European journal of drug metabolism and pharmacokinetics · 2026
Investigating the Impact of Calcium Channel Blockers on the Pharmacokinetics of Lapatinib: Possible Role of Cytochrome P450 Enzymes and P-glycoprotein Efflux Transporters.
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Desai Mrunal Pradeep, Patil Prajakta Harish, Rajpurohit Anithakumari Uttam Singh, Anand Vullendula Sai Krishna, Channabasavaiah Jagadish Puralae
Аннотация
BACKGROUND AND OBJECTIVE: Lapatinib, an oral tyrosine kinase inhibitor used to treat breast cancer, is associated with cardiotoxicity. Therefore, cardioprotective agents, including calcium channel blockers, are often co-prescribed, creating a potential for pharmacokinetic drug-drug interactions that need to be evaluated.
METHODS: The current study assessed the effects of calcium channel blockers on P-glycoprotein-mediated efflux, CYP3A4 (cytochrome P450-3A4)-regulated metabolism, and the overall pharmacokinetics of lapatinib using an ex vivo everted gut sac model, in vitro metabolic stability assays, and in vivo pharmacokinetic interaction studies in rats.
RESULTS: Calcium channel blockers such as verapamil and nicardipine increased the apparent permeability of lapatinib 1.92- and 1.68-fold, respectively. Furthermore, lapatinib's metabolic clearance in human liver microsomes was decreased by 15.78- and 9.47-fold in the presence of nicardipine and diltiazem, respectively, at a concentration of 100 µM. In vivo, the Cmax (maximum plasma concentration) of lapatinib was increased by 29.30% on pretreatment with diltiazem (25 mg/kg) and 36.76% on pretreatment with nicardipine (4 mg/kg). However, verapamil (20 mg/kg) reduced its Cmax by 30.44%.
CONCLUSION: Pretreatment with diltiazem and nicardipine increased lapatinib exposure, whereas pretreatment with verapamil reduced it. These findings from preclinical models suggest the potential for drug-drug interactions between lapatinib and calcium channel blockers, warranting further clinical investigation.
METHODS: The current study assessed the effects of calcium channel blockers on P-glycoprotein-mediated efflux, CYP3A4 (cytochrome P450-3A4)-regulated metabolism, and the overall pharmacokinetics of lapatinib using an ex vivo everted gut sac model, in vitro metabolic stability assays, and in vivo pharmacokinetic interaction studies in rats.
RESULTS: Calcium channel blockers such as verapamil and nicardipine increased the apparent permeability of lapatinib 1.92- and 1.68-fold, respectively. Furthermore, lapatinib's metabolic clearance in human liver microsomes was decreased by 15.78- and 9.47-fold in the presence of nicardipine and diltiazem, respectively, at a concentration of 100 µM. In vivo, the Cmax (maximum plasma concentration) of lapatinib was increased by 29.30% on pretreatment with diltiazem (25 mg/kg) and 36.76% on pretreatment with nicardipine (4 mg/kg). However, verapamil (20 mg/kg) reduced its Cmax by 30.44%.
CONCLUSION: Pretreatment with diltiazem and nicardipine increased lapatinib exposure, whereas pretreatment with verapamil reduced it. These findings from preclinical models suggest the potential for drug-drug interactions between lapatinib and calcium channel blockers, warranting further clinical investigation.