Show simple item record

dc.contributor.authorForkuo, A.D.*
dc.contributor.authorAnsah, C.*
dc.contributor.authorPearson, D.*
dc.contributor.authorGertsch, W.*
dc.contributor.authorCirello, A.*
dc.contributor.authorAmaral, A.*
dc.contributor.authorSpear, J.*
dc.contributor.authorWright, Colin W.*
dc.contributor.authorRynn, C.*
dc.date.accessioned2018-01-16T11:47:32Z
dc.date.available2018-01-16T11:47:32Z
dc.date.issued2017-12
dc.identifier.citationForkuo AD, Ansah C, Pearson D et al (2017) Identification of cryptolepine metabolites in rat and human hepatocytes and metabolism and pharmacokinetics of cryptolepine in Sprague Dawley rats. BMC Pharmacology and Toxicology. 18: 84.
dc.identifier.urihttp://hdl.handle.net/10454/14521
dc.descriptionYes
dc.description.abstractBackground: This study aims at characterizing the in vitro metabolism of cryptolepine using human and rat hepatocytes, identifying metabolites in rat plasma and urine after a single cryptolepine dose, and evaluating the single-dose oral and intravenous pharmacokinetics of cryptolepine in male Sprague Dawley (SD) rats. Methods: The in vitro metabolic profiles of cryptolepine were determined by LC-MS/MS following incubation with rat and human hepatocytes. The in vivo metabolic profile of cryptolepine was determined in plasma and urine samples from Sprague Dawley rats following single-dose oral administration of cryptolepine. Pharmacokinetic parameters of cryptolepine were determined in plasma and urine from Sprague Dawley rats after single-dose intravenous and oral administration. Results: Nine metabolites were identified in human and rat hepatocytes, resulting from metabolic pathways involving oxidation (M2-M9) and glucuronidation (M1, M2, M4, M8, M9). All human metabolites were found in rat hepatocyte incubations except glucuronide M1. Several metabolites (M2, M6, M9) were also identified in the urine and plasma of rats following oral administration of cryptolepine. Unchanged cryptolepine detected in urine was negligible. The Pharmacokinetic profile of cryptolepine showed a very high plasma clearance and volume of distribution (Vss) resulting in a moderate average plasma half-life of 4.5 h. Oral absorption was fast and plasma exposure and oral bioavailability were low. Conclusions: Cryptolepine metabolism is similar in rat and human in vitro with the exception of direct glucuronidation in human. Clearance in rat and human is likely to include a significant metabolic contribution, with proposed primary human metabolism pathways hydroxylation, dihydrodiol formation and glucuronidation. Cryptolepine showed extensive distribution with a moderate half-life.
dc.description.sponsorshipFunded by Novartis Pharma under the Next Generation Scientist Program.
dc.language.isoen
dc.rights© The Author(s). 2017 Open Access This 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.
dc.subjectCryptolepine
dc.subjectCryptolepis sanguinolenta
dc.subjectMetabolism
dc.subjectPharmacokinetics
dc.subjectMetabolite identification
dc.titleIdentification of cryptolepine metabolites in rat and human hepatocytes and metabolism and pharmacokinetics of cryptolepine in Sprague Dawley rats
dc.status.refereedYes
dc.date.Accepted05/12/2017
dc.date.application22/12/2017
dc.typeArticle
dc.type.versionPublished version
dc.identifier.doihttps://doi.org/10.1186/s40360-017-0188-8
dc.rights.licenseCC-BY
refterms.dateFOA2018-07-28T02:26:33Z
dc.openaccess.statusopenAccess


Item file(s)

Thumbnail
Name:
Wright_BMC_Pharmacology_and_To ...
Size:
792.6Kb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record