title: Interspecies variability in expression of hepatobiliary transporters across human, dog, monkey, and rat as determined by quantitative proteomics.
abstract: We quantified, by liquid chromatography tandem mass spectrometry, transporter protein expression of BSEP, MATE1, MRP3, MRP4, NTCP, and OCT1 in our human liver bank (n = 55) and determined the relationship between protein expression and sex, age and genotype. These data complement our previous work in the same liver bank where we quantified the protein expression of OATPs, BCRP, MDR1, and MRP2. In addition, we quantified and compared the interspecies differences in expression of the hepatobiliary transporters, corresponding to the above human transporters, in liver tissue and hepatocytes of male beagle dogs, cynomolgus monkeys, Sprague-Dawley rats, and Wistar rats. In all the species, the sinusoidal OATPs/Oatps were the most abundant hepatic transporters. However, there were notable interspecies differences in the relative abundance of the remaining transporters. For example, the next most abundant transporter in humans and monkeys was OCT1/Oct1, whereas it was Mrp2 and Ntcp in dogs/Wistar rats and Sprague-Dawley rats, respectively. In contrast, the protein expression of the efflux transporters BCRP/Bcrp, MDR1/Mdr1, MRP3/Mrp3, MRP4/Mrp4, and MATE1/Mate1 was much lower across all the species. For most transporters, the expression in the liver tissues was comparable to that in the unplated cryopreserved hepatocytes. These data on human liver transporter protein expression complete the picture of the expression of major human hepatobiliary transporters important in drug disposition and toxicity. In addition, the data on expression of the corresponding hepatobiliary transporters in preclinical species will be helpful in interpreting and extrapolating pharmacokinetic, pharmacological, and toxicological results from preclinical studies to humans.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., B.P., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Drug Metabolism and Pharmacokinetics, Infection DMPK, AstraZeneca Pharmaceuticals LLP, Waltham, Massachusetts (A.G.); and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.).
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., B.P., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Drug Metabolism and Pharmacokinetics, Infection DMPK, AstraZeneca Pharmaceuticals LLP, Waltham, Massachusetts (A.G.); and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.).
authors.forename: Bhagwat
authors.initials: B
authors.lastname: Prasad
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., B.P., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Drug Metabolism and Pharmacokinetics, Infection DMPK, AstraZeneca Pharmaceuticals LLP, Waltham, Massachusetts (A.G.); and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.).
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., B.P., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Drug Metabolism and Pharmacokinetics, Infection DMPK, AstraZeneca Pharmaceuticals LLP, Waltham, Massachusetts (A.G.); and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.).
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chu
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., B.P., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Drug Metabolism and Pharmacokinetics, Infection DMPK, AstraZeneca Pharmaceuticals LLP, Waltham, Massachusetts (A.G.); and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.).
authors.forename: Anshul
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., B.P., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Drug Metabolism and Pharmacokinetics, Infection DMPK, AstraZeneca Pharmaceuticals LLP, Waltham, Massachusetts (A.G.); and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.).
authors.forename: Cornelis E C A
authors.initials: CE
authors.lastname: Hop
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., B.P., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Drug Metabolism and Pharmacokinetics, Infection DMPK, AstraZeneca Pharmaceuticals LLP, Waltham, Massachusetts (A.G.); and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.).
authors.forename: Raymond
authors.initials: R
authors.lastname: Evers
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., B.P., J.D.U.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Drug Metabolism and Pharmacokinetics, Infection DMPK, AstraZeneca Pharmaceuticals LLP, Waltham, Massachusetts (A.G.); and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.) jash@u.washington.edu.
authors.forename: Jashvant D
authors.initials: JD
authors.lastname: Unadkat
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D015925:Cryopreservation / Q000379:methods; D004285:Dogs; D005260:Female; D000882:Haplorhini; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008875:Middle Aged; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D055815:Young Adult
chemical_list: D026901:Membrane Transport Proteins; D020543:Proteome