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Minimal Physiologically Based Pharmacokinetic Model of Intravenously and Orally Administered Delta-9-Tetrahydrocannabinol in Healthy Volunteers

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Lack of information on the pharmacokinetics of the active moiety of Cannabis or the metabolites of delta-9-tetrahydrocannabinol (THC) does not seem to be discouraging medical or recreational use. Cytochrome P450 (CYP) 2C9, the primary enzyme responsible for THC metabolism, has two single nucleotide polymorphisms—Arg144Cys (*2) and Ile359Leu (*3). In the Caucasian population, allelic frequency is between 0.08 and 0.14 for CYP2C9*2 and between 0.04 and 0.16 for CYP2C9*3. In vitro data suggest that metabolic capacity for the variants CYP2C9*2 and CYP2C9*3 is about one-third compared to wild-type CYP2C9. Previous work has suggested exposure to the terminal metabolite is genetically determined. We therefore sought to characterize the pharmacokinetics of THC and its major metabolites 11-hydroxy-delta-9-tetrahydrocannabinol (THC-OH) and 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THC-COOH) in healthy volunteers with known CYP2C9 status by non-compartmental analysis (NCA), compartmental modeling (CM) and minimal physiologically based pharmacokinetic (mPBPK) modeling.

Methods

Blood samples drawn for THC, THC-OH and THC-COOH after a single intravenous (IV) bolus of 0.1 mg/kg (0.32 μM/kg) THC were analyzed using a validated LC–MS/MS method. NCA generated initial estimates and CM and the mPBPK model were then fit to plasma concentration data using non-linear mixed-effects modeling. Blood samples from orally dosed (10, 25 and 50 mg) THC brownies were added to validate the model.

Results

THC can be described as a high hepatic extraction ratio drug with blood flow-dependent metabolism not restricted by protein binding. THC hepatic clearance is dependent on the CYP2C9 genetic variant in the population. High extraction drugs display route-dependent metabolism. When administered via the IV or inhalation routes, induction or inhibition of CYP2C9 should be non-contributory as the elimination of THC is dependent only on liver blood flow. THC-OH is also a high extraction ratio drug, but its hepatic clearance is significantly impacted by the hepatic diffusional barrier that impedes its access to hepatic CYP2C9. THC-COOH is glucuronidated and renally cleared; subjects homozygous for CYP2C9*3 have reduced exposure to this metabolite as a result of the polymorphism reducing THC production, the hepatic diffusional barrier impeding egress from the hepatocyte, and increased renal clearance.

Conclusion

It has recently been reported that the terminal metabolite THC-COOH is active, implying the exposure difference in individuals homozygous for CYP2C9*3 may become therapeutically relevant. Defining the metabolism of THC in humans is important, as it is increasingly being used as a drug to treat various diseases and its recreational use is also rising. We have used NCA, CM, and mPBPK modeling of THC and its metabolites to partially disentangle the complexity of cannabis disposition in humans.

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Acknowledgements

This work is dedicated to the memory of our colleague and friend, Hans Sachs (12.7.1948–10.3.2017), former head of the Forensic and Toxicologic Center, FTC GmbH, Munich, Germany. Doctor Sachs provided all analytic results of the THC data and contributed greatly to the manuscript. Without him, this manuscript would never have been written. Dr. Wolowich would also like to acknowledge personal conversations with KS Pang, WJ Jusko and Dr. Ryan Vandrey who graciously allowed the use of his oral cannabis study data. This work was presented, in part at the American College of Clinical Pharmacology, September, 2016 in Bethesda, MD, USA; the 8th Swiss Pharma Science Day, August, 2015 Bern, Switzerland; the Annual Meeting American Academy of Forensic Science, February, 2014, Seattle, WA, USA; the American Conference of Pharmacometrics Annual Meeting, May, 2013, Ft. Lauderdale FL, USA; and the American Society of Anesthesiology Annual Meeting, Chicago, IL, USA in October, 2011.

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Authors and Affiliations

  1. College of Pharmacy, Nova Southeastern University, 3200 University Dr., Fort Lauderdale, FL, USA

    William R. Wolowich

  2. University Department of Anesthesiology and Pain Therapy, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

    Robert Greif, Maren Kleine-Brueggeney & Lorenz Theiler

  3. Department of Anesthesia, Evelina London Children’s Hospital, Guy’s and St. Thomas NHS Foundation Trust, London, UK

    Maren Kleine-Brueggeney

  4. Institute of Forensic Medicine, University of Bern, Bern, Switzerland

    Werner Bernhard

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  1. William R. Wolowich
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  5. Lorenz Theiler
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Contributions

WRW was responsible for writing the manuscript and all pharmacokinetic data analysis and mPBPK modeling. RG designed and conducted sampling of the probes, and revised the manuscript. MKB designed the study, helped with the conduct of the study and with writing of the manuscript. WB helped design the study, tested the quality of the THC solution used for the injection and coordinated the analysis of the probes. LT designed the study, and helped in writing the manuscript of this study.

Corresponding author

Correspondence to William R. Wolowich.

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No source of funding was used for this study.

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All authors have no conflict of interest to declare.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Review Board approval (Cantonal Ethics Committee Bern Approval#: KEK 241–09, ISRCTN 53019164) and permission of all relevant bodies (BAG, Swissmedic) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Written informed consent was obtained from all volunteers.

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Wolowich, W.R., Greif, R., Kleine-Brueggeney, M. et al. Minimal Physiologically Based Pharmacokinetic Model of Intravenously and Orally Administered Delta-9-Tetrahydrocannabinol in Healthy Volunteers. Eur J Drug Metab Pharmacokinet 44, 691–711 (2019). https://doi.org/10.1007/s13318-019-00559-7

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