TABLE 5.
Prediction of the pharmacokinetic drug interaction potential of kratom using mitragynine as the precipitant.
A basic static model for reversible inhibition was used to predict the drug interaction potential of mitragynine administered orally via inhibition of cytochromes P450. R values indicate the predicted AUC ratio of the object drug in the presence to absence of inhibitor for intestine (R1,gut) or using hepatic (R1,hep) and systemic (R1,sys) concentration.
| Enzyme | IC50 (μM) | Kia (μM) | R1,gut | R1,hep | R1,sys | Reference |
|---|---|---|---|---|---|---|
| CYP1A2 | >45 | >22.5 | NA | 1.01 | 1.00 | (Kamble et al., 2020b) |
| CYP2C8 | 33.5 | 16.8 | NA | 1.01 | 1.00 | (Kamble et al., 2020b) |
| CYP2C9 | 39.7 | 19.9 | NA | 1.01 | 1.00 | (Tanna et al., 2021) |
| CYP2C19 | 10.5 | 5.25 | NA | 1.04* | 1.00 | (Kamble et al., 2020b) |
| CYP2D6 | 0.67 | 0.34 | NA | 1.57* | 1.01 | (Tanna et al., 2021) |
| CYP3A | 11.4 | 5.7 | 71* | 1.03* | 1.00 | (Tanna et al., 2021) |
| P-gpb | 18.2 | — | 22* | — | — | (Manda et al., 2014a) |
—, information not available.
aKi values are estimated as IC50/2 using the Cheng-Prusoff equation assuming competitive inhibition.
bR1,gut = 1 + (Igut/Ki) or (Igut/IC50) for P-gp, where intestinal luminal concentration (Igut) was calculated as dose/250 ml (∼400 μM).
*R1,gut ≥11 and R1,hep or R1,sys ≥1.02 indicates a potential interaction. R1,hep = 1 + (Ihep,u/Ki), where Ihep,u was calculated as fu,p × (Cmax + Fa × ka × dose/Qh/RB) (∼0.19 μM); R1,sys = 1 + (Isys,u/Ki), where Isys,u is fu,p × Cmax.