplementary Table 3. AE=adverse effects, AUC=area under concentration-time curve, AUCx=AUC from time 0 to x, C=concentration, C/D=dose dependent C, C0=trough concentration, C0/D= dose dependent C0, Cmax=maximum concentration, CSF=cerebrospinal fluid,

9

Cx=concentration at time x, CL= apparent body clearance, CL/F=oral clearance, D=required dose, F=bioavailability, NS=not significant, OS=overall survival, PFS=progression free survival, t1/2=elimination half time, tmax=time to Cmax, increase, decrease.

10

Supplementary Table 2 Extended list of effects of ABCB1 polymorphisms on pharmacodynamics

Drug References

C1236T

G2677T/A

C3435T

Haplotypes

Other SN

Ps

No. of patients Ethnicity Parameters EffectAnalgeticMethadone Coller et al. [152] X X X X 10,23 60 patients, opioid

dependentAustralian D 1236TT/2677TT/3435TT: D

Lotsch et al. [153] X X X 51 healthy subjects Caucasian pupil size 9h after administration

NS

Morphine Campa et al. [154] X 145 patients Caucasian pain relief 3435 associated with pain relief variability

Coulbault et al. [155]

X X X 74 patients, post-op Caucasian D, AE 2677GG/3435CC: AE

Fujita et al. [156] X X X 32 cancer patients Japanese AE 1236TT, 2677TT/3435TT: fatigueLotsch et al. [157] X X X 352 patients with chronic

painefficacy (24h-pain score), AE, D

3435TT: D

Ross et al. [158] X X X 8,20 228 cancer patients Caucasian efficacy, AE 2677G: AESia et al. [159] X X X women after C-section Chinese morphine

consumption, pain scores, AE

NS

 Oxycodon Zwisler et al. [160] X X 33 healthy subjects Caucasian efficacy (cold pressor test), AE

3435TT: less AE; 2677TT: AE, efficacy

Zwisler et al. [161] X X 256 patients, post-operative pain

Caucasian pain relief (NRS) NS

Anticancer5-FU/ Capecitabine Gonzales-Haba et al.

[162]X X X 141 patients, CRC Caucasian AE 1236, 3435, 2677: altered risks of

AE: hand-foot syndrome, leukopenia, diarrhea

5-FU+ epirubicin+ cyclophosphamide

Vulsteke et al. [163] X X X 991 patients, breast cancer

Caucasian survival 2677GT: survival

Cetuximab + Irinotecan

Paule et al. [164] X 23 patients, refractory liver metastatic CRC

Caucasian outcome 3435TT: outcome

Cisplatin Chen et al. [165] X X 8 95 patients, NSCLC Chinese response, AE 2677T: resistance;-129T/2677T/3435C: response

Docetaxel Sissung et al. [166] X X X X 73 patients, androgen mainly OS 1236C/2677G/3435C: OS

11

independent prostate cancer

Caucasian

Tsai et al. [167] X X X 6,7 59 patients, breast cancer Chinese AE 2677GG: fever, febrile neutropenia

Choi et al. [168] X X X 92 patients, solid tumors Koreans AE, response 3435TT: neutropenia, anemia. 2677G/T: leucopenia, resistance

Etoposide + Cisplatin

Sohn et al. [169] X X X 54 patients, SCLC Japanese response 3435CC, 2677G/3435C: response

Gemcitabine Kasuya et al. [170] X X 48 patients, pancreatic cancer

Japanese outcome, AE NS

Imatinib Deenik et al. [171] X X X 46 patients, CML Caucasian resistance 1236TT, 1236CT, 2677TT, 3435TT: resistance

Dulucq et al. [172] X X X 90 patients, CML Caucasian response, C0 1236TT: C0, responseElghannam et al. [173]

X 96 patients, CML North African

response 2677TT: response

Ni et al. [174] X X X 52 patients, CML Chinese response 1236TT, 3435TT: resistanceIrinotecan + Cisplatin

Lara et al. [175] X 651 patients, SCLC Japanese AE 3435TT: diarrhea.

