P-glycoprotein-Mediated Impairment of Doxorubicin Clearance in Inflammatory Bowel Disorders: Mechanistic Insights from Rat Studies and Whole-Body PBPK Modeling

Doxorubicin (Dox) cardiotoxicity can worsen due to increased cardiac accumulation. P-glycoprotein (P-gp) downregulation, common in irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), may influence Dox pharmacokinetics (PK) and cardiotoxicity, but its impact remains unexplored. This study investigated the mechanistic effects of IBS/IBD on Dox-induced cardiotoxicity. An IBS/IBD rat model assessed Dox PK after IV-bolus (2.5 mg/kg) and oral (10 mg/kg) dosing. A whole-body physiologically based pharmacokinetic (wbPBPK) model was developed to predict Dox cardiac concentration in rats and humans. In rats, IV Dox clearance decreased by 70% in IBS, tripling plasma concentration, while IBD had a milder effect. Oral Dox bioavailability dropped by 85% in IBS and 50% in IBD, likely due to delayed gastric emptying. The wbPBPK model predicted elevated cardiac interstitial fluid (ISFHeart) Dox concentrations surpassing cardiotoxicity thresholds in IBS/IBD rats. Human simulations showed 4-5-fold higher plasma concentration in IBS/IBD patients receiving IV Dox (60 mg/m 2 ), nearing toxic levels. IBS/IBD prolongs Dox ISFHeart retention, increasing apoptosis-mediated cardiotoxicity risk, especially with bolus dosing. These findings highlight the critical impact of IBS/IBD on Dox PK and toxicity, advocating for personalized chemotherapy approaches.