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Z Amundsen R, Christensen H, Zabihyan B and Asberg A (2010) Cyclosporine A, but not tacrolimus, shows relevant inhibition of organic anion-transporting protein 1B1-mediated transport of atorvastatin. Drug Metab Dispos 38:1499-1504. Aziz MA, Schwartz S and Watson CJ (1964a) Studies of Coproporphyrin. Vii. Adaptation of the Eriksen Paper Chromatographic Method to the Quantitative Analysis of the Isomers in Normal Human Urine. The Journal of laboratory and clinical medicine 63:585-595. Aziz MA, Schwartz S and Watson CJ (1964b) Studies of Coproporphyrin. Viii. Reinvestigation of the Isomer Distribution in Jaundice and Liver Diseases. The Journal of laboratory and clinical medicine 63:596-604. Aziz MA and Watson CJ (1969) An analysis of the porphyrins of normal and cirrhotic human liver and normal bile. Clinica chimica acta; international journal of clinical chemistry 26:525-531. Bednarczyk D and Boiselle C (2015) Organic anion transporting polypeptide (OATP)-mediated transport of coproporphyrins I and III. Xenobiotica:1-10. Ben-Ezzer J, Rimington C, Shani M, Seligsohn U, Sheba C and Szeinberg A (1971) Abnormal excretion of the isomers of urinary coproporphyrin by patients with Dubin-Johnson syndrome in Israel. Clinical science 40:17-30. Benz-de Bretagne I, Respaud R, Vourc'h P, Halimi JM, Caille A, Hulot JS, Andres CR and Le Guellec C (2011) Urinary elimination of coproporphyrins is dependent on ABCC2 polymorphisms and represents a potential biomarker of MRP2 activity in humans. J Biomed Biotechnol 2011:498757. Campbell SD, de Morais SM and Xu JJ (2004) Inhibition of human organic anion transporting polypeptide OATP 1B1 as a mechanism of drug-induced hyperbilirubinemia. Chem Biol Interact 150:179-187. Choi JH, Lee MG, Cho JY, Lee JE, Kim KH and Park K (2008) Influence of OATP1B1 genotype on the pharmacokinetics of rosuvastatin in Koreans. Clin Pharmacol Ther 83:251-257. Chu X, Shih SJ, Shaw R, Hentze H, Chan GH, Owens K, Wang S, Cai X, Newton D, Castro- Perez J, Salituro G, Palamanda J, Fernandis A, Ng CK, Liaw A, Savage MJ and Evers R (2015) Evaluation of cynomolgus monkeys for the identification of endogenous biomarkers for hepatic transporter inhibition and as a translatable model to predict pharmacokinetic interactions with statins in humans. Drug Metab Dispos 43:851-863. French JM and Thonger E (1966) Ether-soluble porphyrins in bile, meconium and urine: a new appraisal by microscale counter-current analysis. Clinical science 31:337-351. Gebril M, Weinkove C, Ead R, McDonald K and Morton R (1990) Plasma porphyrins in chronic renal failure. Nephron 55:159-163. Hivnor C, Nosauri C, James W and Poh-Fitzpatrick M (2003) Cyclosporine-induced pseudoporphyria. Archives of dermatology 139:1373-1374. Izumi S, Nozaki Y, Komori T, Maeda K, Takenaka O, Kusano K, Yoshimura T, Kusuhara H and Sugiyama Y (2013) Substrate-dependent inhibition of organic anion transporting polypeptide 1B1: comparative analysis with prototypical probe substrates estradiol- 17beta-glucuronide, estrone-3-sulfate, and sulfobromophthalein. Drug metabolism and disposition: the biological fate of chemicals 41:1859-1866. 25