Irinotecan + Leukovirin + Cisplatin

De Mattia et al. [176]

X X X X 8,16,2223,27,29

250 patients, metastatic CRC

White response, AUC NS

 Paclitaxel Chang et al. [177] X X X 109 patients, metastatic breast cancer

Korean survival, chemoresistance

3435CT: survival. 2677GG: chemoresistance

Chang et al. [178] X X 43 patients, gastric cancer

Chinese PFS 3435TT: PFS

Hertz et al. [179] X X X X 111 patients, breast cancer

Mixed response, neurotoxicity

NS

Marsh et al. [180] X X X 914 patients, ovarian cancer

Caucasian response, AE NS

Sissung et al. [16] X X X 26 patients, advanced solid tumor

Caucasian AE NS

Paclitaxel + Carboplatin

Green et al. [181] X 23,25 51 patients, advanced ovarian cancer

Caucasian PFS 1199T/A: PFS

Green et al. [182] X X 53 patients, ovarian cancer

Caucasian response 2677TT, 2677TA: response

Sunitinib Beuselinck et al. [183]

X X X 88 patients, renal carcinoma

mainly Caucasian

PFS, OS 1236TT: OS, PFS

12

Beuselinck et al [184]

X X X 96 patients, renal carcinoma

mainly Caucasian

time to dose reduction

1236TT: time to dose reduction

Garcia-Donas et al. [185]

X X X 101 patients, renal carcinoma

Caucasian AE, response NS

van Erp et al. [186] X X X X 219 patients, renal carcinoma

Caucasian AE 1236T/2677T/3435T: hand foot syndrome

Temozolomide Schaich et al. [187] X X X 119 patients, glioblastoma

Caucasian survival 1236CC: survival, independent of MGMT status

Vinorelbin + Cisplatin

Pan et al. [188] X X X 69 patients, NSCLC Chinese response 3435CC, 2677G/3435C: response

Methotrexate Zgheib et al. [189] X X X 127 patients, ALL Lebanese AE 3435T and 1236T: neutropeniaDoxorubicin+ vinvristine+ prednsisolone

Gregers et al. [190] X X X 522 patients, ALL Danish AE 3435TT: bone marrow toxicity

Methotrexate Gregers et al. [190] X X X 522 patients, ALL Danish AE 3435CC: liver toxicityAntidepressantAmitriptylin/ Citalopram/ Mirtazepine/ Paroxetin/ Venlafaxine

Uhr et al. [191] 16,35,3839,41-47

443 patients, major depression

Caucasian response (HAMD-17)

95 SNPs examined. Only SNPs with significant response are listed. NS for mirtazapine

Citalopram Karlsson et al. [192] X X X 23 112 forensic autopsy cases positive for citalopram

mainly Caucasian

rate of lethal intoxication

NS

Ozbey et al. [193] X 54 patients, major depression

Turkish response (HAMD-17)

NS

Escitalopram Lin et al. [194] X X X 3-6,11,1314,17-1932,37,3940,48,50-52

100 patients, major depression

Chinese response (HAMD-17)

rs1922242, rs1202184: association with severity of depressive symptoms; rs1882478/rs2235048/rs2235047/rs1045642/rs6949448 (TTTCC): remission

Paroxetin Kato et al. [195] X X X X Patients with major depression

Japanese response 1236T/2677G/3435C: response

Mihaljevic et al. [196]

X X 127 patients, major depression

Caucasian response (HAMD-17)

NS

Paroxetin/ Mirtazepine

Sarginson et al. [197]

X X 1,8-10,1622,23,26,27

246 patients, major depression

mainly Caucasian

response (HAMD-17)

Paroxetine: rs2032583C, 2235040A: earlier response; mirtazapine: NS

13

31,34,44Venlafaxine Karlsson et al. [192] X X X 23 116 forensic autopsy

cases positive for venlafaxine

mainly Caucasian

rate of lethal intoxication

1236CC+CT, 3435CC+CT: intoxication

Fluoxetine Gassó et al. [198] X X X 83 children and adolescents

Caucasian response (CGII) 2677TT: response

Various drugs Menu et al. [199] X 117 patients, major depression

Caucasian response (HAMD-17, BDI, CGII, TI)

