Interactions between Over-the-Counter and Illicit Drugs Utilizing Cytochrome P450 Metabolism: Potential for Exacerbation of Pharmacological Response

Aim: To determine the interaction of over-the-counter (OTC) and illicit psychostimulants at the cytochrome P450 enzyme, CYP2D6. CYP2D6 is responsible for 20% of hepatic Phase I metabolism and is a site of drug-drug interactions, leading to increased drug toxicity. Materials and Methods: We examined the effects the OTC drugs; 1) the prototype H2-antagonist cimetidine (CMT) and 2) the opioid agonist cough suppressant dextromethorphan (DEX); as well as two scheduled drugs, methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA) for their ability to interfere with CYP2D6 activity. Assays with human CYP2D6 determined the inhibitory potential (IC50) of each drug. Kinetic analysis (Vmax and Km) was accomplished using rodent hepatic microsomes. Results: Maximum inhibition of CYP2D6 activity following exposure to CMT+MDMA was significantly reduced 75-85% compared to quinidine (control) values. These data showed inhibitory effects in CYP2D6 activity in each compound tested. Alterations in CYP2D6 activity may result in complex drug-drug interactions leading to elevated plasma levels of drugs and increased risk for toxicity. Assays using rat CYP2D2 demonstrated Vmax elevations in the CMT group (493%) compared to control (naïve, no treatment) values (19.9±5.1 pmol/mg protein/ min). The Km was increased 218% in CMT compared to controls (3.1±0.5 μM). Collectively, all MA challenged groups exhibited increases in total enzyme [Vmax; 280-490%] and affinity [Km; 165-220%] values compared to the control group. The increase in both Vmax and Km suggests that the low affinity/high capacity CYP2D2 isoform is upregulated. Conclusion: Our findings suggest that in vivo, MA acts as a CYP2D2-inducer, which will lead to altered secondary drug metabolism, increasing the risk of drug-related toxicity. Coupled with the ability of CMT and DEX to interfere with MA metabolism, a complex drug-drug interaction is possible, leading to increased toxicity. Our findings substantiate the hypothesis that the combination of illicit and OTC drugs could result in complex drug-drug interactions increasing the risk for severe drug-related toxicity. KEy WoRDS: Cimetidine; Methamphetamine; Dextromethorphan; Ecstasy; CYP2D6; Hepatosomes; Methylenedioxymethamphetamine. AbbREviATionS: MA: Methamphetamine; AM: Amphetamine; OTC: Over-the-counter; MDMA: 3,4-Methylenedioxymethamphetamine; CMT: Cimetidine; DEX: Dextromethorphan; CYP: Cytochrome P450; NE: Norepinephrine; DA: Dopamine; 5-HT: Serotonin; MDA: 3,4-Methylenedioxymethamphetamine; AMMC: 3-[2-(N,N-diethyl-N-methylamino) ethyl]-7-methoxy-4-methylcoumarin; HHMA: 3,4-Dihydroxymethamphetamine; AHMC: 3-[2-(N,N-diethylamino)ethyl]-7-hydroxy-4-methylcoumarin; PCP: Phencyclidine; DXO: Dextrorphan. TOXICOLOGY AND FORENSIC MEDICINE