Effects of antihypertensive drugs on the metabolism of mobocertinib in rats both in vitro and in vivo

This study investigates the potential drug-drug interactions between commonly prescribed antihypertensive drugs and mobocertinib in clinical practice to provide the scientific basis for the appropriate therapeutic application of drugs. The study used ultra-performance liquid chromatography-mass spectrometry to detect the essential metabolites of mobocertinib in rat liver microsomes. Moreover, several antihypertensive drugs were used as inhibitors and the IC50 values were determined for calcium channel blockers, angiotensin II receptor blockers, and α and β receptor blockers against mobocertinib. The inhibitory mechanism of mobocertinib was further investigated for nicardipine, irbesartan, telmisartan, carvedilol, prazosin hydrochloride, and spironolactone. Twenty-five Sprague-Dawley rats were randomly divided into 5 groups: benidipine, nicardipine, telmisartan, irbesartan and blank control groups. The drugs were administered over a period of 7 days. Mobocertinib was administered once by gavage to 5 groups, and then blood samples were collected for further analysis. Ultra-performance liquid chromatography-mass spectrometry was performed to analyze the concentration of mobocertinib and its metabolites in rat plasma. Most antihypertensive drugs were found to inhibit the metabolism of mobocertinib in vitro. Several antihypertensive drugs were also found to increase the plasma concentration and decrease the metabolic rate of mobocertinib when administered multiple times. More importantly, we found that benidipine, nicardipine, telmisartan, and irbesartan inhibited the metabolism of mobocertinib in vitro and in vivo. In summary, our data reveal that antihypertensive drugs interact with mobocertinib and additional attention is needed when coadministering the 2 drugs. SIGNIFICANCE STATEMENT: This study investigates the potential drug-drug interactions between commonly prescribed antihypertensive drugs and mobocertinib in clinical practice to provide the scientific basis for the appropriate therapeutic application of drugs. In this study, the most common antihypertensive drugs were found to inhibit the metabolism of mobocertinib in vitro. We found that benidipine, nicardipine, telmisartan, and irbesartan inhibited the metabolism of mobocertinib in vitro and in vivo.