Supplemental Data for:

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1 Supplemental Data for: Interindividual variability in hepatic OATPs and P-glycoprotein (ABCB1) protein expression: Quantification by LC-MS/MS and influence of genotype, age and sex Bhagwat Prasad, Raymond Evers, Anshul Gupta, Cornelis E.C.A. Hop, Laurent Salphati, Suneet Shukla, Suresh V. Ambudkar and Jashvant D. Unadkat Department of Pharmaceutics, University of Washington, Seattle, P.O. Box , WA 98195, USA (B.P., J.D.U.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, NJ 07065, USA (R.E.); Drug Metabolism and Pharmacokinetics, Infection DMPK, AstraZeneca Pharmaceuticals LLP, Waltham, MA 02451, USA (A.G.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA, 94080, USA (C.E.H., L.S.); Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA (S.S., S.V.A.)

2 Supplemental Table 1: Background and demographic information of liver donors. Liver Age (Yr) Sex Ethnicity Liver Cause of Death Donor Medical History Medications at home Pathology HL Male C Normal Head trauma Normal HL Female C Normal Head trauma Normal Labetalol HL Male B(NOH) Fatty Cerebrovascular Epilepsy, ism Phenobarbital, Phenytoin (off for 3 months) HL Male B(NOH) Normal Head trauma Normal HL Female C Normal Cerebrovascular Hypothyroid Levothyroxine HL Female C Normal Brain infarction Normal HL Male C Fatty Head trauma ism, Obesity, Propranolol HL Male C Normal Head trauma Normal HL Male C Normal Head trauma Normal HL113 9 Female C Normal Head trauma Normal HL Male C Normal Head trauma Normal HL Female C Normal Subarachnoid Atenolol HL Male C Fatty Head trauma Depression, multiple drug abuse HL Male C Normal Head trauma Normal HL Female C Fatty Cerebrovascular Depression Fluoxetine, Doxepin, Codeine, Promethazine HL Female C Fatty Subarachnoid Hypothyroid Levothyroxine HL Female C Fibrosis, cysts Subarachnoid HL Male C Acute injury Head trauma ism HL Female C Fatty Respiratory arrest Obesity HL Male C Normal Head trauma Crypotococcal infection, lung node, at harvest HL Male C Fatty Head trauma ism HL Female C Normal, split Subarachnoid Heart transplant in 1990 Cyclosporine A, Azathioprine, liver Prednisone, Nifedipine, Lovastatin HL Male C Fatty Head trauma Diabetes, ism Insulin, HL Female C Normal Subarachnoid Prazepine, Indapamide

3 HL Female C Fatty Subarachnoid Normal HL134 7 Male C Normal, split Head trauma Normal liver HL Female C Mild Fatty Cerebrovascular Aneurysm clipping (after injury) HL Male C Acute injury Head trauma Normal HL Male B(NOH) Normal, split Head trauma Normal liver HL138 9 Female C Acute injury, Head trauma Normal split liver HL Female C Normal Head trauma HL Male C Poorly Head trauma ism perfused HL Male C Fe deposition? Cerebrovascular ism (abst for 14 yr), atherosclerosis HL Female C Fatty Subarachnoid ism HL Male C Fibrotic Cerebrovascular Stroke (8 yrs ago) HL Female C Fatty Subarachnoid Calcium channel blockers HL Male C Fibrotic Respiratory arrest Quadriplegia (12 yr), multiple Cimetidine, diazepam, baclofen pneumonias HL Male C Acute injury Head trauma Normal HL Female C Fibrotic Cerebrovascular 48 hr smoker; stopped 2 yrs Metoclopramide, Misoprostol ago HL Female C Fatty Cerebrovascular Fibromyalgia, arthritis Unknown HL Female C Fibrotic Subarachnoid, heart disease, ism HL Male C Fatty Cardiac arrest Diabetes, ism, drug abuse (not intravenous), insulin HL Female C Fatty Subarachnoid Obese, asthma Terfenadine, Hyoscyamine, Pirbuterol, Acetaminophen/codeine, clorazepate HL Female C Normal Cerebrovascular Hypothyroid Premarin, Levothyroxine, Diazepam HL Female C Mild Fatty, Subarachnoid Back surgery, alcohol (2-4, Ibuprofen

