Planta Med 2015; 81 - SL1A_02
DOI: 10.1055/s-0035-1565286

Pre-clinical pharmacokinetics of the hERG blocking iboga alkaloid voacangine from Voacanga africana

CE Mair 1, CM Silva 2, U Grienke 1, F Carreño 2, KM Jadel 3, T Dalla Costa 2, JM Rollinger 1
  • 1Department of Pharmacognosy, University of Vienna, Vienna, Austria
  • 2Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
  • 3Cristália Produtos Químicos Farmacêuticos LTDA, São Paulo, Brazil

The bark of Voacanga africana Stapf ex Scott Elliot and related species is not only used in African folk medicine, but also as legal high with increasing popularity in Europe. Voacangine (1), its major iboga-type alkaloid, was recently identified as potent hERG channel blocker in vitro which might point towards possible cardiotoxicity [1]. Since there is no in vivo characterisation of 1, the aim of this study was to assess its pharmacokinetics after oral administration of both, the pure compound and an ethanol extract of V. africana bark (VABE) containing 9.71% of 1, to allow for a critical discussion of its potential cardiotoxic risk in vivo. A precise and sensitive LC-MS/MS method was developed and validated according to FDA guidelines to detect 1 in plasma of male Wistar rats. Within the investigated drug concentration, 1 showed a high plasma protein binding of 98.7 ± 0.29%. Pharmacokinetics was evaluated by comparing four groups (G1-G4; n = 5 – 7/group). G1 received a single 5 mg/kg i.v. bolus of 1; G2 and G3 received single 25 mg/kg or 50 mg/kg doses of 1 p.o., resp.; G4 received a single oral dose of 500 mg/kg of VABE. Non compartmental analysis showed a volume of distribution (Vz) of 6.1 ± 3.4 L/kg after i.v. dosing, a clearance (CL) of 1.4 ± 1 L/h/kg, and an average half-life (t1/2) of 6.0 ± 2.0h. No statistical differences were observed in CL, Vz and t1/2 after oral application of 1, and indicated linear pharmacokinetics. Oral bioavailability (F) of 1 was 12% when given as pure compound. In VABE, a decrease of F was observed for 1 (8%). These findings provide first data to estimate the in vivo hERG channel related cardiotoxic risk of 1.

Acknowledgement: Supported by EU-FP7-PEOPLE-IRSES Marie Curie: hERGscreen, 295174

References:

[1] Kratz JM, Schuster D, Edtbauer M, Saxena P, Mair CE, Kirchebner J, Matuszczak B, Baburin I, Hering S, Rollinger JM. Experimentally validated hERG pharmacophore models as cardiotoxicity prediction tools. J. Chem. Inf. Model. 2014; 54: 2887 – 2901