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Abstract: TH-PO358

Effect of CKD on the Ex Vivo Metabolism of Δ9-THC into 11-OH-Δ9-THC

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Tonial, Nicholas, University of Western Ontario, London, Ontario, Canada
  • Hartjes, Emily D., Western University, London, Ontario, Canada
  • Lim, Yong Jin (James), University of Western Ontario, London, Ontario, Canada
  • Weir, Matthew A., Western University, London, Ontario, Canada
  • Urquhart, Brad, Western University, London, Ontario, Canada
Background

Over 40% of chronic kidney disease (CKD) patients experience adverse drug reactions. Cytochrome P450s (CYPs) are major contributors to drug disposition, as they mediate drug metabolism to help facilitate clearance. Rodent models of CKD have shown reduced CYP expression and drug metabolic activity. The use of cannabis for both medicinal and recreational purposes has increased recently and cannabis has been legalized in several regions of the world. While CKD is known to impact the disposition of many drugs, there have been no studies investigating the impact of CKD on the hepatic metabolism of cannabis. This study utilized a rat model of CKD to investigate the impact of CKD on the metabolism of the psychoactive component of cannabis (△9-THC) to its primary metabolite 11-OH-△-THC. It was hypothesized that CKD would decrease △9-THC metabolism.

Methods

CKD was induced in male Wistar rats (n=13) by feeding chow supplemented with 0.5% adenine (n=7) for a total of 42 days while controls (n=6) received standard chow. Blood and organs were collected, and plasma creatinine concentrations were measured utilizing ultraperformance liquid chromatography coupled to mass spectrometry (UPLC-MS). Hepatic microsomal fractions, isolated by differential centrifugation, were incubated with THC (10mM and 20 mM) for 4 minutes, and 11-OH-△9-THC concentrations were measured by UPLC-MS, and the metabolite formation rate (pmol/min/mg protein) was calculated.

Results

Plasma creatinine was significantly elevated eleven-fold in adenine-fed rats compared to controls (p < 0.05). Metabolite formation rate of 11-OH-△9-THC (pmol/min/mg protein) was 30% and 45% higher in CKD samples, when microsomal fractions were incubated with 10 mM and 20 mM, respectively (p < 0.01; p < 0.05).

Conclusion

Contrary to our hypothesis, this data suggests that CKD results in increased metabolism of △9-THC into 11-OH-△9-THC. Further analysis, performing Michalis-Menten kinetics will better elucidate the effect of CKD on THC metabolism.

Funding

  • Government Support - Non-U.S.