Drug Transporters ABCB1 (P-gp) and OATP, but not Drug-Metabolizing Enzyme CYP3A4, Affect the Pharmacokinetics of the Psychoactive Alkaloid Ibogaine and its Metabolites

Wenlong Li,Paniz Heydari,Nikkie Venekamp,Alfred H. Schinkel,Luc Lucas,Alejandra Martínez-Chávez,Margarida L. F. Martins,Maria C. Lebre,Jos H. Beijnen

doi:10.3389/fphar.2022.855000

Abstract

The psychedelic alkaloid ibogaine is increasingly used as an oral treatment for substance use disorders, despite being unlicensed in most countries and having reported adverse events. Using wild-type and genetically modified mice, we investigated the impact of mouse (m)Abcb1a/1b and Abcg2 drug efflux transporters, human and mouse OATP drug uptake transporters, and the CYP3A drug-metabolizing complex on the pharmacokinetics of ibogaine and its main metabolites. Following oral ibogaine administration (10 mg/kg) to mice, we observed a rapid and extensive conversion of ibogaine to noribogaine (active metabolite) and noribogaine glucuronide. Mouse Abcb1a/1b, in combination with mAbcg2, modestly restricted the systemic exposure (plasma AUC) and peak plasma concentration (Cmax) of ibogaine. Accordingly, we found a ∼2-fold decrease in the relative recovery of ibogaine in the small intestine with fecal content in the absence of both transporters compared to the wild-type situation. Ibogaine presented good intrinsic brain penetration even in wild-type mice (brain-to-plasma ratio of 3.4). However, this was further increased by 1.5-fold in Abcb1a/1b;Abcg2 −/− mice, but not in Abcg2 −/− mice, revealing a stronger effect of mAbcb1a/1b in restricting ibogaine brain penetration. The studied human OATP transporters showed no major impact on ibogaine plasma and tissue disposition, but the mOatp1a/1b proteins modestly affected the plasma exposure of ibogaine metabolites and the tissue disposition of noribogaine glucuronide. No considerable role of mouse Cyp3a knockout or transgenic human CYP3A4 overexpression was observed in the pharmacokinetics of ibogaine and its metabolites. In summary, ABCB1, in combination with ABCG2, limits the oral availability of ibogaine, possibly by mediating its hepatobiliary and/or direct intestinal excretion. Moreover, ABCB1 restricts ibogaine brain penetration. Variation in ABCB1/ABCG2 activity due to genetic variation and/or pharmacologic inhibition might therefore affect ibogaine exposure in patients, but only to a limited extent. The insignificant impact of human CYP3A4 and OATP1B1/1B3 transporters may be clinically advantageous for ibogaine and noribogaine use, as it decreases the risks of undesirable drug interactions or interindividual variation related to CYP3A4 and/or OATP activity.

Highlights

Ibogaine is a psychoactive indole alkaloid found in the root bark of the rainforest shrub Tabernanthe iboga, which is native to Central-West Africa (Alper, 2001; Mačiulaitis et al, 2008)
The area under the plasma concentration-time curves (AUC0–2h) revealed a modest but significant increase in ibogaine oral availability between WT and Abcb1a/1b; Abcg2−/− mice, but not for Abcg2−/− mice (Figure 2; Table 1). This suggests that the mouse (m)Abcb1a/1b transporter plays a significant role in ibogaine clearance and perhaps in limiting its absorption; when absent, more ibogaine is available systemically, as the AUC significantly increased by 2.3-fold compared to WT mice (Figure 2; Table 1)
Our results indicate that mOatp1a transporters are not instrumental in the intestinal absorption of ibogaine, but they do contribute to noribogaine and noribogaine glucuronide small intestine together with the fecal content (SIWC) disposition, perhaps reflecting the reduced liver accumulation of the metabolites

Summary

Introduction

Ibogaine is a psychoactive indole alkaloid found in the root bark of the rainforest shrub Tabernanthe iboga, which is native to Central-West Africa (Alper, 2001; Mačiulaitis et al, 2008). A major concern is the occurrence of possible adverse events related to the use of ibogaine, which include cardiac arrhythmias, psychosis, mania, seizures, and even fatalities (Koenig and Hilber, 2015; Litjens and Brunt, 2016; Schep et al, 2016; dos Santos et al, 2017; Wasko et al, 2018; Aćimović et al, 2021; Luz and Mash, 2021; Ona et al, 2021). Most of these morbidities and mortalities occurred in uncontrolled/non-medical settings, where unknown or extremely high doses and variable purity of ibogaine were used (Alper et al, 2008; dos Santos et al, 2017). Ibogaine seems to be reasonably safe when administered in more controlled/supervised contexts to individuals without previous cardiac complications or not under the acute effects of drugs (dos Santos et al, 2017)

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