Investigation of the Experimental Pharmacokinetics of the Bis-Chlorinated Bis-pyridinium Mono-aldoxime Cholinesterase Reactivator K-868 in Rats

Background: The widespread use of organophosphorus compounds in agriculture and their existence in some military arsenals present continuous threats. Quaternary bis-pyridinium aldoximes are potent, highly polar cholinesterase reactivators and the most intensively studied candidate antidotes against poisoning with organophosphorus compounds. Objective: The in vivo experimental pharmacokinetic properties of K-868, a novel bis-chlorinated, bis-pyridinium mono-aldoxime are detailed and put in context with regard to similar compounds described earlier. Methods: Rats received 30 µmol K-868 i.m. and were sacrificed at various time points following treatment. Blood, cerebrospinal fluid and tear were collected, while the brains, eyes, kidneys, livers, lungs and testes were removed, dissected and homogenized. K-868 concentrations were determined using high performance liquid chromatography with ultraviolet absorption detection. Results: K-868 was detected in the eyes, kidneys, lungs and tear within 5 minutes in maximal serum concentrations attained 15 minutes following administration. Elimination was slow for K-868 which remained detectable at 120 minutes in the blood and the kidneys, and at 60 minutes in the eyes, lungs and tear following its administration. Nevertheless, its distribution was overall poor with areas under the 120-minute concentration curves (AUC120) showing close similarity in the blood and the kidneys, while reaching just approximately 5% of serum AUC120 in the eyes and lungs. Conclusion: K-868 is a potent candidate antidote against organophosphate poisoining with a prolonged presence in the circulation.

EXPERIMENTAL PHARMACOKINETIC STUDY OF ZINC WHEN ZINC HYDROXIDE NANOFORM IS ADMINISTERED ENTERALY AND INTRAVASCULARY

In vivo experiments on rabbits studied pharmacokinetic properties of Zn2+ under administration of zinc hydroxide nanoparticles (2-3 nm) that were obtained by sol-gel me-thod. Soluble zinc sulfate was selected as a comparison compound. Measurement of plasma Zn2+ levels was carried out by atomic absorption spectrometry with preliminary sample preparation method by wet ashing. Pharmacokinetic parameters were calculated after sin-gle enteral administration (doses 10, 50 and 100 mg/kg) and single intravenous injection (doses 10, 50 and 100 mg/kg). Absolute bioavailability for nanoparticles was found to have high values 33,013,55%, 45,153,68% and 43,182,71% for 10, 50 and 100 mg/kg enteral administration respectively.

Consideration of Pharmacokinetics and Temporal Sensitivity for Hydroxyurea in Relation to Teratogenic Potential

A compartmental pharmacokinetic-mathematical model for the time-dependent distribution of hydroxyurea (HU) in both the maternal plasma and embryonic fluids of pregnant rats and rhesus monkeys was developed. Across species scaling was based on maternal plasma clearance rates and compartmental sizes as a percent of the body weight of the dam. Mathematical optimization provided the compartmental transfer rates. The estimated maternal and embryonic concentrations of HU correlated well with the experimental pharmacokinetic data regarding both time and quantity for both the rat and the monkey. When the biological effective dose was considered to be the embryonic HU concentration over time (AUC), the dose to the individual embryos was higher in the monkeys (392 mg HU hr/L/day) than in the rats (69 mg HU hr/L/day) at an applied dose of 100 mg HU/kg administered to the dams. The AUC doses are consistent with the evaluation of the embryos of both species for teratogenic changes and embryonic death. The effect of repeated doses as compared with a single dose given only on one day of gestation was examined in the rat. Because of the rapid maternal clearance the carryover of embryonic HU concentration from one day to the next was minimal. A single treatment on Day 9 only was estimated to be sufficient to produce the adverse embryonic effects of HU on Days 9 through 12 as reported by Wilson et al. The sensitivity of the embryo to HU decreased with increasing embryonic age. The implications of the pharmacokinetic simulation and the temporal susceptibility for ongoing clinical trials of HU in the treatment of sickle cell anemia were reviewed. A human embryo dose of 69 mg HU hr/L/day was estimated to result from an i.v. dose of 10 mg/kg to the mother. This concentration produced no effect in the rat. An i.v. dose of 50 mg HU/mg was estimated to result in a human embryo dose of 353 mg HU hr/L/day which approaches a Rhesus monkey embryo dose that produced adverse effects in all embryos.