Background: 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.

• Identification of cryptolepine metabolites in rat and human hepatocytes and metabolism and pharmacokinetics of cryptolepine in Sprague Dawley rats