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EP37926
Poster Title: P-glycoprotein Inhibition Cannot Explain Predominantly Efflux at Steady-State of Mitragynine Brain Uptake
Submitted on 08 Dec 2021
Author(s): Juzaili Azizi, Siti Rafidah Yusof
Affiliations: Universiti Sains Malaysia
This poster was presented at International Conference on Drug Discovery and Translational Medicine 2021 (ICDTTM 2021)
Poster Views: 507
Submitted on 08 Dec 2021
Author(s): Juzaili Azizi, Siti Rafidah Yusof
Affiliations: Universiti Sains Malaysia
This poster was presented at International Conference on Drug Discovery and Translational Medicine 2021 (ICDTTM 2021)
Poster Views: 507
Abstract: Introduction: Mitragynine, a major compound isolated from the leaves of Mitragyna speciosa Korth. (kratom), acts as a mu-opioid receptor agonist and may be developed as a treatment for chronic pain and opioid addiction. Earlier work established that mitragynine was predominantly effluxed at steady-state in rat brain, with an unbound
brain-to-blood partition coefficient (Kpuu ) of 0.091. Most CNS drugs are limited in their cellular uptake and brain accumulation by the P-glycoprotein (P-gp) efflux pump. The purpose of this study was to determine the involvement of P-gp-mediated efflux across the blood-brain barrier (BBB) in rats using the P-gp inhibitor verapamil. Methods: The transport of radiolabeled mitragynine ( 3 H-mitragynine) across the rat BBB was measured with or without verapamil, a well-known P-gp inhibitor by bilateral in-situ brain perfusion technique. By comparing the difference in brain transport achieved with or without verapamil, it is possible to determine the P-gp-mediated efflux component of mitragynine across BBB using this technique. Cerebral vascular volume and the BBB integrity was determined by co-perfusion with radiolabeled sucrose ( 14 C-sucrose), a non-permeating BBB marker in all experiments. Results: 14 C-Sucrose perfusions indicated that the vascular space was within a normal range (~2% brain volume) in all the studies, indicating that the BBB integrity remained intact. The volume of distribution of 3 H-mitragynine in the brain was approximately 9-fold than that of 14 C-sucrose, indicating that mitragynine was transported across the BBB under physiological conditions. Bilateral in-situ brain perfusion in rat demonstrated that the transport co-efficient, Kin of mitragynine perfused without verapamil (0.2262±0.1003 mL/min/g brain) was no different with Kin of mitragynine perfused with verapamil (0.1756±0.0957 mL/min/g brain). Conclusion: This result implies that P-gp had no influence on the uptake of mitragynine in rat brains. Additional research is required to elucidate the role of other key efflux pumps, including Multi-Drug Resistance Proteins (MRPs) and Breast Cancer Resistance Proteins (BCRPs).
Keywords Mitragynine, Mitragyna speciosa Korth., BBB, in-situ brain perfusion, P-gp efflux pump Summary: This work shows that P-gp had no influence on the uptake of mitragynine in rat brains. Additional research is required to elucidate the role of other key efflux pumps, including Multi-Drug Resistance Proteins (MRPs) and Breast Cancer Resistance Proteins (BCRPs).
References: Adkins, C., et al., 2013. Front Pharmacol, 4.
Bousquet, M., et al., J Neurochem, 114, 1651-8.
Davis, T. P., et al., Adv Pharmacol, 71, 25-44.
Hammarlund-Udenaes, M. 2014. Pharmacokinetic concepts in brain drug delivery.
Huber, J. D., et al., 2001. Am J Physiol Heart Circ Physiol, 280, H1241-8.
Joseph, A., et al., 2017. Sci Adv, 3, e1700362.
Kruegel, A. C., et al., 2016. J Am Chem Soc, 138, 6754-6764.
Saunders, N. R., et al., 2015.Front Neurosci, 9.
Yusof, S. R., et al., 2019. Addict Biol, 24, 935-945.
brain-to-blood partition coefficient (Kpuu ) of 0.091. Most CNS drugs are limited in their cellular uptake and brain accumulation by the P-glycoprotein (P-gp) efflux pump. The purpose of this study was to determine the involvement of P-gp-mediated efflux across the blood-brain barrier (BBB) in rats using the P-gp inhibitor verapamil. Methods: The transport of radiolabeled mitragynine ( 3 H-mitragynine) across the rat BBB was measured with or without verapamil, a well-known P-gp inhibitor by bilateral in-situ brain perfusion technique. By comparing the difference in brain transport achieved with or without verapamil, it is possible to determine the P-gp-mediated efflux component of mitragynine across BBB using this technique. Cerebral vascular volume and the BBB integrity was determined by co-perfusion with radiolabeled sucrose ( 14 C-sucrose), a non-permeating BBB marker in all experiments. Results: 14 C-Sucrose perfusions indicated that the vascular space was within a normal range (~2% brain volume) in all the studies, indicating that the BBB integrity remained intact. The volume of distribution of 3 H-mitragynine in the brain was approximately 9-fold than that of 14 C-sucrose, indicating that mitragynine was transported across the BBB under physiological conditions. Bilateral in-situ brain perfusion in rat demonstrated that the transport co-efficient, Kin of mitragynine perfused without verapamil (0.2262±0.1003 mL/min/g brain) was no different with Kin of mitragynine perfused with verapamil (0.1756±0.0957 mL/min/g brain). Conclusion: This result implies that P-gp had no influence on the uptake of mitragynine in rat brains. Additional research is required to elucidate the role of other key efflux pumps, including Multi-Drug Resistance Proteins (MRPs) and Breast Cancer Resistance Proteins (BCRPs).
Keywords Mitragynine, Mitragyna speciosa Korth., BBB, in-situ brain perfusion, P-gp efflux pump Summary: This work shows that P-gp had no influence on the uptake of mitragynine in rat brains. Additional research is required to elucidate the role of other key efflux pumps, including Multi-Drug Resistance Proteins (MRPs) and Breast Cancer Resistance Proteins (BCRPs).
References: Adkins, C., et al., 2013. Front Pharmacol, 4.
Bousquet, M., et al., J Neurochem, 114, 1651-8.
Davis, T. P., et al., Adv Pharmacol, 71, 25-44.
Hammarlund-Udenaes, M. 2014. Pharmacokinetic concepts in brain drug delivery.
Huber, J. D., et al., 2001. Am J Physiol Heart Circ Physiol, 280, H1241-8.
Joseph, A., et al., 2017. Sci Adv, 3, e1700362.
Kruegel, A. C., et al., 2016. J Am Chem Soc, 138, 6754-6764.
Saunders, N. R., et al., 2015.Front Neurosci, 9.
Yusof, S. R., et al., 2019. Addict Biol, 24, 935-945.
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