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Clinical Assessment of Drug Transporter Inhibition Using Biomarkers: Review of the Literature (2015-2024).
J Clin Pharmacol
January 2025
Drug Metabolism and Nonclinical Pharmacokinetics, Translational Medicine, Incyte, Wilmington, DE, USA.
As part of a narrative review of various publications describing the clinical use of urine- and plasma-based drug transporter biomarkers, it was determined that the utilization of coproporphyrin I, a hepatic organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 biomarker, has been reported for 28 different drug-drug interaction (DDI) perpetrator drugs. Similarly, biomarkers for liver organic cation transporter 1 (isobutyryl-l-carnitine, N = 7 inhibitors), renal organic cation transporter 2 and multidrug and toxin extrusion proteins (N-methylnicotinamide, N = 13 inhibitors), renal organic anion transporter (OAT) 1 and 3 (pyridoxic acid, N = 7 inhibitors), and breast cancer resistance protein (riboflavin, N = 3 inhibitors) have also been described. Increased use of biomarkers has also been accompanied by modeling efforts to enable DDI predictions and development of multiplexed methods to facilitate their bioanalysis.
View Article and Find Full Text PDFEndogenous plasma riboflavin is not a viable BCRP biomarker in human.
Clin Transl Sci
December 2024
Clinical Pharmacology, AbbVie Inc., North Chicago, Illinois, USA.
Recent reports suggest that plasma riboflavin may serve as a biomarker for BCRP inhibition in humans. However, the clinical data supporting this claim have been limited, with only two studies showing modest increases in riboflavin levels after administration of a BCRP inhibitor. We have recently demonstrated that co-administration of 375 mg once daily (q.
View Article and Find Full Text PDFUltra-Sensitive Quantification of Coproporphyrin-I and -III in Human Plasma Using Ultra-Performance Liquid Chromatography Coupled to Quadrupole Time-of-Flight Mass Spectrometry.
ACS Omega
November 2024
Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
Organic anion transporting polypeptides (OATP) 1B1 and 1B3 are expressed in liver cells and are involved in drug uptake in the liver. OATP1B activity varies due to polymorphisms and is decreased by OATP1B inhibitors. Variability of OATP1B activity impacts the pharmacokinetics of OATP1B substrate drugs through drug-drug interactions.
View Article and Find Full Text PDFStructural insights into the recognition of tetrapyrrole substrates by ancestral class II chelatase CfbA.
Protein Sci
December 2024
Department of Biochemistry and Molecular Biology, Graduate School of Science and Engineering, Saitama University, Saitama, Japan.
Nickel-chelatase CfbA, unlike descendant chelatases, is an ancestral class II chelatase with a symmetric active site architecture. CfbA utilizes sirohydrochlorin (SHC) as a physiological substrate in the biosynthesis of coenzyme F430. CbiX, a structural analog of CfbA, can use uroporphyrin III (UPIII) and uroporphyrin I (UPI) as non-physiological substrates.
View Article and Find Full Text PDFIncreased coproporphyrin serum levels in healthy volunteers treated with the cholesterol uptake inhibitor ezetimibe.
Clin Transl Sci
October 2024
Biopharmacy, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Ezetimibe undergoes glucuronidation that results in the active metabolite ezetimibe phenoxy-glucuronide (ezetimibe-glucuronide). This phase-II metabolite was shown to interact with the clinically relevant hepatic transporter organic anion transporting polypeptide (OATP) 1B1. In recent years, coproporphyrin I (CPI) was established as a Tier 1 biomarker for OATP1B-mediated interactions among other endogenous substrates like CPIII.
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