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 ($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.

Primaquine revisited six decades after its discovery

“…Recently, Mehrotra et al suggested that in vitro protein binding and red blood cell (RBC) uptake studies should be carried out at around systemic concentrations obtained from in vivo studies, so that a realistic insight into the pharmacokinetics of the drug candidate could be obtained [214].…”

Resistance to Therapies for Infection by Plasmodium vivax

“…Elubaquine is a prodrug of primaquine invented at the Central Drug Research Institute, India. It is rapidly metabolized to primaquine and exhibits most of primaquine's pharmacokinetic characteristics (145). The two drugs showed similar efficacies against relapse in a limited number of trials, each with inherent limitations.…”

In Vitro and in Vivo Studies on Plasma-to-Blood Ratio of Paclitaxel in Human, Rabbit and Rat Blood Fractions

“…It would be worthwhile to consider erythrocytes as a separate compartment while modeling concentration time data for high erythrocytes partitioning drugs. 22) Several previous studies have found evidence that drug binding to erythrocytes can act as a barrier to hepatic elimination. Additionally, the importance of the erythrocyte uptake of drugs and the influence of drug-drug combination on their erythrocyte-plasma partition ratios has also been recognized.…”