Pharmacokinetics of Codeine in Mitragynine-pretreated Rats

Abstract

Kratom (Mitragyna speciosa (Korth.) Havil.) belonging to the family Rubiaceae is the native plant in Southern Thailand. Mitragynine is the major alkaloid from kratom leaves. It has many pharmacological activities such as analgesic, antidiarrheal as well as anti-inflammatory effects. However, it has been reported as CYP450 enzymes inhibitors, especially CYP2D6. CYP2D6 is an enzyme which plays a role in the codeine metabolism to morphine. The combination use of kratom leaves and codeine may alter the pharmacokinetics of codeine. The objective of this study is to investigate the effect of mitragynine on the pharmacokinetics of codeine in mitragynine-pretreated rats. Rats were divided into two groups (n=13 per group). The first was the control group, rats were orally pretreated with the vehicle and another group was pretreated once a day with 15 mg/kg of mitragynine for seven consecutive days. After mitragynine or vehicle pretreatments, rats were administered single oral dose of codeine (25 mg/kg). Blood was collected from the tail vein at 0 before, and after 5, 10, 15, 30, 45, 60, 90, 120, 180, and 240 min of codeine administration. The plasma concentration versus time profile of codeine and morphine were analyzed by non-compartment pharmacokinetics model. Compared with the control group, the result showed that plasma concentration of codeine was significant increase in mitragynine pretreatment group. The relevant pharmacokinetic parameters were as follow: Cmax from 1.76 to 8.44 μg/mL, AUC4h from 193.74 to 774.87 μg min/mL and AUC0→∞ from 306.08 to 993.93 μg min/mL (p<0.05). Whereas the plasma concentration of morphine was significant decrease with Cmax from 2.32 to 0.45 μg/mL and AUC from 415.42 to 58.03 ug·h/mL (p<0.05). This study suggested that mitragynine was altered the pharmacokinetics of codeine in rats by increase codeine absorption and decrease codeinemetabolism to morphine. The inhibition of CYP2D6 isoenzyme by mitragynine postulated, which needs to further confirm this evidence.