Pharmacokinetics in Sprague-Dawley rats and Beagle dogs and in vitro metabolism of ZJM-289, a novel nitric dioxide donor

Abstract

1. The aim was to evaluate the prodrug hypothesis by investigating the pharmacokinetics of ZJM-289 and its pharmacological metabolite 3-n-butylphthalide (NBP) in Sprague-Dawley rats and Beagle dogs following intravenous and intragastric administration of ZJM-289. The in vitro metabolic patterns in plasma and microsomal system were assessed to elucidate PK properties.

2. In rats, ZJM-289 was eliminated rapidly (t_1/2 = 19.2 ± 3.85 min), along with the fast formation of NBP (formation rate constant k_a = 0.29 ± 0.092 min^–1 for intravenous group, and k_a = 0.16 ± 0.064 min⁻¹ for intragastric group), accounting for about 47.4 ± 4.0% of ZJM-289. Both ZJM-289 (t_1/2 = 239 ± 70.4 min) and NBP (t_1/2 = 249 ± 39.0 min) were depleted slowly in Beagle dogs, with NBP formation rate constant at 0.12 ± 0.052 min⁻¹ (k_a = 0.15 ± 0.040 min⁻¹ for intragastric group).

3. In rat plasma, ZJM-289 was degraded rapidly (t_1/2 = 24.3 ± 0.93 min) at 37 °C, but remained stable with almost no cleavage in dog and human plasma. In hepatic microsomes from rat, dog and human, the hydrolysis metabolites including the active metabolite NBP (M5), and their subsequent hydroxylation and conjugate metabolite, were all detected but varied greatly in the quantities.

4. The findings testified the prodrug design hypothesis that ZJM-289 could be hydrolyzed to NBP. The pharmacokinetic profiles in both rats and dogs brought useful information in the pharmacokinetics prediction in human.

• 3-n-butylphthalide
• in vitro hydrolysis
• pharmacokinetic
• ZJM-289

Acknowledgements

The authors sincerely appreciate the kind help of Dr. Yuancheng Chen from Institute of Antibiotics (Huashan Hospital, Fudan University, Shanghai, China) in the experimental improvement and optimizing.