Sex differences in the disposition of cannabidiol and its metabolites in mice

Abstract Background While cannabidiol (CBD) is widely used globally as a therapeutic agent, sex as a biological variable remains underexplored in determining its metabolism and overall pharmacokinetic patterns. The present study systematically evaluated sex differences in the pharmacokinetics of CBD and its major metabolites, 7-hydroxy-CBD (7-OH-CBD) and 7-carboxy-CBD (7-COOH-CBD), in a mouse model. Methods Male and female C57BL/6J mice received an intraperitoneal dose of CBD (120 mg/kg) and plasma concentrations of CBD and its metabolites were quantified by UPLC–MS/MS. Pharmacokinetic parameters were derived using non-compartmental analysis and compared between sexes. Results Females exhibited significantly higher early exposure to CBD, with a ~ 1.5-fold higher $$\:{C}_{\text{m}\text{a}\text{x}}\:$$ than male mice ( p = 0.03). The apparent clearance (CL/F) and ultimate total systemic exposure $$\:{\:AUC}_{0-\text{I}\text{N}\text{F}}$$ were comparable between sexes. In contrast, male mice demonstrated a markedly larger apparent volume of distribution (Vz/F; ~2.2-fold increase, p = 0.02) and consequently a longer terminal half-life (t 1/2 ; ~2.2-fold increase, p = 0.04), indicating greater tissue sequestration. Both metabolites were significantly higher in female vs. male mice (7-OH-CBD $$\:{C}_{\text{m}\text{a}\text{x}}\:$$ ~1.6-fold, p = 0.03; 7-COOH-CBD $$\:{C}_{\text{m}\text{a}\text{x}}$$ ~1.7-fold, p = 0.03). The $$\:{AUC}_{0-\text{I}\text{N}\text{F}}$$ tended to be higher for 7-OH-CBD in female mice but was not significant (~ 1.4-fold, p = 0.11), whereas the 7-COOH-CBD $$\:{AUC}_{0-24\text{h}}$$ was significantly greater in females (~ 1.8-fold, p = 0.04). Male mice displayed substantially longer terminal half-lives for both metabolites (7-OH-CBD ~2.4-fold, p = 0.0051; 7-COOH-CBD ~3.7-fold, p = 0.02). Conclusions These results demonstrate that sex is a critical determinant of CBD pharmacokinetics and highlight the need for sex-informed dosing considerations in both preclinical study design and potentially for future clinical applications of CBD.