title: In Vitro and In Vivo pharmacokinetic studies of bulaquine (analogue of primaquine), a novel antirelapse antimalarial, in rat, rabbit and monkey--highlighting species similarities and differences.
abstract: Bulaquine (BQ) is a potent antirelapse antimalarial developed by CDRI, India. Bulaquine was rapidly absorbed in rats and rabbits with no distinct absorption phase while in monkeys a variable irregular absorption profile was observed. BQ was extensively converted to primaquine (PQ) after oral administration and the conversion was maximum in rats and minimum in rabbits, which is possibly due to the species difference. Clearance was higher in rats (3.2 l/h/kg) than in rabbits and monkeys (1.2 l/h/kg) and it was found be negligibly excreted in rat urine and feces. The elimination half-life in rats and rabbits was comparable after both oral and i.v. administration ( approximately 1.2 h). In all three species, PQ was resident in the body for a period longer than BQ. PQ, being the major active metabolite of BQ, might be responsible for the extended therapeutic effect of BQ. The oral bioavailability of BQ was 3.12%, 5.3% and 12% in rats, rabbits and monkeys, respectively, which could be mainly due to the high instability of BQ at acidic pH as demonstrated from a simulated gastric fluid stability study. Protein binding in various species was in the range 50-65% while the partition coefficient between RBCs and plasma (K(rbc/pl)) was between 0.75 and 1, indicating significant RBC uptake.
authors.affiliation: Pharmacokinetics and Metabolism Division, Central Drug Research Institute, 6980., Lucknow 226001, India.
authors.forename: Nitin
authors.initials: N
authors.lastname: Mehrotra
authors.forename: Jawahar
authors.initials: J
authors.lastname: Lal
authors.forename: Sunil Kumar
authors.initials: SK
authors.lastname: Puri
authors.forename: Kunnath P
authors.initials: KP
authors.lastname: Madhusudanan
authors.forename: Ram Chandra
authors.initials: RC
authors.lastname: Gupta
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002853:Chromatography, Liquid; D004912:Erythrocytes / Q000378:metabolism; D006207:Half-Life; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D011319:Primaquine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012996:Solutions; D013045:Species Specificity; D053719:Tandem Mass Spectrometry
chemical_list: D000962:Antimalarials; D012996:Solutions; D011319:Primaquine; C063469:bulaquine