UHPLC–MS/MS Bioanalysis of Human Plasma Coproporphyrins as Potential Biomarkers for Organic Anion-Transporting Polypeptide-Mediated Drug Interactions

Kandoussi, Hamza; Zeng, Jianing; Shah, Kumar A.; Paterson, Patricia; Santockyte, Rasa; Kadiyala, Pathanjali; Shen, Hong; Shipkova, Petia; Langish, Robert; Burrrell, Richard; Easter, John A.; Mariannino, Thomas; Marathe, Punit; Lai, Yurong; Zhang, Yan; Pillutla, Renuka

doi:10.4155/bio-2017-0246

Cited by 15 publications

(16 citation statements)

References 11 publications

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“…The correlation coefficient from four standard curves was greater than 0.990, and accuracy and precision were confirmed within 15.0% of quality controls at low, middle and high concentrations. There was no indication of matrix instability for 98 days in surrogate matrix and 400 days in plasma samples protected from light during storage, suggesting no apparent stability issues (Kandoussi et al, 2018).…”

Section: Quantification Of Rif Cpi and Cpiii In Plasma By Liquid Chrmentioning

confidence: 92%

“…Tandem Mass Spectrometry. The plasma concentrations of RIF, CPI, and CPIII were measured in plasma samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays described previously with slight modifications (Kandoussi et al, 2018, Zhang et al, 2019. A lower limit of quantification (LLOQ) of 0.078 nM was achieved for both CPI and CPIII using optimized sample extraction and LC-MS/MS conditions.…”

Section: Quantification Of Rif Cpi and Cpiii In Plasma By Liquid Chrmentioning

confidence: 99%

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Absence of OATP1B (Organic Anion–Transporting Polypeptide) Induction by Rifampin in Cynomolgus Monkeys: Determination Using the Endogenous OATP1B Marker Coproporphyrin and Tissue Gene Expression

Zhang

Chen

et al. 2020

J Pharmacol Exp Ther

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Organic anion-transporting polypeptide (OATP)1B induction is an evolving mechanism of drug disposition and interaction. However, there are contradictory reports describing OATP1B expression in hepatocytes and liver biopsies after administration of an inducer. This study investigated the in vivo effects of the common inducer rifampin (RIF) on the activity and expression of cynomolgus monkey OATP1B1 and OATP1B3 transporters, which are structurally and functionally similar their human OATP1B counterparts. Multiple doses of oral RIF (15 mg/kg) resulted in a steady 3.9-fold increase of CYP3A biomarker, 4β-hydroxycholesterol (4βHC), in the plasma samples collected before each RIF dose during the treatment period (i.e., predose). In contrast, the predose plasma levels of OATP1B biomarkers coproporphyrin (CP) I and CPIII did not change when compared to RIF treatment. The trough concentration, AUC, and half-life of RIF decreased markedly during RIF treatment, suggesting that RIF induced its own clearance. Consequently, RIF treatment increased CPI and CPIII AUCs substantially after a single administration and, to a lesser extent, after multiple administrations, compared to preadministration AUCs. In addition, OATP1B1 and OATP1B3 mRNA expressions were not modulated by RIF treatment (0.85-to 1.3-fold) whereas CYP3A8 expression was increased 3.7to 5.0-fold, which correlated well with the predose levels of CP and 4βHC. Rifampin treatment showed 2.0-to 3.3-fold increases in P-gp, BCRP, and MRP2 expression in the small intestine. Collectively, these findings indicate that monkey OATP1B and OATP1B3 are not induced by RIF and further investigation of OATP1B induction by RIF and other nuclear receptor activators in humans is warranted.

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Section: Quantification Of Rif Cpi and Cpiii In Plasma By Liquid Chrmentioning

confidence: 92%

Section: Quantification Of Rif Cpi and Cpiii In Plasma By Liquid Chrmentioning

confidence: 99%

Absence of OATP1B (Organic Anion–Transporting Polypeptide) Induction by Rifampin in Cynomolgus Monkeys: Determination Using the Endogenous OATP1B Marker Coproporphyrin and Tissue Gene Expression

Zhang

Chen

et al. 2020

J Pharmacol Exp Ther

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“…Both high mass accuracy and the possibility of breaking the analyte molecules in the gas phase and measuring their fragments (MS/MS) contribute to unequivocal species identification, because complex samples can often not be fully chromatographically resolved. HPLC-MS was applied for the determination of porphyrin profiles in biological matrices [11,[39][40][41][42][43] using predominantly electrospray ionization (ESI) interfaces. Additionally, there were efforts to explore atmospheric pressure chemical ionization [42] for the purpose.…”

Section: Mass Spectrometrymentioning

confidence: 99%

“…For the investigation of porphyrins in blood, predominantly plasma or red blood cells were used [11,40,43]. In plasma, MS was applied for the quantification of coproporphyrin isomers for monitoring of drug interactions [43], the elucidation of fluorescing compounds after detection of elevated fluorescence [11], and the qualitative analysis of porphyrin patterns facilitating the differential diagnosis of human porphyrias [40]. Despite all these efforts, no short and sensitive HPLC-MS/MS method for specific PPIX quantification from whole blood or serum was yet available although great data have been shown for less complex cell culture extracts [44,45].…”

Section: Structures Of Type I and Iii Isomers Of Uro-and Coproporphyrmentioning

confidence: 99%

Protoporphyrin IX Analysis from Blood and Serum in the Context of Neurosurgery of Glioblastoma