Izumi S, Nozaki Y, Maeda K, Komori T, Takenaka O, Kusuhara H and Sugiyama Y (2015) Investigation of the Impact of Substrate Selection on In Vitro Organic Anion Transporting Polypeptide 1B1 Inhibition Profiles for the Prediction of Drug-Drug Interactions. Drug Metab Dispos 43:235-247. Kalliokoski A, Neuvonen M, Neuvonen PJ and Niemi M (2008) The effect of SLCO1B1 polymorphism on repaglinide pharmacokinetics persists over a wide dose range. Br J Clin Pharmacol 66:818-825. Kalliokoski A and Niemi M (2009) Impact of OATP transporters on pharmacokinetics. Br J Pharmacol 158:693-705. Kaplowitz N, Javitt N and Kappas A (1972) Coproporphyrin I and 3 excretion in bile and urine. The Journal of clinical investigation 51:2895-2899. Katz DA, Carr R, Grimm DR, Xiong H, Holley-Shanks R, Mueller T, Leake B, Wang Q, Han L, Wang PG, Edeki T, Sahelijo L, Doan T, Allen A, Spear BB and Kim RB (2006) Organic anion transporting polypeptide 1B1 activity classified by SLCO1B1 genotype influences atrasentan pharmacokinetics. Clin Pharmacol Ther 79:186-196. Kivisto KT and Niemi M (2007) Influence of drug transporter polymorphisms on pravastatin pharmacokinetics in humans. Pharm Res 24:239-247. Koskelo P, Eisalo A and Toivonen I (1966) Urinary excretion of porphyrin precursors and coproporphyrin in healthy females on oral contraceptives. British medical journal 1:652-654. Koskelo P and Toivonen I (1966) Separation of urinary coproporphyrin isomers 1 and 3 by thinlayer chromatography. Studies in healthy subjects and patients with myocardial infarction. Scandinavian journal of clinical and laboratory investigation 18:543-549. Koskelo P, Toivonen I and Adlercreutz H (1967) Urinary coproporphyrin isomer distribution in the Dubin-Johnson syndrome. Clinical chemistry 13:1006-1009. Lee E, Ryan S, Birmingham B, Zalikowski J, March R, Ambrose H, Moore R, Lee C, Chen Y and Schneck D (2005) Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment. Clin Pharmacol Ther 78:330-341. Maeda K, Ieiri I, Yasuda K, Fujino A, Fujiwara H, Otsubo K, Hirano M, Watanabe T, Kitamura Y, Kusuhara H and Sugiyama Y (2006) Effects of organic anion transporting polypeptide 1B1 haplotype on pharmacokinetics of pravastatin, valsartan, and temocapril. Clin Pharmacol Ther 79:427-439. Millar JW (1980) Rifampicin-induced porphyria cutanea tarda. British journal of diseases of the chest 74:405-408. Mwinyi J, Johne A, Bauer S, Roots I and Gerloff T (2004) Evidence for inverse effects of OATP-C (SLC21A6) 5 and 1b haplotypes on pravastatin kinetics. Clin Pharmacol Ther 75:415-421. Nezasa K, Higaki K, Matsumura T, Inazawa K, Hasegawa H, Nakano M and Koike M (2002) Liver-specific distribution of rosuvastatin in rats: comparison with pravastatin and simvastatin. Drug Metab Dispos 30:1158-1163. Niemi M, Pasanen MK and Neuvonen PJ (2011) Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev 63:157-181. Nishizato Y, Ieiri I, Suzuki H, Kimura M, Kawabata K, Hirota T, Takane H, Irie S, Kusuhara H, Urasaki Y, Urae A, Higuchi S, Otsubo K and Sugiyama Y (2003) Polymorphisms of 26
OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther 73:554-565. Ozer J, Ratner M, Shaw M, Bailey W and Schomaker S (2008) The current state of serum biomarkers of hepatotoxicity. Toxicology 245:194-205. Pasanen MK, Neuvonen PJ and Niemi M (2008) Global analysis of genetic variation in SLCO1B1. Pharmacogenomics 9:19-33. Prueksaritanont T, Chu X, Evers R, Klopfer SO, Caro L, Kothare PA, Dempsey C, Rasmussen S, Houle R, Chan G, Cai X, Valesky R, Fraser IP and Stoch SA (2014) Pitavastatin is a more sensitive and selective organic anion-transporting polypeptide 1B clinical probe than rosuvastatin. Br J Clin Pharmacol 78:587-598. Prueksaritanont