Interaction of porphyrins with human organic anion transporting polypeptide 1B1

Campbell, Scott; Lau, Wan F.; Xu, Jinghai J.

doi:10.1016/j.cbi.2009.06.010

Cited by 10 publications

(7 citation statements)

References 49 publications

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“…In vitro interaction of several porphyrins including CPs I and III with OATP1B1 has been reported (Campbell et al, 2009;Li et al, 2015). In addition, while this paper was in preparation, Bednarczyk and Boiselle (2016) assessed the in vitro transport of CP by OATP1B1 and OATP1B3 using transporter-overexpressing cells.…”

Section: Discussionmentioning

confidence: 99%

Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species

Shen

Dai

Liu

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

109

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Inhibition of organic anion-transporting polypeptide (OATP)1B function can lead to serious clinical drug-drug interactions, thus a thorough evaluation of the potential for this type of interaction must be completed during drug development. Therefore, sensitive and specific biomarkers for OATP function that could be used in conjunction with clinical studies are currently in demand. In the present study, preclinical evaluations were conducted to characterize the suitability of coproporphyrins (CPs) I and III as markers of hepatic OATP functional activity. Active uptake of CPs I and III was observed in human embryonic kidney (HEK) 293 cells singly expressing human OATP1B1 (hOATP1B1), hOATP1B3, cynomolgus monkey OATP1B1 (cOATP1B1), or cOATP1B3, as well as human and monkey hepatocytes. Cyclosporin A (100 mg/kg, oral) markedly increased the area under the curve (AUC) plasma concentrations of CPs I and III by 2.6-and 5.2-fold, while rifampicin (15 mg/kg, oral) increased the AUCs by 2.7-and 3.6-fold, respectively. As the systemic exposure increased, the excretion of both isomers in urine rose from 1.6-to 4.3-fold in monkeys. In agreement with this finding, the AUC of rosuvastatin (RSV) in cynomolgus monkeys increased when OATP1B inhibitors were coadministered. In Oatp1a/1b gene cluster knockout mice (Oatp1a/1b 2/2 ), CPs in plasma and urine were significantly increased compared with wild-type animals (7.1-to 18.4-fold; P , 0.001), which were also in agreement with the changes in plasma RSV exposure (14.6-fold increase). We conclude that CPs I and III in plasma and urine are novel endogenous biomarkers reflecting hepatic OATP function, and the measurements have the potential to be incorporated into the design of early clinical evaluation.

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Section: Discussionmentioning

confidence: 99%

Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species

Shen

Dai

Liu

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

109

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“…Indeed, interaction of several porphyrins with OATP1B1 has recently been demonstrated (40). Phenotypic abnormalities in RS subjects are surprisingly moderate.…”

Section: Figurementioning

confidence: 99%

Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver

Stránecký²,

et al. 2012

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Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotorsyndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.

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“…OATP1B1/3 deficiency also explains the marked impairment of BSP uptake and storage capacity in RS patients (BSP is a substrate of these transporters 5 ), as well as their increased urinary coproporphyrin excretion, in line with the interaction of several porphyrins with OATP1B1. 29 Finally, the obligatory deficiency in two different genes explains the rarity of RS, which has an estimated frequency of about 1 in 10 overall, although it may be several times lower or higher in specific populations. 8…”

Section: Genetic and Molecular Basismentioning

confidence: 99%

Inherited Disorders of Bilirubin Transport and Conjugation: New Insights Into Molecular Mechanisms and Consequences

2014

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Interaction of porphyrins with human organic anion transporting polypeptide 1B1

Cited by 10 publications

References 49 publications

Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species

Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species

Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver

Inherited Disorders of Bilirubin Transport and Conjugation: New Insights Into Molecular Mechanisms and Consequences

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