Development and validation of an HPLC–MS/MS method for the determination of arginine-vasopressin receptor blocker conivaptan in human plasma and rat liver microsomes: application to a metabolic stability study

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Abstract

Purpose

To develop and validate a bio-analytical HPLC–MS/MS method for the determination of conivaptan (CVA) an arginine-vasopressin receptor blocker in human plasma and in rat liver microsomes (RLMs).

Methods

Analytes were separated on a reversed phase C18 column (50 mm × 2.1 mm, 1.8 μm). The mobile phase was a mixture of acetonitrile and 10 mM ammonium formate (40:60 v/v, pH 4.0) and was pumped isocratically for 4 min at a flow rate of 0.2 ml/min. Multiple reaction monitoring in positive ionization mode was used for the assay.

Results

The method yielded a linear calibration plot ( r ²= 0.9977 and 0.9998) over 5–500 ng/ml with a limit of detection at 1.52 and 0.88 ng/ml for human plasma and RLMs, respectively. The reproducibility of detection of CVA in human plasma and RLMs was found to be in an acceptable range.

Conclusion

The method developed in this study is applicable for accurately quantifying CVA in human plasma and rat liver microsomal samples. The optimized procedure was applied to study of metabolic stability of CVA. Conivaptan concentration rapidly decreased in the first 2 min of RLMs incubation and the conversion reached a plateau for the remainder of the incubation period. The in vitro half-life (t _1/2) was estimated at 11.51 min and the intrinsic clearance (CL _in) was 13.8 ± 0.48 ml/min/kg.

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Incidence and prevalence of hyponatremia.

Ashish Dutt Upadhyay, Bertrand Jaber, Nicolaos Madias (2006)

Hyponatremia is the most common electrolyte abnormality encountered in clinical practice. The reported frequency of the disorder is determined by a number of factors, including the definition of hyponatremia, the frequency of testing, the healthcare setting, and the patient population. This review focuses on the incidence and prevalence of hyponatremia. In acute hospital care, particular attention is given to admission versus hospital-acquired hyponatremia. Although less well studied, the epidemiology of hyponatremia in the ambulatory-based setting and the geriatric/nursing home population is also summarized. Finally, the frequency of hyponatremia occurring in special clinical conditions--including congestive heart failure, cirrhosis, pneumonia, and acquired immunodeficiency syndrome--as well as in marathon runners will be reviewed. Substantial additional work is still required to determine the true occurrence of hyponatremia in the various clinical settings. Beyond the phenomenologic value, advances in the epidemiology of hyponatremia should also provide insights in the prognostic implications as well as the preventive and management strategies of the disorder in various clinical settings.

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The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data.

B Michael Silber, P Wastall, Sarah Liston … (1997)

We describe a comprehensive retrospective analysis in which the abilities of several methods by which human pharmacokinetic parameters are predicted from preclinical pharmacokinetic data and/or in vitro metabolism data were assessed. The prediction methods examined included both methods from the scientific literature as well as some described in this report for the first time. Four methods were examined for their ability to predict human volume of distribution. Three were highly predictive, yielding, on average, predictions that were within 60% to 90% of actual values. Twelve methods were assessed for their utility in predicting clearance. The most successful allometric scaling method yielded clearance predictions that were, on average, within 80% of actual values. The best methods in which in vitro metabolism data from human liver microsomes were scaled to in vivo clearance values yielded predicted clearance values that were, on average, within 70% to 80% of actual values. Human t1/2 was predicted by combining predictions of human volume of distribution and clearance. The best t1/2 prediction methods successfully assigned compounds to appropriate dosing regimen categories (e.g., once daily, twice daily and so forth) 70% to 80% of the time. In addition, correlations between human t1/2 and t1/2 values from preclinical species were also generally successful (72-87%) when used to predict human dosing regimens. In summary, this retrospective analysis has identified several approaches by which human pharmacokinetic data can be predicted from preclinical data. Such approaches should find utility in the drug discovery and development processes in the identification and selection of compounds that will possess appropriate pharmacokinetic characteristics in humans for progression to clinical trials.

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Introduction to in vitro estimation of metabolic stability and drug interactions of new chemical entities in drug discovery and development.

Paweł Baranczewski, Andrzej Stańczak, Kathrin Sundberg … (2015)

Determination of metabolic properties of a new chemical entity (NCE) is one of the most important steps during the drug discovery and development process. Nowadays, in vitro methods are used for early estimation and prediction of in vivo metabolism of NCEs. Using in vitro methods, it is possible to determine the metabolic stability of NCEs as well as the risk for drug-drug interactions (DDIs) related to inhibition and induction of drug metabolic enzymes. Metabolic stability is defined as the susceptibility of a chemical compound to biotransformation, and is expressed as in vitro half-life (t(1/2)) and intrinsic clearance (CL(int)). Based on these values, in vivo pharmacokinetic parameters such as bioavailability and in vivo half-life can be calculated. The drug metabolic enzymes possess broad substrate specificity and can metabolize multiple compounds. Therefore, the risk for metabolism-based DDIs is always a potential problem during the drug development process. For this reason, inhibition and induction in vitro screens are used early, before selection of a candidate drug (CD), to estimate the risk for clinically significant DDIs. At present, most pharmaceutical companies perform in vitro drug metabolism studies together with in silico prediction software and automated high-throughput screens (HTS). Available data suggest that in vitro methods are useful tools for identification and elimination of NCEs with unappreciated metabolic properties. However, the quantitative output of the methods has to be improved. The aim of this review is to highlight the practical and theoretical basis of the in vitro metabolic methods and the recent progress in the development of these assays.

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Author and article information

Contributors

Gamal A. E. Mostafa: gmostafa@ksu.edu.sa , gamal_most@yahoo.com

Journal

Journal ID (nlm-ta): Chem Cent J

Journal ID (iso-abbrev): Chem Cent J

Title: Chemistry Central Journal

Publisher: Springer International Publishing (Cham )

ISSN (Electronic): 1752-153X

Publication date (Electronic): 2 May 2018

Publication date PMC-release: 2 May 2018

Publication date Collection: 2018

Volume: 12

Electronic Location Identifier: 47

Affiliations

[1 ]ISNI 0000 0004 1773 5396, GRID grid.56302.32, Department of Pharmaceutical Chemistry, College of Pharmacy, , King Saud University, ; P.O. Box 2457, Riyadh, 11451 Saudi Arabia

[2 ]ISNI 0000 0001 2151 8157, GRID grid.419725.c, Micro-analytical Lab, Applied Organic Chemistry Department, , National Research Center, ; Dokki, Cairo, Egypt

Article

Publisher ID: 414

DOI: 10.1186/s13065-018-0414-5

PMC ID: 5930294

PubMed ID: 29717376

SO-VID: 1765a0ff-59c6-4cdd-ae05-87643dc1a172

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 17 July 2017

Date accepted : 19 April 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100002383, King Saud University;

Award ID: RGP-1436-024

Award Recipient : Gamal A. E. Mostafa

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ScienceOpen disciplines: Chemistry

Keywords: conivaptan,lc–ms/ms,human plasma,rlms,metabolic stability study

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ScienceOpen disciplines: Chemistry

Keywords: conivaptan, lc–ms/ms, human plasma, rlms, metabolic stability study

Development and validation of an HPLC–MS/MS method for the determination of arginine-vasopressin receptor blocker conivaptan in human plasma and rat liver microsomes: application to a metabolic stability study

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Most cited references 16

Incidence and prevalence of hyponatremia.

The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data.

Introduction to in vitro estimation of metabolic stability and drug interactions of new chemical entities in drug discovery and development.

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