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Background and Objective <p>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.</p> Methods <p>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.</p> Results <p>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&#xa0;15.78- and 9.47-fold in the presence of nicardipine and diltiazem, respectively, at a concentration of 100 µM. In vivo, the <i>C</i><sub>max</sub> (maximum plasma concentration) of lapatinib was increased&#xa0;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 <i>C</i><sub>max</sub> by 30.44%.</p> Conclusion <p>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.</p>

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Investigating the Impact of Calcium Channel Blockers on the Pharmacokinetics of Lapatinib: Possible Role of Cytochrome P450 Enzymes and P-glycoprotein Efflux Transporters

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月26日

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  • Mrunal Pradeep Desai,
  • Prajakta Harish Patil,
  • Anithakumari Uttam Singh Rajpurohit,
  • Vullendula Sai Krishna Anand,
  • Jagadish Puralae Channabasavaiah

摘要

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.