T, Chu X, Gibson C, Cui D, Yee KL, Ballard J, Cabalu T and Hochman J (2013) Drug-drug interaction studies: regulatory guidance and an industry perspective. AAPS J 15:629-645. Seithel A, Glaeser H, Fromm MF and Konig J (2008) The functional consequences of genetic variations in transporter genes encoding human organic anion-transporting polypeptide family members. Expert Opin Drug Metab Toxicol 4:51-64. Shen H, Dai J, Liu T, Cheng Y, Chen W, Freeden C, Zhang Y, Humphreys WG, Marathe P and Lai Y (2016a) Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species. J Pharmacol Exp Ther 357:382-393. Shen H, Liu T, Jiang H, Titsch C, Taylor K, Kandoussi H, Qiu X, Chen C, Sukrutharaj S, Kuit K, Mintier G, Krishnamurthy P, Fancher RM, Zeng J, Rodrigues AD, Marathe P and Lai Y (2016b) Cynomolgus Monkey as a Clinically Relevant Model to Study Transport Involving Renal Organic Cation Transporters: In Vitro and In Vivo Evaluation. Drug Metab Dispos 44:238-249. Shen H, Su H, Liu T, Yao M, Mintier G, Li L, Fancher RM, Iyer R, Marathe P, Lai Y and Rodrigues AD (2015) Evaluation of rosuvastatin as an organic anion transporting polypeptide (OATP) probe substrate: in vitro transport and in vivo disposition in cynomolgus monkeys. J Pharmacol Exp Ther 353:380-391. Shen H, Yang Z, Mintier G, Han YH, Chen C, Balimane P, Jemal M, Zhao W, Zhang R, Kallipatti S, Selvam S, Sukrutharaj S, Krishnamurthy P, Marathe P and Rodrigues AD (2013) Cynomolgus monkey as a potential model to assess drug interactions involving hepatic organic anion transporting polypeptides: in vitro, in vivo, and in vitro-to-in vivo extrapolation. J Pharmacol Exp Ther 344:673-685. Shitara Y, Maeda K, Ikejiri K, Yoshida K, Horie T and Sugiyama Y (2013a) Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption. Biopharm Drug Dispos 34:45-78. Shitara Y, Takeuchi K and Horie T (2013b) Long-lasting inhibitory effects of saquinavir and ritonavir on OATP1B1-mediated uptake. J Pharm Sci 102:3427-3435. Tweedie D, Polli JW, Berglund EG, Huang SM, Zhang L, Poirier A, Chu X, Feng B and International Transporter C (2013) Transporter studies in drug development: experience to date and follow-up on decision trees from the International Transporter Consortium. Clin Pharmacol Ther 94:113-125. van de Steeg E, Stranecky V, Hartmannova H, Noskova L, Hrebicek M, Wagenaar E, van Esch A, de Waart DR, Oude Elferink RP, Kenworthy KE, Sticova E, al-edreesi M, Knisely AS, Kmoch S, Jirsa M and Schinkel AH (2012) Complete OATP1B1 and OATP1B3 27
deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest 122:519-528. Varma MV, Steyn SJ, Allerton C and El-Kattan AF (2015) Predicting Clearance Mechanism in Drug Discovery: Extended Clearance Classification System (ECCS). Pharm Res 32:3785-3802. Watanabe T, Miyake M, Shimizu T, Kamezawa M, Masutomi N, Shimura T and Ohashi R (2015) Utility of bilirubins and bile acids as endogenous biomarkers for the inhibition of hepatic transporters. Drug metabolism and disposition: the biological fate of chemicals 43:459-466. Wolkoff AW, Wolpert E, Pascasio FN and Arias IM (1976) Rotor's syndrome. A distinct inheritable pathophysiologic entity. The American journal of medicine 60:173-179. Yoshida K, Maeda K and Sugiyama Y (2012) Transporter-mediated drug--drug interactions involving OATP substrates: predictions based on in vitro inhibition studies. Clin Pharmacol Ther 91:1053-1064. 28
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