In vitro assessment of kratom pharmacokinetic CYP interactions with HIV ART drug metabolism

项目总结

PROJECT SUMMARY Kratom use is common among polydrug users, including persons living with HIV/AIDS (PLWHA). The botanical is gaining in popularity due to its psychoactive and opioid properties. Its use has become an important safety issue; and federal databases have linked kratom to multiple deaths. Kratom comes from the leaves of Mitragyna speciosa, is legal in many states, widely available, and used by over 13 million U.S. consumers. These data plus the bioactivity of its major compound, mitragynine, suggest kratom has the potential for pharmacokinetic (PK) interactions with HIV antiretroviral therapies (ART), widely prescribed for PLWHA. PK interactions between drugs used for HIV ART, toxicity, and/or lack of ART efficacy result if kratom inhibits or induces Phase I metabolizing enzymes (particularly the cytochromes P450 [CYPs]). Limited studies demonstrated concerning interactions between kratom and CYPs but, to date, highly potent kratom dosages have not been evaluated for any PK drug interactions. Our multi-institutional team from Auburn University and Oregon State University proposes to fill this knowledge gap by combining our specialized expertise to evaluate the hypothesis that kratom has PK interactions with HIV ART drugs mediated by CYPs. Preclinical studies will address this hypothesis in two specific aims: Aim 1 will assay botanically-authenticated kratom extract and mitragynine for inhibition of human hepatic Phase I CYPs that metabolize HIV ART drugs. To determine a mechanism of action, kratom preparations and compounds that inhibit specific CYPs will be re-assayed in combination with the widely used first- and second- line HIV ART drug regimens, and the apparent and total intrinsic clearances calculated. To account for the displacement of HIV ART drugs from plasma proteins (e.g., human serum albumin) which can also cause kratom- drug interactions, rapid equilibrium dialysis and LC-MS/MS will measure the binding of each kratom alkaloid to human plasma proteins (from pooled donors). The serum protein binding of HIV ART drugs will also be determined for comparison. Aim 2 will assay kratom extract and compounds for induction of human hepatocyte CYPs that metabolize HIV ART drugs. To determine the extent of any PK interactions, active extract or compound will be re-tested with first- and second-line HIV ART drugs that are substrates for the CYP enzyme, and calculate the apparent intrinsic clearance. The anticipated outcome of this study is a quantitative evaluation of PK drug interactions between kratom and HIV ART CYP substrates. These data should provide a fundamental understanding of PK interactions between HIV ART and kratom and a rationale for future confirmatory clinical trials and approaches to improve the safety and efficacy of HIV ART among kratom users. Ultimately, insight from this study should improve education and knowledge-sharing among patients and clinicians.