NS

AntiemeticDomperidone Parkman et al. [200] X X X 10 48 patients, gastroparesis Caucasian D 61G: DGranisetron/ Tropisetron/ Ondansetron

Babaoglu et al. [201]

X 216 cancer patients Turkish response (self-report)

3435TT: response

Granisetron + Dexamethasone

Tsuji et al. [202] X X 64 patients, breast cancer Japanese response (control of emesis)

2677TT: response

Ondansetron Choi et al. [203] X X 198 patients, postoperative

Korean vomiting after surgery

2677TT, 3435TT: vomiting 2h post-op; NS 24h post-op

Ondansetron + Metoclopramide

Perwitasari et al. [204]

X X X X 202 patients, cisplatin therapy

South Asian

nausea, vomiting 1236T/2677G/3435C: response

Ondansetron/ Granisetron

Zoto et al. [205] X X X 239 cancer patients Turkish response (control of emesis)

3435TT: response

AntiepilepticCarbamazepine Subenthiran et al.

[206]X 314 patients, focal

epilepsySouth Asian

responder status 2677TT: response

Phenytoin Ebid et al. [207] X 100 patients, epilepsy North African

response 3435CC: resistance

Valproic acid Haerian et al. [208] X X X X 249 patients, epilepsy South Asian

responder status NS

Various drugs Alpman et al. [209] X X X 39 children, epilepsy, 92 controls

Turkish resistant epilepsy NS

Bournissen et al. [210]

X 3371 patients, epilepsy, (MA)

Mixed responder status NS

Dong et al. [211] X X X 350 children, epilepsy Chinese responder status NSEmich-Widera et al. [212]

X 85 patients, epilepsy Caucasian responder status NS

Haerian et al. [213] X 6755 patients, epilepsy, (MA)

Mixed responder status NS

Haerian et al. [214] X X X X 7067 patients, epilepsy, Mixed responder status NS

14

(MA)Hung et al. [215] X X X X 331 patients, epilepsy,

287 controlsAsian responder Status Complex haplotypic effects

Kwan et al. [216] X X X X 464 patients, epilepsy Chinese responder status 2677: related to drug resistanceLeschziner et al. [217]

X X X X 503 patients, epilepsy UK responder status NS

Sanchez et al. [218] X X 289 patients, epilepsy Caucasian responder status NSSiddiqui et al. [219] X 315 patients, epilepsy,

200 controlsmainly Caucasian

responder status 3435CC: resistance

Tan et al. [220] X 609 patients, epilepsy mainly Caucasian

responder status NS

Manna et al. [221] X 175 patients, epilepsy Caucasian response NSAntiinfectiousAtazanavir Park et al. [222] X X 129 HIV-patients Korean AE 2677TT: severe

hyperbilirubinemiaMefloquine Aarnoudse et al.

[223]X X X X 89 healthy travelers White neuropsychiatric

AE1236TT, 2677TT, 3435TT, 1236TT/2677TT/3435TT: AE

Nevirapine Ciccacci et al. [224] X 156 HIV-patients Caucasian hepatotoxicity 3435TT: hepatotoxicityHaas et al. [225] X 53 HIV-patients Mixed hepatotoxicity 3435T: hepatotoxicity

AntipsychoticOlanzapine Bozina et al. [226] X X 87 schizophrenic patients Caucasian response (PANSS) 2677T, 2677TT: response

Lin et al. [227] X X X 41 schizophrenic patients Caucasian response (BPRS), weight gain

NS

Risperidone Kuzman et al. [228] X X X 108 schizophrenic patients

Caucasian weight gain NS

Xing et al. [229] X X X 48 130 schizophrenic patients

Chinese response (BPRS) 1236TT: response

ImmunosuppressantAzathioprine Mendoza et al. [230] X X X 76 patients with Crohn's

diseaseBrazilian resistance 2677TT, 3435TT, 2677T/3435T:

resistance Colchicine Rustemoglu et al.

