Urinary Elimination of Coproporphyrins Is Dependent on<i>ABCC2</i> Polymorphisms and Represents a Potential Biomarker of MRP2 Activity in Humans

Bretagne, Isabelle Benz-de; Respaud, Renaud; Vourc’h, Patrick; Halimi, Jean‐Michel; Caille, Agnès; Hulot, Jean‐Sébastien; Andres, Christian R.; Guellec, Chantal Le

doi:10.1155/2011/498757

Cited by 22 publications

(30 citation statements)

References 35 publications

(41 reference statements)

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“…Average percentage of isomer I in our DJS carriers was 43-57%, which is similar to data from literature. 23,24,35 Excretion pattern of coproporphyrin isomers in four patients with dual hereditary jaundice was the same as in other DJS patients with no defect in UGT1A1 (see Table 2). Our findings for coproporphyrin I was 92, 97, 99 and 100% in patients with dual defect compared with 89, 93, 96 and 98% in DJS patients with heterozygous NG_002601.2: g.175492_175493insTA and 89% in DJS patient with the wild-type UGT1A gene.…”

Section: Effect Of a Double Defectsupporting

confidence: 59%

Genetic and biochemical study of dual hereditary jaundice: Dubin–Johnson and Gilbert’s syndromes. Haplotyping and founder effect of deletion in ABCC2

et al. 2015

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Section: Effect Of a Double Defectsupporting

confidence: 59%

Genetic and biochemical study of dual hereditary jaundice: Dubin–Johnson and Gilbert’s syndromes. Haplotyping and founder effect of deletion in ABCC2

et al. 2015

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“…The results suggested that CPs could be potential endogenous biomarkers of OATP activity in vivo (Benz-de Bretagne et al, 2011;van de Steeg et al, 2012). Indeed, the plasma concentrations of both CP-I and CP-III in cynomolgus monkeys were markedly increased following administration of OATP inhibitors cyclosporine A (100 mg/kg oral) or RIF (15 mg/kg oral) (Shen et al, 2015(Shen et al, , 2016b.…”

Section: Discussionmentioning

confidence: 97%

Coproporphyrins in Plasma and Urine Can Be Appropriate Clinical Biomarkers to Recapitulate Drug-Drug Interactions Mediated by Organic Anion Transporting Polypeptide Inhibition

Lai

Mandlekar

Shen

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

142

203

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In the present study, an open-label, three-treatment, threeperiod clinical study of rosuvastatin (RSV) and rifampicin (RIF) when administered alone and in combination was conducted in 12 male healthy subjects to determine if coproporphyrin I (CP-I) and coproporphyrin III (CP-III) could serve as clinical biomarkers for organic anion transporting polypeptide 1B1 (OATP1B1) and 1B3 that belong to the solute carrier organic anion gene subfamily. Genotyping of the human OATP1B1 gene was performed in all 12 subjects and confirmed absence of OATP1B1*5 and OATP1B1*15 mutations. Average plasma concentrations of CP-I and CP-III prior to drug administration were 0.91 6 0.21 and 0.15 6 0.04 nM, respectively, with minimum fluctuation over the three periods. CP-I was passively eliminated, whereas CP-III was actively secreted from urine. Administration of RSV caused no significant changes in the plasma and urinary profiles of CP-I and CP-III. RIF markedly increased the maximum plasma concentration (C max ) of CP-I and CP-III by 5.7-and 5.4-fold (RIF) or 5.7-and 6.5-fold (RIF1RSV), respectively, as compared with the predose values. The area under the plasma concentration curves from time 0 to 24 h (AUC 0-24h ) of CP-I and CP-III with RIF and RSV increased by 4.0-and 3.3-fold, respectively, when compared with RSV alone. In agreement with this finding, C max and AUC 0-24h of RSV increased by 13.2-and 5.0-fold, respectively, when RIF was coadministered. Collectively, we conclude that CP-I and CP-III in plasma and urine can be appropriate endogenous biomarkers specifically and reliably reflecting OATP inhibition, and thus the measurement of these molecules can serve as a useful tool to assess OATP drug-drug interaction liabilities in early clinical studies.

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“…Although CPs have been suggested as putative endogenous markers of OATP1B activity (Benz-de Bretagne et al, 2011;van de Steeg et al, 2012), no studies to date have reported their in vivo disposition, in comparison with known OATP1B probe substrates, after administration of a potent OATP Fig. 5.…”

Section: Discussionmentioning

confidence: 99%

“…The urinary CP isomer ratio has been proposed as a biomarker of MRP2 activity, although there is no in vitro evidence indicating CPs I and III are substrates for MRP2 (Benz-de Bretagne et al, 2011). The proportion of each CP isomer in urine of patients with Dubin-Johnson syndrome Data on plasma concentrations of CPs I and III in healthy subjects are from Kanayama et al (1992).…”

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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Urinary Elimination of Coproporphyrins Is Dependent onABCC2 Polymorphisms and Represents a Potential Biomarker of MRP2 Activity in Humans

Cited by 22 publications

References 35 publications

Genetic and biochemical study of dual hereditary jaundice: Dubin–Johnson and Gilbert’s syndromes. Haplotyping and founder effect of deletion in ABCC2

Genetic and biochemical study of dual hereditary jaundice: Dubin–Johnson and Gilbert’s syndromes. Haplotyping and founder effect of deletion in ABCC2

Coproporphyrins in Plasma and Urine Can Be Appropriate Clinical Biomarkers to Recapitulate Drug-Drug Interactions Mediated by Organic Anion Transporting Polypeptide Inhibition

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

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