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

@article{Lai2016CoproporphyrinsIP,
  title={Coproporphyrins in Plasma and Urine Can Be Appropriate Clinical Biomarkers to Recapitulate Drug-Drug Interactions Mediated by Organic Anion Transporting Polypeptide Inhibition},
  author={Yurong Lai and Sandhya Mandlekar and Hong Shen and Vinay K. Holenarsipur and Robert A Langish and Prabhakar K Rajanna and Senthilkumar Murugesan and Nilesh Gaud and Sabariya Selvam and Onkar Date and Yaofeng Cheng and Petia A. Shipkova and Jun Dai and W Griffith Humphreys and Punit H. Marathe},
  journal={The Journal of Pharmacology and Experimental Therapeutics},
  year={2016},
  volume={358},
  pages={397 - 404}
}
In the present study, an open-label, three-treatment, three-period 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… Expand

Paper Mentions

Observational Clinical Trial
This is a single center, comparative cohort study to investigate alterations in hepatic transporter function in subjects with autosomal dominant polycystic kidney disease (ADPKD… Expand
ConditionsADPKD, Autosomal Dominant Polycystic Kidney Disease, Renal Disease
Clinical Investigation of Coproporphyrins as Sensitive Biomarkers to Predict Mild to Strong OATP1B-Mediated Drug–Drug Interactions
TLDR
The results demonstrate the selectivity of CPI and CPIII towards the OATP1B/MRP pathway, and the herein reported data further underline the potential of CPIand CPIII as selective and sensitive clinical biomarkers to quantify OATp1B-mediated DDIs. Expand
Further Studies to Support the Use of Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition
TLDR
Findings provide further evidence supporting the translational value of CPI and CPIII as suitable endogenous clinical probes to gauge OATP1B activity and potential for OATp1B-mediated DDIs. Expand
Detection of Weak Organic Anion–Transporting Polypeptide 1B Inhibition by Probenecid with Plasma-Based Coproporphyrin in Humans
TLDR
It is suggested that PROB is a weak clinical inhibitor of OATP1B based on the totality of evidence from the clinical interaction between PROB and CP and the in vitro inhibitory effect of PROB on OATp1B-mediated CP uptake and that coproporphyrin is a sensitive endogenous probe of OatP1 B inhibition. Expand
PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3
TLDR
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Investigation of Endogenous Compounds Applicable to Drug–Drug Interaction Studies Involving the Renal Organic Anion Transporters, OAT1 and OAT3, in Humans
TLDR
It is suggested that taurine and GCDCA-S can be used as probes for evaluating pharmacokinetic drug–drug interactions involving OAT1 and OAT3, respectively, in humans. Expand
Absence of OATP1B (Organic Anion–Transporting Polypeptide) Induction by Rifampin in Cynomolgus Monkeys: Determination Using the Endogenous OATP1B Marker Coproporphyrin and Tissue Gene Expression
TLDR
Combined endogenous biomarker and gene expression data suggested that RIF did not induce OATP1B in cynomolgus monkeys, and this study provides evidence to strengthen the claim that coproporphyrin is a suitable endogenous probe of OATp1B activity. Expand
Absorption and Disposition of Coproporphyrin I (CPI) in Cynomolgus Monkeys and Mice: Pharmacokinetic Evidence to Support the Use of CPI to Inform the Potential for Organic Anion-Transporting Polypeptide Inhibition
TLDR
It is suggested that hepatic OATP considerably affects the disposition of CPI in animal models, indicating CPI is a sensitive and selective endogenous biomarker of OatP inhibition. Expand
Dose‐Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs
TLDR
These endogenous substrates can complement existing OATP1B‐mediated drug–drug interaction risk assessment approaches based on agency guidelines in early clinical trials and are supported by the good correlation of AUC0‐24h between the endogenous compounds and the probe drugs. Expand
Comparative Evaluation of Plasma Bile Acids, Dehydroepiandrosterone Sulfate, Hexadecanedioate, and Tetradecanedioate with Coproporphyrins I and III as Markers of OATP Inhibition in Healthy Subjects
TLDR
Investigation of bile acids and fatty acid dicarboxylates in plasma as endogenous probes for OATP inhibition and compared these candidate probes to CPs confirmed that CPs are novel biomarkers suitable for clinical use. Expand
Discovery and Validation of Pyridoxic Acid and Homovanillic Acid as Novel Endogenous Plasma Biomarkers of Organic Anion Transporter (OAT) 1 and OAT3 in Cynomolgus Monkeys
TLDR
Findings suggest that PDA and HVA might serve as blood-based endogenous probes of cynomolgus monkey OAT1 and OAT3, and investigation of PDAand HVA as circulating endogenous biomarkers of human OAT 1 and Oat3 function is warranted. Expand
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Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species
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  • Biology, Medicine
  • The Journal of Pharmacology and Experimental Therapeutics
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TLDR
It is concluded 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. Expand
Evaluation of Rosuvastatin as an Organic Anion Transporting Polypeptide (OATP) Probe Substrate: In Vitro Transport and In Vivo Disposition in Cynomolgus Monkeys
TLDR
The high levels of unchanged RSV recovered in urine and bile and the relatively low levels of metabolites observed indicated that RSV was eliminated largely by excretion, and further support the use of the cynomolgus monkey as a model to assess interactions involving OATP inhibition. Expand
Pitavastatin is a more sensitive and selective organic anion-transporting polypeptide 1B clinical probe than rosuvastatin.
TLDR
It is indicated that pitavastatin is a more sensitive and selective and thus preferred clinical OATP1B probe substrate than rosuvastatin, and that a single IV dose of rifampicin is aMore selective OATp1B inhibitor than a PO dose. Expand
Urinary Elimination of Coproporphyrins Is Dependent on ABCC2 Polymorphisms and Represents a Potential Biomarker of MRP2 Activity in Humans
TLDR
This study provides a proof of concept that UCP I/(I + III) ratio can be used as a biomarker of MRP2 function in clinical studies as it provides quantitative information about the in vivo activity of MRp2 in a given patient. Expand
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
TLDR
The cynomolgus monkey has the potential to serve as a useful model for the assessment of OATP-mediated DDIs in a nonclinical setting and a number of in vitro–in vivo extrapolation approaches were explored. Expand
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
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Whether cynomolgus monkeys are a suitable translational model to study OATP1B-mediated DDIs is evaluated and the inhibitory effect of RIF is determined on in vitro transport and pharmacokinetics of rosuvastatin (RSV) and atorvASTatin (ATV). Expand
Utility of Bilirubins and Bile Acids as Endogenous Biomarkers for the Inhibition of Hepatic Transporters
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The monitoring of bilirubins and bile acids in plasma is useful in evaluating the inhibitory potential of their corresponding transporters, although there were differences between the free plasma or liver concentrations and IC50 values of rNtcp or rBsep, respectively. Expand
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The estimation of the contribution of OATP1B1 to the total hepatic uptake of drugs is described from the data of fold-increases in the plasma concentration of substrate drugs by the genetic polymorphism of this transporter. Expand
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TLDR
OATP1B1 substrate drugs except for torasemide and nateglinide, or E2G as a surrogate, is recommended as an in vitro probe in the inhibition experiments, which will help mitigate the risk of false-negative DDI predictions potentially caused by substrate-dependent Ki variation. Expand
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TLDR
Evidence is provided that the calculated fraction of OATP1B1 inhibited at the clinical exposure level correlated very well with the observed hyperbilirubinemia outcome for these drugs in humans, which supports the hypothesis that inhibition of OatP1 B1 is an important mechanism for drug-induced unconjugated hyperbilIRubinemi. Expand
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