[231]X X X X 104 patients, Behcet's

diseaseTurkish response 3435TT: response

Saricaoglu et al. [232]

X 97 patients, Behcet's disease

Turkish response NS

Tufan et al. [233] X 120 patients, familial mediterranean fever

Turkish resistance 3435C: resistance

 Cyclosporine Grinyo et al. [234] X X X 10,53 237 renal recipients Caucasian graft rejection 2677T, 1236T/2677T/3435T: rejection

15

Hauser et al. [235] X X 97 renal recipients, 97 donors

Caucasian C0/D, AE 3435TT: nephrotoxicity

van Ahsen 2001 [236]

X 124 renal recipients Caucasian graft rejection, C0 NS

Wang et al. [237] X X X 208 renal recipients Chinese response, AE NSWoillard et al. [238] X X X X 259 renal recipients, 227

donorsCaucasian graft rejection 1236T/2677T/3435T: rejection

 Cyclosporine/ Tacrolimus

Hebert et al. [239] X X X 120 liver recipients Caucasian chronic renal dysfunction

2677TT: risk; 2677G/3435C, 2677G/3435T: risk

Klauke et al. [240] X 106 renal recipients Caucasian nephrotoxicity NSYamauchi et al. [241]

X X X 7,8,53 17 liver recipients Japanese AE 2677TT: neurotoxicity

Yanagimachi et al. [242]

X X X X 30/ 33 patients after HSCT

Japanese neurotoxicity 1236T neurotoxicity

Zheng et al. [243] X X 117 lung recipients Mixed graft rejection 3435TT: rejectionMethotrexate Takatori et al. [244] X 124 patients, RA Japanese response, AE 3435TT: resistance

Samara et al. [245] X 159 patients, RA Middle Eastern

response, AE 3435T: hepatotoxicity

Methotrexate/ Sulfasalazine

Drozdzik et al. [246] X 174/ 81 patients, RA Caucasian remission Methotrexate: 3435T: remission

Steroids Chiou et al. [247] X X X 74 children, idopathic nephrotic syndrome

Chinese steroid resistance 1236T: resistance

Methylprednisolone Akin et al. [248] X 31 children, ITP Turkish response (platelet count)

NS

Platelet InhibitionClopidogrel Carlquist et al. [249] X 1034 patients, coronary

DESMixed cardiovascular

event rateNS

Simon et al. [250] X 2208 patients, acute myocardial infarction

mainly Caucasian

death of any cause, stroke or myocardial infarction

3435TT cardiovascular events

Singh et al. [251] X 19601 patients Mixed cardiovascular events

NS

Su et al. [252] X MA Mixed early/ long-term major cardiovascular events, platelet activity

3435T,TT: early/ long-term events

16

Verschuren et al. [253]

X 1327 patients, STEMI Caucasian cardiac death, recurrent infarction

NS

Xie et al. [254] X 162 patients, coronary heart disease

Chinese platelet reactivity (VASP-PRI)

NS

Clopidogrel/ Prasugrel

Mega et al. [255] X X X X 2932 patients, acute coronary syndrome

mainly Caucasian

ischemic events Clopidogrel: 3435TT: ischemic events

Clopidogrel/ Ticagrelor

Wallentin et al. [256]

X 10285 patients, acute coronary syndrome

mainly Caucasian

ischemic/ bleeding events

Clopidogrel: 3435CC: ischemic events

StatinsAtorvastatin Hoenig et al. [257] X 117 patients Caucasian cholesterol

reduction3435CC: efficacy in LDL-C reduction

Shabana et al. [258] X 50 patients, high cholesterol

North African

change of HDL-, LDL-, total cholesterol

3435TT: HDL-C

Simvastatin Becker et al. [259] X X X X 85 patients, simvastatin user

Caucasian cholesterol reduction

1236T/2677T/3435T, 1236C/2677G/3435T: reduction of total cholesterol and LDL-C male subjects only

