title: In Vitro and In Vivo Pharmacokinetics of Aminoalkylated Diarylpropanes NP085 and NP102.
abstract: Malaria remains a great burden on humanity. Although significant advances have been made in the prevention and treatment of malaria, malaria control is now hindered by an increasing tolerance of the parasite to one or more drugs within artemisinin combination therapies; therefore, an urgent need exists for development of novel and improved therapies. The University of the Free State Chemistry Department previously synthesized an antimalarial compound, NP046. In vitro studies illustrated an enhanced efficacy against Plasmodium falciparum However, NP046 showed low bioavailability. Efforts to enhance the bioavailability of NP046 have resulted in the synthesis of a number of aminoalkylated diarylpropanes, including NP085 and NP102. Pharmacokinetic studies were conducted in C57BL/6 mice, with 15 mg/kg NP085 or NP102 administered orally and the 5 mg/kg NP085 or NP102 administered intravenously. Blood samples were collected by means of tail bleeding at predetermined time intervals. Drug concentrations were determined using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and subsequently pharmacokinetic modeling was done for both compounds. NP085 and NP102 were incubated in vitro with human and mouse liver microsomes. Both compounds were also subjected to a parallel artificial membrane permeation assay. In vitro studies of NP085 and NP102 illustrated that both of the compounds are rapidly absorbed and undergo rapid hepatic metabolism. The maximum concentration of drug (Cmax) obtained following oral administration of NP085 and NP102 was 0.2 ± 0.4 and 0.7 ± 0.3 μM, respectively; the elimination half-life of both compounds was 6.1 h. NP085 and NP102 showed bioavailability levels of 8% and 22%, respectively.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Western Cape, South Africa liezl.gibhard@uct.ac.za lubbe.wiesner@uct.ac.za.
authors.forename: Liezl
authors.identifier: 0000-0003-0089-2136
authors.initials: L
authors.lastname: Gibhard
authors.affiliation: Department of Chemistry, University of the Free State, Bloemfontein, South Africa.
authors.forename: Kendrekar
authors.initials: K
authors.lastname: Pravin
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Western Cape, South Africa.
authors.forename: Efrem
authors.initials: E
authors.lastname: Abay
authors.affiliation: Department of Chemistry, University of the Free State, Bloemfontein, South Africa.
authors.forename: Anke
authors.initials: A
authors.lastname: Wilhelm
authors.affiliation: Department of Chemistry, University of the Free State, Bloemfontein, South Africa Parexel International Clinical Research Organization, Bloemfontein, South Africa.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Swart
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Western Cape, South Africa.
authors.forename: Nina
authors.initials: N
authors.lastname: Lawrence
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Western Cape, South Africa.
authors.forename: Rosal
authors.initials: R
authors.lastname: Khoury
authors.affiliation: Parexel International Clinical Research Organization, Bloemfontein, South Africa.
authors.forename: Jan
authors.initials: J
authors.lastname: van der Westhuizen
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Western Cape, South Africa.
authors.forename: Peter
authors.initials: P
authors.lastname: Smith
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Western Cape, South Africa liezl.gibhard@uct.ac.za lubbe.wiesner@uct.ac.za.
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008962:Models, Theoretical; D010963:Plasmodium falciparum / Q000187:drug effects
chemical_list: D000962:Antimalarials