α-PHP: Acute effects and pharmacokinetic in male and female mice, and clinical data on related intoxications

Alpha-Pyrrolidinohexanophenone (alpha-PHP) is a synthetic pyrovalerone derivative with structural characteristics and stimulant effects on humans comparable to alpha-PVP and MDPV. Since its pharmaco-toxicological effects have been poorly investigated, the aim of this study was to evaluate the acute effects of alpha-PHP (0.1-30 mg/kg; i.p.) on behavioral responses in CD-1 male and female mice. Sex-related differences in pharmacokinetic profile of alpha-PHP (30 mg/kg; i.p.) in mice were evaluated by analyzing i) the urine concentration of alpha-PHP and its metabolites at different time points, and ii) alpha-PHP levels in plasma, brain, and kidneys at 35 min after the injection. Clinical data related to alpha-PHP intoxications, recorded by the Pavia Poison Control Centre (PCC) are also described. The present study shows that female mice were more sensitive to the effects of alpha-PHP on visual object, tactile, mobility time, and hypothermia, but males showed a deeper effect on visual placing. Both sexes developed analgesia to the mechanical stimulation, but only males showed a slight increase in enduring the thermal stimulation. Male mice showed higher plasma levels of alpha-PHP and a different elimination of alpha-PHP and metabolites than females. Case reports highlighted severe toxidromes characterized by Central Nervous System alterations (psychomotor agitation, tremors/fasciculations, hallucinations), cardiovascular toxicity signs (tachycardia, tachypnoea, thoracic pain) and other peripheral symptoms (hyperthermia, rhabdomyolysis). Our findings highlight the importance of the in vivo investigation of the effects and pharmacokinetic differences in male and female mice, to make contribution to the translational toxicological and forensic sex-related value.