“X” denotes that this variant was tested. “Other SNPs” are found in supplementary Table 3. AE=adverse effects, ALL, acute lymphoblastic leukemia, AUC=area under the curve, AUCx=AUC from time 0 to x, BDI=Becks Depression Inventory, BPRS=Brief psychiatric rating scale, C=concentration, C0=trough concentration, CGII=Clinician Global Impression Improvement, CML=chronic myeloid leukemia, CRC=colorectal cancer, D=required dose, DES=drug eluting stent, HAMD-17=Hamilton Depression Rating Scale, HDL-C=high density lipoprotein cholesterol, HSCT=hematopoietic stem cell transplantation, ITP=idiopathic thrombocytopenic purpura, LDL-C=low density lipoprotein cholesterol, MA=metanalysis, NSCLC=non-small cell lung cancer, NRS=numeric rating scale, NS=not significant, OS=overall survival, PANSS=Positive and negative syndrome scale, PFS=progression free survival, RA=rheumatoid arthritis, SCLC=small cell lung cancer, STEMI=ST-elevation myocardial infarction, TI=Therapeutic Index, VASP PRI=platelet reactivity index VASP, increase, decrease.

17

Supplementary Table 3 List of ABCB1 SNPs investigated in pharmacogenetic studies

Position Code Amino acid or effect

1. n.a. rs10245483 approximately 2.4 mb upstream of MDR1

2. c.-330-14566G>A rs13233308 Intron 1

3. c.-330-1517T>C rs28381796 Intron 1

4. c.-330-21247T>C rs1978095 Intron 1

5. c.-330-3655A>G rs4148732 Intron 1

6. c.-330-41A>G rs2188524 Intron 1

7. c.-145C>G rs34976462 5'UTR

8. c.-129T->C rs3213619 5'UTR

9. c.-1A->G rs2214102 5'UTR

10. c.61A->G rs9282564 Asn21Asp

11. c.117+4196T>C rs3789243 Intron 3

12. c.239C→A rs9282565 Ala80Glu

13. c.286+927G>A rs1202184 Intron 5

14. c.287-1234G>C rs10256836 Intron 5

15. c.287-1547G>A rs2520464 Intron 5

16. c.287-25G>T rs2235015 Intron 5

17. c.287-5940A>T rs1989831 Intron 5

18. c.338+123A>G rs2235018 Intron 6

19. c.338+76T>G rs2235016 Intron 6

20. c.530+139C>T rs1202168 Intron7

21. c.781A→G rs36008564 Ile261Val

22. c.1000-44G>A rs10276036 Intron 10

23. c.1199G→A rs2229109 Ser400Asn

24. c.1236C→T rs1128503 Gly412=25. c.1308A>G rs35068177 Thr436=

26. c.1350+44C>T rs2032588 Intron 13

27. c.1554+24T>C rs2235033 Intron 14

28. c.1659 G→C rs2235012 Leu554Leu

29. c.1725+38G>A rs2235013 Intron 15

30. c.1795C→T rs2235036 Ala599Thr

31. c.1887+38G>A rs28381916 Intron 16

32. c.2064+73A>G rs2235046 Intron 17

33. c.2065-76T>A rs1922242 Intron 17

34. c.2212-27A>G rs2235063 Intron 18

35. c.2320-695G>A rs12720067 Intron 19

36. c.2320-88G>A rs4728699 Intron 19

37. c.2397+557G>A rs3789246 Intron 20

38. c.2481+24G>A rs2235040 Intron 21

39. c.2481+788T>C rs10248420 Intron 21

40. c.2481+882A>T rs10234411 Intron 21

41. c.2482-236A>G rs4148739 Intron 21

42. c.2482-707A>G rs11983225 Intron 21

43. c.2677G→T/A rs2032582 Ser893Ala/Thr44. c.2685+49T>C rs2032583 Intron 22

18

45. c.2686-1911T>C rs4148740 Intron 22

46. c.2686-3393T>G rs10280101 Intron 22

47. c.2786+170G>A rs2235067 Intron 23

48. c.3282+2733A>G rs6949448 Intron 26

49. c.3435C→T rs1045642 Ile1145=50. c.3489+1573G>A rs1882478 Intron 27

51. c.3489+59T>G rs2235047 Intron 27

52. c.3489+80C>T rs2235048 Intron 27

53. c.*193A>G rs3842 3′ UTR

19

Supplementary References

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23

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