Inhibition and stimulation of the human breast cancer resistance protein as in vitro predictor of drug-drug interactions of drugs of abuse.

Inhibition and stimulation of the human breast cancer resistance protein as in vitro predictor of drug-drug interactions of drugs of abuse. Arch Toxicol. 2018 Aug 06;: Authors: Wagmann L, Maurer HH, Meyer MR Abstract Transporter-mediated drug-drug interactions (DDI) may induce adverse clinical events. As drugs of abuse (DOA) are marketed without preclinical safety studies, only very limited information about interplay with membrane transporters are available. Therefore, 13 DOA of various classes were tested for their in vitro affinity to the human breast cancer resistance protein (hBCRP), an important efflux transporter. As adenosine 5'-triphosphate (ATP) hydrolysis is crucial for hBCRP activity, adenosine 5'-diphosphate (ADP) formation was measured and used as in vitro marker for hBCRP ATPase activity. ADP quantification was performed by hydrophilic interaction liquid chromatography coupled to high-resolution tandem mass spectrometry and its amount in test compound incubations was compared to that in reference incubations using the hBCRP substrate sulfasalazine or the hBCRP inhibitor orthovanadate. If DOA caused stimulation or inhibition, further investigations such as Michaelis-Menten kinetic modeling or IC50 value determination were conducted. Among the tested DOA, seven compounds showed statistically significant hBCRP ATPase stimulation. The entactogen 3,4-BDB and the plant alkaloid mitragynine were identified as strongest stimul...
Source: Archives of Toxicology - Category: Toxicology Authors: Tags: Arch Toxicol Source Type: research