LC-MS/MS method for co-estimation of doxorubicin and piperine: formulation development and pharmacokinetic studies

Oral metronomic chemotherapy employs a low-dose combination of chemotherapeutics administered regularly to minimize toxicity while enhancing anticancer efficacy. The clinical utility of Doxorubicin (DOX) is limited due to severe cardiotoxicity. Interestingly, Piperine (PIP) has been explored to mitigate DOX-induced toxicity while enhancing its therapeutic efficacy. Solid lipid nanoparticles (SLNs) offer an efficient drug delivery approach to improve oral bioavailability and controlled release of DOX and PIP. LC-MS/MS method was developed and validated per US-FDA bioanalytical guidelines to quantify DOX and PIP in plasma simultaneously. SLNs were developed and optimized using design expert software and exhibited particle size of 151.56 ± 0.32 nm, polydispersity index (PDI) of 0.172 ± 0.02, and surface charge of −22.83 ± 0.66 mV. Pharmacokinetic evaluation in female Sprague-Dawley rats showed enhanced AUC₀–∞ for DOX (31911.78 ± 226.92 ng/mL) and PIP (7377.66 ± 655.78 ng/mL), indicating improved systemic exposure. The findings highlight the potential of SLN-based co-delivery of DOX and PIP for oral metronomic chemotherapy. The validated LC-MS/MS method ensures precise pharmacokinetic assessment, which is crucial for future clinical translation. This study provides a promising strategy for enhancing oral chemotherapy efficacy. This study focuses on improving cancer treatment by using a special type of oral chemotherapy that involves giving low doses of drugs regularly to reduce side effects. Doxorubicin (DOX) is a common cancer drug but can harm the heart. Piperine (PIP), a natural compound found in black pepper, may help reduce this damage and make DOX work better. To deliver these drugs more effectively, scientists used tiny fat-based particles called solid lipid nanoparticles (SLNs). These SLNs were carefully designed and tested, showing they can carry both drugs in the body more efficiently. A highly sensitive testing method was also developed to measure the drug levels in the blood. The results showed that the SLNs helped both DOX and PIP stay in the body longer, which could make the treatment more effective. This approach may offer a safer and more efficient way to deliver chemotherapy drugs by mouth in the future. Solid lipid nanoparticles co-delivering doxorubicin and piperine improved oral bioavailability and reduced toxicity. A validated LC-MS/MS method enabled accurate plasma quantification.