EMAIL THIS PAGE TO A FRIEND

European journal of drug metabolism and pharmacokinetics

An LC-MS based study of the metabolic profile of primaquine, an 8-aminoquinoline antiparasitic drug, with an in vitro primary human hepatocyte culture model.


PMID 23797843

Abstract

The 8-aminoquinoline drug primaquine (PQ) is currently the only drug in use against the persistent malaria caused by the hypnozoite-forming strains P. vivax and P. ovale. However, despite decades of research, its complete metabolic profile is still poorly understood. In the present study, the metabolism of PQ was evaluated by incubating the drug with pooled human hepatocytes cultured in vitro as well as with recombinant cytochrome P450 (CYP) iso- enzymes, monoamine oxidases (MAO), and flavin-containing monooxygenases (FMO). Targeted LC-MS/MS analysis of hepatocyte incubations using chemical inhibitors indicated that PQ was predominantly metabolized by CYPs 3A4, 1A2 and 2D6, MAO-A, -B and FMO-3. Confirmation of these results was sought by incubation of PQ with the corresponding recombinant enzymes. Small amounts of carboxyprimaquine (CPQ), the major observed PQ metabolite in vivo, were detected in recombinant MAO-A incubations along with another peak at m/z 261, and no significant formation of CPQ with any other recombinant enzymes was observed. Incubations with all recombinant enzymes identified as potentially active towards PQ from the hepatocyte-based assay resulted in significant parent loss over the course of 1 h. These results suggest that several enzymes, including CYPs in combination with FMOs and MAOs, play a role in the overall metabolism of PQ and indicate a major role for MAO-A. Future studies to elucidate the potential role in cytotoxicity and/or efficacy of the PQ metabolite observed at m/z 261, as observed in MAO-A isoenzyme studies, are needed.

Related Materials

Product #

Image

Description

Molecular Formula

Add to Cart

301507
2-Mercapto-1-methylimidazole, ≥99%
C4H6N2S
K1003
Ketoconazole, ≥98% (HPLC)
C26H28Cl2N4O4
1356508
Ketoconazole, United States Pharmacopeia (USP) Reference Standard
C26H28Cl2N4O4
K0600000
Ketoconazole, European Pharmacopoeia (EP) Reference Standard
C26H28Cl2N4O4
UC280
Ketoconazole
C26H28Cl2N4O4
PHR1385
Ketoconazole, Pharmaceutical Secondary Standard; Certified Reference Material
C26H28Cl2N4O4
46429
Methimazole, VETRANAL, analytical standard
C4H6N2S
1411005
Methimazole, United States Pharmacopeia (USP) Reference Standard
C4H6N2S
M8506
Methimazole, analytical standard
C4H6N2S
M7316
Monoamine Oxidase A human, recombinant, expressed in baculovirus infected BTI insect cells
B25606
N-Benzylmethylamine, 97%
C8H11N
77440
Phenacetin, ≥98.0% (HPLC)
C10H13NO2
PHR1249
Phenacetin
C10H13NO2
PHR1094
Phenacetin melting point standard, Pharmaceutical Secondary Standard; Certified Reference Material
C10H13NO2
1514008
Phenacetin Melting Point Standard, United States Pharmacopeia (USP) Reference Standard
C10H13NO2
407267
Phenethylamine, purified by redistillation, ≥99.5%
C8H11N
241008
Phenethylamine, ≥99%
C8H11N
128945
Phenethylamine, 99%
C8H11N
160393
Primaquine bisphosphate, 98%
C15H21N3O · 2H3PO4
P2940000
Primaquine diphosphate, European Pharmacopoeia (EP) Reference Standard
C15H21N3O · 2H3PO4
1561507
Primaquine phosphate, United States Pharmacopeia (USP) Reference Standard
C15H21N3O · 2H3PO4
Q3625
Quinidine, anhydrous
C20H24N2O2
22600
Quinidine, crystallized, ≥98.0% (dried material, NT)
C20H24N2O2
S0758
Sulfaphenazole, ≥98%
C15H14N4O2S
UC166
Sulfaphenazole, ≥98% (HPLC)
C15H14N4O2S
Y0000336
Thiamazole, European Pharmacopoeia (EP) Reference Standard
C4H6N2S
T0891
Tolbutamide, analytical standard
C12H18N2O3S
46968
Tolbutamide, VETRANAL, analytical standard
C12H18N2O3S
T1700000
Tolbutamide, European Pharmacopoeia (EP) Reference Standard
C12H18N2O3S