Drug Transporters ABCB1 (P-gp) and OATP, but not Drug-Metabolizing Enzyme CYP3A4, Affect the Pharmacokinetics of the Psychoactive Alkaloid Ibogaine and its Metabolites.
Margarida L F Martins, Paniz Heydari, Wenlong Li, Alejandra Martínez-chávez, Nikkie Venekamp, Maria C Lebre, Luc Lucas, Jos H Beijnen, Alfred H Schinkel
Frontiers in Pharmacology 2022 DOI: 10.3389/fphar.2022.855000 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study using wild-type and genetically modified mice Peer reviewed |
|---|---|
| Population | Mice (wild-type and genetically modified for Abcb1a/1b, Abcg2, OATP, and CYP3A) |
| Intervention | oral ibogaine administration |
| Dose | 10 mg/kg |
| Topics | Ibogaine |
| Keywords | Abcg2/bcrp Cyp3a4 Oatp P-glycoprotein/abcb1 Brain penetration Ibogaine/iboga Oral availability Ibogaine pharmacokinetics Drug transporters Drug metabolism |
| Citations | 9 |
| Key findings | ABCB1, in combination with ABCG2, modestly restricts ibogaine oral availability and brain penetration, while human CYP3A4 and OATP transporters have no major impact on ibogaine pharmacokinetics. |
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.
Comparable studies
Other preclinical and animal studies on ibogaine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Noncompetitive Functional Inhibition at Diverse, Human Nicotinic Acetylcholine Receptor Subtypes by Bupropion, Phencyclidine, and Ibogaine TE671/RD cells (human muscle-type nAChR) and SH-SY5Y neuroblastoma cells (human... | 1999 | In vitro study | |
| Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline. Ibogaine- or harmaline-treated rats | 1993 | Experimental animal study | |
| Effects and aftereffects of ibogaine on morphine self-administration in rats. Rats | 1991 | Preclinical experimental study | |
| Effects of iboga alkaloids on morphine and cocaine self-administration in rats: relationship to tremorigenic effects and to effects on dopamine release in nucleus accumbens and striatum. Rats | 1994 | Experimental study | |
| Glial Cell Line-Derived Neurotrophic Factor Mediates the Desirable Actions of the Anti-Addiction Drug Ibogaine against Alcohol Consumption Rats | 2005 | Experimental study |
Citations in the library
Cited by 7
- Main targets of ibogaine and noribogaine associated with its putative anti-addictive effects: A mechanistic overview. Journal of Psychopharmacology December 1, 2023
- Harnessing Pharmacogenomics in Clinical Research on Psychedelic‐Assisted Therapy Clinical Pharmacology & Therapeutics September 30, 2024
- Psychedelic Therapy: A Primer for Primary Care Clinicians—Ibogaine American Journal of Therapeutics March 1, 2024
- Development and validation of a UPLC-MS/MS method for real-time neuropharmacokinetic monitoring of iboga alkaloids in rat brain. Journal of Pharmaceutical and Biomedical Analysis June 24, 2026
- Ibogaine’s potential role in supporting reward system recovery across diagnostic boundaries Frontiers in Pharmacology December 4, 2025
and 2 more in the library
Cites 37
- The ibogaine medical subculture. Journal of Ethnopharmacology January 4, 2008
- Glial Cell Line-Derived Neurotrophic Factor Mediates the Desirable Actions of the Anti-Addiction Drug Ibogaine against Alcohol Consumption Journal of Neuroscience January 19, 2005
- Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes. The American Journal of Drug and Alcohol Abuse 2018
- Ibogaine treatment outcomes for opioid dependence from a twelve-month follow-up observational study. The American Journal of Drug and Alcohol Abuse 2018
- Ibogaine: complex pharmacokinetics, concerns for safety, and preliminary efficacy measures. Annals of the New York Academy of Sciences September 1, 2000
and 32 more in the library