A novel liquid chromatography/tandem mass spectrometry based depletion method for measuring red blood cell partitioning of pharmaceutical compounds in drug discovery

Yu, Sheng; Li, Shelly; Yang, Hua; Lee, Frank; Wu, Jingtao; Qian, Mark G.

doi:10.1002/rcm.1777

Cited by 83 publications

(55 citation statements)

References 23 publications

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“…Blood to plasma concentration ratio (R B ) was determined following incubation in fresh whole blood as described previously. 22) R B values were 1.23±0.06 and 0.88±0.14 for streptochlorin and HIS, respectively. Fraction unbound in blood ( f ub ) was calculated as follows:…”

Section: Methodsmentioning

confidence: 93%

Pharmacokinetics and Metabolism of Streptochlorin and Its Synthetic Derivative, 5-Hydroxy-2′-isobutyl Streptochlorin, in Mice

Zhou

Choi

Kim

et al. 2018

Biological & Pharmaceutical Bulletin

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The purpose of this study was to investigate the pharmacokinetics and metabolism of streptochlorin and its derivative 5-hydroxy-2′-isobutyl streptochlorin (HIS) in mice. Plasma concentration of streptochlorin declined rapidly resulting in a high sustemic plasma clearance (CL p ) (5.8 1.7 L/h/kg), a large volume of distribution (V ss ) (1.4 0.9 L/kg) and a short half-life (t 1/2 ) (0.4 0.1 h) after a single intravenous administration (5 mg/kg). Oral bioavailability (F) was 10.3 3.4% after a single oral administration (10 mg/kg). HIS also showed a rapid plasma decline with a high CL p (11.3 8.8 L/h/kg), a high V ss (0.8 1.0 L/kg) and a short t 1/2 (0.070 0.004 h) following intravenous administration. It was not detected in plasma after oral administration. Metabolic stability studies using mouse liver microsomes and S9 fractions predicted a high hepatic clearance for both compounds, consistent with the in vivo data. Metabolite identification studies revealed three metabolic pathways for streptochlorin: monooxygenation, glucuronidation of the indole moiety and oxidative opening of the 4-chlorooxazole ring. HIS was metabolized via monooxygenation of the isobutyl chain and glucuronidation of the indole ring. These results may aid in structural optimization to mitigate the metabolic liability of streptochlorin.Key words streptochlorin; 5-hydroxy-2′-isobutyl streptochlorin; pharmacokinetics; metabolism Terrestrial organisms have been a rich source of natural products for drug discovery and development for thousands of years. Since the mid-twentieth century, studies have shown that marine creatures, especially microbes, have provided many bioactive compounds with novel structures. These include compounds such as ziconotide which is an analgesic agent for severe and chronic pain treatment, trabectedin, an anticancer drug, and eribulin for metastatic breast cancer and liposarcoma treatment.

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Section: Methodsmentioning

confidence: 93%

Pharmacokinetics and Metabolism of Streptochlorin and Its Synthetic Derivative, 5-Hydroxy-2′-isobutyl Streptochlorin, in Mice

Zhou

Choi

Kim

et al. 2018

Biological & Pharmaceutical Bulletin

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“…Blood-to-plasma ratios were determined in fresh mouse, rat, dog, and human blood using the indirect method (Yu et al, 2005); compounds were incubated for 0.5 hour at a concentration of 1 mM.…”

Section: Methodsmentioning

confidence: 99%

A Pharmacokinetic Modeling Approach to Predict the Contribution of Active Metabolites to Human Efficacious Dose

Martin

Hill

Baker

et al. 2016

Drug Metabolism and Disposition

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A preclinical drug candidate, MRK-1 (Merck candidate drug parent compound), was found to elicit tumor regression in a mouse xenograft model. Analysis of samples from these studies revealed significant levels of two circulating metabolites, whose identities were confirmed by comparison with authentic standards using liquid chromatography-tandem mass spectrometry. These metabolites were found to have an in vitro potency similar to that of MRK-1 against the pharmacological target and were therefore thought to contribute to the observed efficacy. To predict this contribution in humans, a pharmacokinetic (PK) modeling approach was developed. At the mouse efficacious dose, the areas under the plasma concentration time curves (AUCs) of the active metabolites were normalized by their in vitro potency compared with MRK-1. These normalized metabolite AUCs were added to that of MRK-1 to yield a composite efficacious unbound AUC, expressed as "parent drug equivalents," which was used as the target AUC for predictions of the human efficacious dose. In vitro and preclinical PK studies afforded predictions of the PK of MRK-1 and the two active metabolites in human as well as the relative pathway flux to each metabolite. These were used to construct a PK model

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“…S. Yu et al reported a method for measuring compound partitioning between human plasma and red blood cells (RBC) in a drug discovery field with LC-MS/MS-based depletion assay. 10 The information on the partitioning of a compound of pharmaceutical interest in RBC is important in understanding the pharmacokinetics and pharmacodynamics of the compound and is sometimes critical in screening candidates of a drug without a lost opportunity.…”

Section: 5mentioning

confidence: 99%

Rapid and Sensitive Analysis of Valproic Acid in Human Red Blood Cell by LC-MS/MS

Han¹,

Kim²,

Jeon³

et al. 2012

Bulletin of the Korean Chemical Society

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A sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed to determine valproic acid in human red blood cell (RBC). It is important to measure the drug concentration of the RBC as well as that of the plasma because of drug partitioning for pharmacokinetic and pharmacodynamic study. The method was linear over the dynamic range of 1-100 µg/mL with a correlation coefficient r = 0.9997. The linearity of this method was established from 1 to 100 µg/mL for valproic acid in red blood cell with accuracy and precision within 15% at all concentrations. The intra-run and inter-run assay accuracy and coefficient of variations are all within 15% for all QC samples prepared in plasma and red blood human samples. Then, valproic acid amount by protein precipitation in plasma was quantified by LC-MS/MS mass spectrometry. The distribution ratio of VPA in RBC and plasma was analyzed by clinical samples. Based on measurement of the valproic acid in human red blood cell, this method has been applied to clinical research for study of distribution ratio of valproic acid in blood.

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A novel liquid chromatography/tandem mass spectrometry based depletion method for measuring red blood cell partitioning of pharmaceutical compounds in drug discovery

Cited by 83 publications

References 23 publications

Pharmacokinetics and Metabolism of Streptochlorin and Its Synthetic Derivative, 5-Hydroxy-2′-isobutyl Streptochlorin, in Mice

Pharmacokinetics and Metabolism of Streptochlorin and Its Synthetic Derivative, 5-Hydroxy-2′-isobutyl Streptochlorin, in Mice

A Pharmacokinetic Modeling Approach to Predict the Contribution of Active Metabolites to Human Efficacious Dose

Rapid and Sensitive Analysis of Valproic Acid in Human Red Blood Cell by LC-MS/MS

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