(T1330-02-08) Pharmacokinetics of Speciofoline, a Minor Kratom Alkaloid in Sprague-Dawley Rats

Purpose: Kratom is a tree native to Southeast Asia that has been used for centuries for its stimulant- and opioid-like effects. More than 40 alkaloids have been isolated from kratom, including speciofoline, a minor oxindole alkaloid. Previous studies have shown that kratom alkaloids interact at various receptors including adrenergic, dopamine, opioid, and serotonin (Avery BA, 2019). Commercial kratom products can be grouped into separate “high-speciofoline” and “low-speciofoline” chemotypes, with a variation more than 90-fold in commercial products. Although speciofoline does not show in vitro binding to mu-opioid receptors (Todd DA, 2020), the original patent by Smith, Kline and French (now GlaxoSmithKline), states that speciofoline is an orally effective analgesic and antitussive agent. A single-dose pharmacokinetic study was performed to better understand speciofoline’s role in the overall effects reported with kratom product use.

Methods: Single-dose pharmacokinetic studies of speciofoline were performed following an oral (10 mg/kg) and intravenous administration (2.5 mg/kg) (N=3, each study) in male Sprague-Dawley rats. Blood samples were collected pre-dose, 0.08, 0.17, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 18, and 24 hours after dosing and plasma was analyzed to determine speciofoline concentration. The results were subjected to non-compartmental analysis to determine pharmacokinetic parameters using Phoenix® WinNonlin 6.4 (Certara).

Results: When dosed intravenously, speciofoline had a clearance of 3.7 ± 0.2 L/h/kg, volume of distribution of 28.6 ± 7.7 L/kg, and elimination half-life of 12.8 ± 2.9 h. The clearance of speciofoline when dosed intravenously is lower than the rat hepatic blood flow (4.8 L/h/kg), indicative of no extrahepatic clearance. Speciofoline also exhibited a very large volume of distribution indicating extravascular distribution. Speciofoline pharmacokinetic parameters when dosed orally, exhibited a C_max (plasma peak concentration) of 28.4 ± 7.0 ng/mL with a T_max (time to reach C_max) of 0.75 ± 0.0 h, and an oral bioavailability of 2.0%.

Conclusion: Speciofoline showed very low oral bioavailability. Clearance and volume of distribution values indicate extensive tissue distribution and no contribution of additional extrahepatic clearance of speciofoline. Due to these pharmacokinetic parameters, it is unlikely speciofoline has a contribution to the overall effect of kratom.

References: 1. Avery, B.A., Boddu, S.P., Sharma, A., Furr, E.B., Leon, F., Cutler, S.J., McCurdy, C.R. Comparative pharmacokinetics of mitragynine after oral administration of Mitragyna speciosa (kratom) leaf extracts in rats. Planta Med 85(04): 340-346 (2019).
2. Todd, D.A., Kellogg, J.J., Wallace, E.D. et al. Chemical composition and biological effects of kratom (Mitragyna speciosa): In vitro studies with implications for efficacy and drug interactions. Sci Rep 10, 19158 (2020).
3. Arnold Heyworth Beckett. UNITED STATES PATENT OFFICE Patent No. 3,324,111 (1967).