Pharmacokinetic properties of Ibogaine and Noribogaine in plasma of mice

Abstract

Ibogaine is an indole alkaloid found in African plant Tabernanthe iboga Baill. (Apocynaceae). This substance facilitates the symptoms of abstinence [1]. In the late 20th century many scientific researches started to be conducted with an aim to find out the mechanism of action of ibogaine. The pharmacology of ibogaine is quite complex, affecting many different neurotransmitter systems simultaneously. However, the pharmacological targets underlying the physiological and psychological actions of ibogaine are not completely understood [2]. Ibogaine is metabolized into active metabolite noribogaine which can condition the long-term effect of ibogaine [3,4]. According to the results of researches, noribogaine is deemed to be more safe and less toxic and causing less undesirable reactions as compared with its predecessor. Objective. To evaluate pharmacokinetic constants of ibogaine and noribogaine in plasma of mice. Material and methods. White laboratory mice were used for the experiments. All experiments performed according to the Republic of Lithuania Law on the Care, Keeping and Use of animals (License of State veterinary service for working with laboratory animals No 0172). Ibogaine (26.3 mg/kg) and noribogaine (31.5 mg/kg) were administered intragastrically to mice via a stomach tube. After 15 min, 30 min, 2 h, 4 h, 6 h, 8 h, 16 h, 24 h mice were decapitated. Ibogaine and noribogaine were measured in plasma by high performance liquid chromatography (HPLC).Pharmacokinetic constants were estimated by program „Kinetica“ using noncompartment model. Calculated pharmacokinetic parameters include the following: volume of distribution (Vd), area under curve (AUC), elimination halflife (t1/2), maximum concentration (Cmax), clearance (CL), elimination rate constant (ke). Results. The variation of ibogaine, noribogaine and metabolite N1 concentrations in laboratory mice blood plasma within the period of 24 hours after the administration of substances is illustrated i n Fig.1. Fig.1. Time-concentration profiles for ibogaine, metabolite N1 and noribogaine in plasma of mice after intragastric administration of ibogaine (26.3 mg/kg) or noribogaine (31.5 mg/kg)(n=3) The pharmacokinetic parameters in blood plasma of mice determined during our research after single dose of ibogaine (26.3 mg/kg intragastrically) and noribogaine (31.5 mg/kg intragastrically) are presented in Table 1. Following intragastric administration circulating levels of ibogaine and metabolite N1 peaked (Cmax) at 30 min, whereas levels of noribogaine increased slowly to plateau at 4 h. Metabolite N1 Cmax (185±0.02 ng/ml) was much less than that of ibogaine (475±0.05 ng/ml), giving a noribogaine-to-ibogaine Cmax ratio of 0.39. These data show, a much smaller fraction of ibogaine is converted to metabolite N1 (noribogaine) when ibogaine is administered intragastrically. Noribogaine Cmax was three-fold less than that of ibogaine. Established ibogaine Vd was 0.04±0.01 ml/mg in laboratory mice blood plasma, whereas Vd of noribogaine which is slightly soluble in fat [5] was nearly 10 times higher, i.e., 0.37±0.05 ml/mg (Table 1). When comparing distribution of ibogaine and metabolite N1 as a product of its biotransformation, it was also established that volume of distribution of metabolite N1 is higher – its established value is equal to 0.20±0.01 ml/mg.[...].