Walke¹,

Molina²,

Stummer³

et al. 2021

Mass Spectrometry in Life Sciences and Clinical Laboratory

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Protoporphyrin IX (PPIX) is formed from δ-aminolevulinic acid (ALA) during heme biosynthesis. Due to its cyclic tetrapyrrole core structure, it absorbs in the visible region of the electromagnetic spectrum and is thus colored. Both ALA and PPIX have become of great interest to neurosurgery, because in high-grade glioma, ALA diffuses into the tumor and is converted to PPIX. Fluorescence-guided resection (FGR) takes advantage of both the enrichment of PPIX in the tumor and its fluorescent properties, which enable visualization of tumor tissue. ALA-mediated FGR thus maximizes the extent of resection with better prognosis for patients. Tumor cells are able to produce porphyrins naturally or after administration of ALA, which is also reflected in elevated plasma fluorescence of cancer patients. PPIX might thus serve as a biomarker for monitoring of the tumor burden. A liquid chromatography-mass spectrometry (LC-MS)-based method is presented to quantify PPIX in blood and serum in the context of current fluorescence-based diagnostics. The method is able to distinguish between zinc PPIX, a component of red blood cells of importance in the detection of lead poisoning and iron deficiency anemia, and metal-free PPIX. In a proof-of-principle study, it was used to follow a time course of a glioblastoma patient undergoing surgery and confirmed elevated PPIX blood levels before ALA administration. During surgery, these blood levels increased about four-fold. The here developed 10 min reversed-phase LC-target MS method now allows patient screening with high specificity and throughput.

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“…Atorvastatin is used as a probe drug for evaluating OATP-mediated DDIs. Similarly, the article by Kandoussi et al [38] demonstrates a robust UHPLC-MS/MS assay using the singly charged ([M+H] + ) precursor ions of CP-I/CP-III at m/z 655.3 and a supported liquid extraction method for sample clean-up and automation. The assay was validated and applied to clinical studies to confirm suitability of CPs as a potential substitute for DDI study.…”

Section: Under Typical Lc-ms Conditions Cp-i and Cp-iii Form Both Singly ([M+h] + ) And Doubly Charged ([M+2h] 2+mentioning

confidence: 99%

Novel LC–MS Assays Impacting CYP and Transporter Drug–Drug Interaction Evaluations

Ramanathan

2018

Bioanalysis

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Drug-drug interaction (DDI) potentials of new chemical entities (NCEs) are a major concern when patients require treatment with multiple drug regimens at the same time. When drug X is co-administered with drug Y, either drug has the potential to partially or totally alter absorption, distribution, metabolism and excretion (ADME) properties of the other. The alterations in the ADME properties of the drug X could result from inhibition or induction of Cytochrome P450 (CYP) enzymes or transporters and, thus, alter the co-administered drug's efficacy and safety. To ensure safety and efficacy of drugs, regulatory agencies across the globe and the pharmaceutical industries have embraced evaluations of DDI potential of an NCE early in the drug development program and continued postmarketing. The guidance documents, from the US FDA, provide recommendations on drug interaction study design, data analysis, implications for dosing and labeling recommendations [1,2]. In addition, a collaborative group of scientists, from the academia, regulatory agencies, pharmaceutical industry and contract research organizations (CROs), regularly organize conferences and publish white papers based on new research, new clinical studies and findings from recent regulatory reviews. For example, breakthroughs and outcomes, from rapidly growing transporter sciences, are disseminated through outputs from the International Transporter Consortium [3][4][5].There is a growing interest in exploring novel LC-MS/MS, LC-high resolution accurate mass spectrometry (LC-HRMS) or LC-MS/HRMS assays early in drug development to ensure DDI-related liabilities to establish safety and efficacy of an NCE. This special issue brings together some of the novel LC-MS applications and outlook from leaders in the field.In vitro cytochrome P450 DDI projections before the start of clinical trials DDI potentials, related to CYP and UDP-glucuronosyltranferase (UGT) enzymes, have been extensively investigated because collectively both enzymes account for more than 90% of the biotransformation of the NCEs used for human treatments [6,7]. Very recently, Yu et al. [8] reviewed a total of 103 drugs, including 14 combination therapies and published the data under a title of 'Risk of clinically relevant pharmacokinetic-based drug-drug interactions with drugs approved by the US Food and Drug Administration between 2013 and 2016'. Investigations of the ADME properties and DDI profiles of the drugs approved between 2013 and 2016, using the University of Washington Drug Interaction Database and each drug's NDA information, showed CYP3A to be involved in >65% of DDIs. Several LC-MS/MS-based high-throughput CYP inhibition and induction assays have been reported over the last 20 years to ensure the safety and efficacy of drugs when required for co-administration [9,10]. The commentary entitled 'Application of in vitro CYP and transporter assays to predict clinical drug-drug interactions' by Volpe and Balimane [11] provides the needed background on enzymes including Phase I, Phase II and...

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UHPLC–MS/MS Bioanalysis of Human Plasma Coproporphyrins as Potential Biomarkers for Organic Anion-Transporting Polypeptide-Mediated Drug Interactions

Abstract: A robust UHPLC-MS/MS assay was developed and validated for CP-I and CP-III in plasma, and is currently applied to clinical studies to confirm suitability of Coproporphyrins as a potential substitute for drug-drug interaction study.

Cited by 15 publications

References 11 publications

Absence of OATP1B (Organic Anion–Transporting Polypeptide) Induction by Rifampin in Cynomolgus Monkeys: Determination Using the Endogenous OATP1B Marker Coproporphyrin and Tissue Gene Expression

Absence of OATP1B (Organic Anion–Transporting Polypeptide) Induction by Rifampin in Cynomolgus Monkeys: Determination Using the Endogenous OATP1B Marker Coproporphyrin and Tissue Gene Expression

Protoporphyrin IX Analysis from Blood and Serum in the Context of Neurosurgery of Glioblastoma

Novel LC–MS Assays Impacting CYP and Transporter Drug–Drug Interaction Evaluations

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