Abstract
BackgroundThis 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.MethodsThe 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.ResultsNine 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.ConclusionsCryptolepine 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.
Highlights
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
This study aims at evaluating the metabolic profile and the mechanisms of biotransformation of cryptolepine by (1) characterization of metabolites following in vitro metabolism of cryptolepine in human and rat hepatocytes, (2) identification of the metabolites present in rat plasma and urine after single dose administration as well as (3) evaluation of the single-dose pharmacokinetics (PK) of cryptolepine in male Sprague Dawley (SD) rats
Amount excreted in urine (Ae) was calculated from measured urine concentrations and volumes
Summary
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. Malaria is a major cause of morbidity and mortality, especially in Africa [1, 2]. The disease is commonly found in the tropical and subtropical regions of the world with about 214 million new cases and 438,000 deaths reported in 2015 worldwide [3]. According to the WHO [3], 90% of all malaria deaths reported in 2015 occurred in sub-Saharan Africa. Despite the reduction in malaria morbidity and mortality between 2000 and 2015, the major problem associated with further reduction or complete eradication of this disease is the increasing resistance of Plasmodium falciparum to most of the commonly used antimalarial drugs. Traditional medicines have been a major starting point for the development of antimalarial agents [4].
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