Michaelis–Menten kinetic analysis of drugs of abuse to estimate their affinity to human P-glycoprotein

The pharmacokinetics of various important drugs are known to be significantly influenced by the human ABC transporter P-glycoprotein (P-gp), which may lead to clinically relevant drug–drug interactions. In contrast to therapeutic drugs, emerging drugs of abuse (DOA) are sold and consumed without any safety pharmacology testing. Only some studies on their metabolism were published, but none about their affinity to the transporter systems. Therefore, 47 DOAs from various classes were tested for their P-gp affinity using human P-gp (hP-gp) to predict possible drug–drug interactions. DOAs were initially screened for general hP-gp affinity and further characterized by modeling classic Michaelis–Menten kinetics and assessing their Km and Vmax values. Among the tested drugs, 12 showed a stimulation of ATPase activity. The most intensive stimulating DOAs were further investigated and compared with the known P-gp model substrates sertraline and verapamil. ATPase stimulation kinetics could be modeled for the entactogen 3,4-methylenedioxy-α-ethylphenethylamine (3,4-BDB), the hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI), the abused alkaloid glaucine, the opioid-like drugs N-iso-propyl-1,2-diphenylethylamine (NPDPA), and N-(1-phenylcyclohexyl)-3-ethoxypropanamine (PCEPA), with Km and Vmax values within the same range as for verapamil or sertraline. As a consequence interactions with other drugs being P-gp substrates might be considered to be very likely and further studies should be encouraged.

► First report on possible interaction of drugs of abuse with p-glycoprotein. ► 47 drugs of abuse tested for stimulation of P-glycoprotein. ► 12 drugs of abuse with ATPase stimulation. ► Several drugs of abuse within the same range as verapamil or sertraline. ► Interactions with other drugs to be very likely.