title: Assessment of pharmacokinetic compatibility of short acting CDRI candidate trioxane derivative, 99-411, with long acting prescription antimalarials, lumefantrine and piperaquine.
abstract: The pharmacokinetic compatibility of short-acting CDRI candidate antimalarial trioxane derivative, 99-411, was tested with long-acting prescription antimalarials, lumefantrine and piperaquine. LC-ESI-MS/MS methods were validated for simultaneous bioanalysis of lumefantrine and 99-411 and of piperaquine and 99-411 combinations. The interaction studies were performed in rats using these validated methods. The total systemic exposure of 99-411 increased when administered with either lumefantrine or piperaquine. However, co-administration of 99-411 significantly decreased the systemic exposure of piperaquine by half-fold while it had no effect on the kinetics of lumefantrine. 99-411, thus, seemed to be a good alternative to artemisinin derivatives for combination treatment with lumefantrine. To explore the reason for increased plasma levels of 99-411, an in situ permeability study was performed by co-perfusing lumefantrine and 99-411. In presence of lumefantrine, the absorption of 99-411 was significantly increased by 1.37 times than when given alone. Lumefantrine did not affect the metabolism of 99-411 when tested in vitro in human liver microsomes. Additionally, ATPase assay suggest that 99-411 was a substrate of human P-gp, thus, indicating the probability of interaction at the absorption level in humans as well.
authors.affiliation: Academy of Scientific and Innovative Research, New Delhi, India.|Pharmacokinetics and Metabolism Division, CSIR- Central Drug Research Institute, Lucknow-226031, India.
authors.forename: Isha
authors.initials: I
authors.lastname: Taneja
authors.affiliation: Academy of Scientific and Innovative Research, New Delhi, India.|Pharmacokinetics and Metabolism Division, CSIR- Central Drug Research Institute, Lucknow-226031, India.
authors.forename: Kanumuri Siva Rama
authors.initials: KS
authors.lastname: Raju
authors.affiliation: Analytical Chemistry Division, CSIR-Indian Institute of Toxicology Research, Lucknow-226001, India.
authors.forename: Sheelendra Pratap
authors.initials: SP
authors.lastname: Singh
authors.affiliation: Academy of Scientific and Innovative Research, New Delhi, India.|Pharmacokinetics and Metabolism Division, CSIR- Central Drug Research Institute, Lucknow-226031, India.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Wahajuddin
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004983:Ethanolamines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D005449:Fluorenes / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D006207:Half-Life; D006571:Heterocyclic Compounds / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D000078102:Lumefantrine; D008862:Microsomes, Liver / Q000378:metabolism*; D010616:Phenanthrenes / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D011804:Quinolines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D013141:Spiro Compounds / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D010879:Piperazines
chemical_list: D000962:Antimalarials; D004983:Ethanolamines; D005449:Fluorenes; D006571:Heterocyclic Compounds; D000078102:Lumefantrine; D010616:Phenanthrenes; D011804:Quinolines; D013141:Spiro Compounds; C529215:99-411 compound; C034759:piperaquine; D010879:Piperazines; C023768:halofantrine