2 research outputs found
Identification of cryptolepine metabolites in rat and human hepatocytes and metabolism and pharmacokinetics of cryptolepine in Sprague Dawley rats
YesBackground: 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.Funded by Novartis Pharma under the Next Generation Scientist Program
In vitro anti-malarial interaction and gametocytocidal activity of cryptolepine
YesBackground: Discovery of novel gametocytocidal molecules is a major pharmacological strategy in the elimination
and eradication of malaria. The high patronage of the aqueous root extract of the popular West African anti-malarial
plant Cryptolepis sanguinolenta (Periplocaceae) in traditional and hospital settings in Ghana has directed this study
investigating the gametocytocidal activity of the plant and its major alkaloid, cryptolepine. This study also investigates
the anti-malarial interaction of cryptolepine with standard anti-malarials, as the search for new anti-malarial combinations
continues.
Methods: The resazurin-based assay was employed in evaluating the gametocytocidal properties of C. sanguinolenta
and cryptolepine against the late stage (IV/V) gametocytes of Plasmodium falciparum (NF54). A fixed ratio method
based on the SYBR Green I fluorescence-based assay was used to build isobolograms from a combination of cryptolepine
with four standard anti-malarial drugs in vitro using the chloroquine sensitive strain 3D7.
Results: Cryptolepis sanguinolenta (
IC50 = 49.65 nM) and its major alkaloid, cryptolepine (
IC50 = 1965 nM), showed
high inhibitory activity against the late stage gametocytes of P. falciparum (NF54). In the interaction assays in asexual
stage, cryptolepine showed an additive effect with both lumefantrine and chloroquine with mean ΣFIC50s of
1.017 ± 0.06 and 1.465 ± 0.17, respectively. Cryptolepine combination with amodiaquine at therapeutically relevant
concentration ratios showed a synergistic effect (mean ΣFIC50 = 0.287 ± 0.10) whereas an antagonistic activity (mean
ΣFIC50 = 4.182 ± 0.99) was seen with mefloquine.
Conclusions: The findings of this study shed light on the high gametocytocidal properties of C. sanguinolenta and
cryptolepine attributing their potent anti-malarial activity mainly to their effect on both the sexual and asexual stages
of the parasite. Amodiaquine is a potential drug partner for cryptolepine in the development of novel fixed dose
combinations