Pharmacokinetics and Metabolism of the Plant Cannabinoids Tetrahydrocannabinol Cannabidiol and Cannabinol

M.A. Huestis

Chemistry and Drug Metabolism, Intramural Research Program, 5500 Nathan Shock Drive, Baltimore MD, 21224, USA [email protected]

1 Introduction 658

2 Pharmacokinetics of THC 660

2.1 Absorption 660

2.1.1 Smoked Administration 660

2.1.2 Oral Administration 662

2.1.3 Rectal Administration 664

2.1.4 Sublingual and Dermal Administration 664

2.2 Distribution 665

2.3 Metabolism 666

2.3.1 Hepatic Metabolism 666

2.3.2 Extrahepatic Metabolism 668

2.4 Elimination 668

2.4.1 Terminal Elimination Half-Lives of THCCOOH 669

2.4.2 Percentage THC Dose Excreted as Urinary THCCOOH 669

2.4.3 Cannabinoid Glucuronide Conjugates 670

2.4.4 Urinary Biomarkers of Recent Cannabis Use 670

3 Pharmacokinetics of Cannabidiol 671

4 Pharmacokinetics of Cannabinol 672

5 Interpretation of Cannabinoid Concentrations in Biological Fluids 672

5.1 Plasma Concentrations of THC, 11-OH-THC, and THCCOOH 672

5.1.1 Following Intravenous THC Administration 673

5.1.2 Following Smoked Cannabis Administration 673

5.1.3 Oral THC 674

5.1.4 Cannabinoid Concentrations After Frequent Use 675

5.1.5 Prediction Models for Estimation of Cannabis Exposure 675

5.2 Urinary THCCOOH Concentrations 677

5.2.1 THCCOOH Detection Windows in Urine 677

5.2.2 Normalization of Cannabinoid Urine Concentrations to Urine Creatinine Concentrations 678

5.3 Oral Fluid Testing 679

5.4 Cannabinoids in Sweat 681

5.5 Cannabinoids in Hair 682

References 683

Abstract Increasing interest in the biology, chemistry, pharmacology, and toxicology of cannabinoids and in the development of cannabinoid medications necessitates an understanding of cannabinoid pharmacokinetics and disposition into biological fluids and tissues. A drug's pharmacokinetics determines the onset, magnitude, and duration of its pharmacodynamic effects. This review of cannabinoid pharmacokinetics encompasses absorption following diverse routes of administration and from different drug formulations, distribution of analytes throughout the body, metabolism by different tissues and organs, elimination from the body in the feces, urine, sweat, oral fluid, and hair, and how these processes change over time. Cannabinoid pharmacokinetic research has been especially challenging due to low analyte concentrations, rapid and extensive metabolism, and physicochem-ical characteristics that hinder the separation of drugs of interest from biological matrices—and from each other—and lower drug recovery due to adsorption of compounds of interest to multiple surfaces. ^-Tetrahydrocannabinol, the primary psychoactive component of Cannabis sativa, and its metabolites 11-hydroxy-49-tetrahydrocannabinol and 11-nor-9-carboxy-tetrahydrocannabinol are the focus of this chapter, although cannabidiol and cannabinol, two other cannabinoids with an interesting array of activities, will also be reviewed. Additional material will be presented on the interpretation of cannabinoid concentrations in human biological tissues and fluids following controlled drug administration.

Keywords Cannabinoids ■ Pharmacokinetics ■ Tetrahydrocannabinol ■ Cannabidiol ■ Absorption ■ Distribution ■ Metabolism ■ Excretion ■ Interpretation ■ Oral fluid ■ Sweat ■ Hair ■ Plasma ■ Urine ■ Alternate matrix ■ Marijuana

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