(T1230-10-67) Pharmacokinetic Profiles of Paynantheine and Its Diastereomer, Isopaynantheine, in Sprague-Dawley Rats

Purpose: Kratom (Mitragyna speciosa), is an indigenous tropical tree found in Southeast Asia with dose-dependent stimulant, mood enhancing, and depressant-like effects (Cinosi E, 2015; Grundmann O, 2022). Over 40 alkaloids have been isolated from kratom. Many studies investigating in vitro binding show that kratom alkaloids exhibit affinity and activity at adrenergic, dopamine, opioid, and serotonin receptors (Obeng S, 2020; Chakraborty S, 2021; Avery BA, 2019). One of the more abundant alkaloids, paynantheine showed a 5-HT_1A mediated lower lip retraction and antinociception in rats, and may contribute to the mood-enhancing effects. Although, binding activity in vitro shows that there is affinity to 5-HT_2B, it does not activate the receptor in vivo (Leon F, 2021). Both paynantheine and its diastereomers, isopaynantheine are indole alkaloids and differ at chiral center position 3 (paynantheine 3S; isopaynantheine 3R) (Philipp AA, 2011). Paynantheine has low affinity for opioid receptors (κ and μ ~1 μM) but has higher binding affinities at serotonin receptors; 5-HT_1A (K_i=71.8 nM), 5-HT_2B (K_i=83.1 nM), and adrenergic receptors; α_2A (K_i=389 nM), α_2C (K_i=168 nM). Isopaynantheine does not show binding affinity to serotonin or adrenergic receptors but has high affinity for κ (K_i=72 nM) opioid receptor as well as affinity at μ (K_i=366 nM) opioid receptor. Due to the binding affinity exhibited at multiple receptors, single-dose pharmacokinetic studies of paynantheine and isopaynantheine were independently performed in male Sprague-Dawley rats to help understand the role these alkaloids play in the mood enhancing, stimulant- and depressant-effects reported with the use of kratom products.

Methods: Single-dose pharmacokinetic studies of paynantheine were performed following an oral (20 mg/kg) and intravenous administration (2.5 mg/kg) (N=5, N=4, respectively) in male Sprague-Dawley rats. While, isopaynantheine single-dose pharmacokinetic studies were conducted after an oral (5 mg/kg) and intravenous administration (1.5 mg/kg) (N=4, each) in male Sprague-Dawley rats. Blood samples were collected pre-dose, and 0.08, 0.17, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 18, and 24 hours after dosing. Plasma was separated and analyzed to determine paynantheine and isopaynantheine concentrations for each study. These results were subjected to non-compartmental analysis to determine pharmacokinetic parameters using Phoenix® 6.4 (Certara).

Results: After intravenous administration, paynantheine had a clearance of 4.6 ± 0.4 L/h/kg, volume of distribution of 62.0 ± 5.6 L/kg, and elimination half-life of 9.4 ± 1.6 h. While isopaynantheine had a clearance of 2.7 ± 0.3 L/h/kg, volume of distribution of 17.7 ± 5.3 L/kg, and elimination half-life of 4.5 ± 0.9 h. Paynantheine and isopaynantheine’s clearance values when dosed intravenously are lower than the rat hepatic blood flow (4.8 L/h/kg), indicating there is no extrahepatic elimination of either compound. Both compounds also exhibited a very large volume of distribution indicating extravascular distribution, although isopaynantheine had a 3.5-fold lower volume of distribution when compared to paynantheine. Paynantheine’s pharmacokinetic parameters after oral administration, exhibited a C_max/Dose (plasma peak concentration correct for dose) of 11.6 ± 2.8 kg*ng/mL/mg with a T_max (time to reach C_max) of 0.2 ± 0.1 h, and an oral bioavailability of 5.9%. The pharmacokinetic parameters of isopaynantheine after oral administration had a C_max/Dose of 4.8 ± 0.6 kg*ng/mL/mg, T_max of 4.3 ±3.3 h, and an oral bioavailability of 8.7%.

Conclusion: Isopaynantheine had a 1.5-fold higher bioavailability than paynantheine but both compounds had very low oral bioavailability. The clearance and volume of distribution values of paynantheine and isopaynantheine also indicate there is extensive tissue distribution with no contribution of additional extrahepatic clearance. After investigating these pharmacokinetic parameters, the contribution of paynantheine and isopaynantheine to the overall effects associated with kratom use are unlikely.

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