4 Fibrotic glass/day) HL Male C Mild Fatty Head trauma ism, testicular Marijuana, carcinoma HL Male C Normal Head trauma Normal HL Male C Fatty Head trauma ism, depression (less recently) HL Female C Normal, split Subarachnoid Antihypertensives (Unknown) liver HL Male C Fatty Unknown Unknown Unknown HL Female C Mild Fatty Unknown Unknown Unknown HL Male C Fatty Unknown Unknown Unknown HL Male C Mild Fatty Cerebrovascular ic, palsy symptoms, (1/2 bottle day) psoriasis, sleep apnea HL Female C Moderate Unknown Unknown Unknown microvesicular fat HL Male C Mild Fatty Cerebrovascular Untreated HL Female C Normal CO poisoning Normal HL Male A Mild Fatty Cerebrovascular Parkinson's since 1990 Drugs for Parkinson's (Unknown) HL Female C Some fibrosis, Unknown Normal Unknown no fat HL Male C Normal Unknown Unknown Unknown (excellent) HL Male C Normal (split Cerebrovascular Unknown liver) HL Male C Fatty Unknown Normal Unknown HL Female C Moderate macrovesicular fat Cerebrovascular Epileptic, alcoholic HL Female C Normal (split) Cerebrovascular HL Male C Normal (split) Head trauma Untreated, non- IV drug abuse C= Caucasian; B(NOH), black, not of Hispanic origin Phenytoin,, Estrogen, Doxepin, Acyclovir, Cannabis

5 Supplemental Table 2. Summary of input parameters for OATP1B1 substrates used in Simcyp models Parameter Rosuvastatin Repaglinide Physiochemical properties Mol wt (g/mol) Log P (O:W) Compound type Monoprotic Ampholyte pka pka Blood binding (B/P) Fraction unbound in plasma Absorption Absorption type ADAM ADAM Caco-2 permeability (x10 6 cm/s) Distribution Distribution model Full PBPK model Full PBPK model Elimination HLM Clearance (L/h) Vmax (CYP2C8) (pmol/min/mg microsomal protein) Vmax (CYP3A4) (pmol/min/mg microsomal protein) km (CYP2C8) (µm) 2.3 km (CYP3A4) (µm) 13.2 Renal Clearance (L/h) Intestinal transporters BCRP (µl/min million hepatocytes)* 18 Hepatic transporters OATP1B1 (µl/min/million hepatocytes)* OATP1B3 (µl/million hepatocytes)* 36 OATP2B1+NTCP (µl/million hepatocytes)* 78 BCRP(µl/million hepatocytes)* 1.23 Passive diffusion Clearance (µl/min/ cells) Clearance Int, Bile (µl/min/10 6 cells) 15 0 Relative expression factor (REF) Genotype/haplotype Variant, Mean (90% confidence interval) SLCO1B1 c.388gg 1.8 (1.4, 2.1) 1.0 (0.8, 1.2) SLCO1B1 c.463aa 2.1 (1.6, 2.6) 1.0 (0.9, 1.1) SLCO1B1 c.463ca 1.8 (1.5, 2.1) 1.0 (0.9, 1.1) SLCO1B1 c.597tt 1.7 (1.4, 2.1) 1.0 (0.9, 1.1) SLCO1B1*14/* (1.6, 2.7) 1.0 (0.9, 1.1) SLCO1B1*14/*1a 1.9 (1.6, 2.2) 1.0 (0.9, 1.1) All the values are default from Simcyp library except REF. *Fitted values Wild-type, Mean (90% confidence interval)