A Simple and Sensitive LC-MS/MS Method for Simultaneous Quantification of Dasatinib and Erythromycin in Mice Plasma:
Avinash Kumar1, Nirbhay Kumar Tiwari2, Sanjeev Giri2
1Department of Chemistry, Pacific Academy of Higher Education and Research University (PAHER), Udaipur, Rajasthan, India.
Abstract:
Dasatinib (DAS) is a tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia (CML) and erythromycin (ERY) is macrolide antibiotic used to treat a range of inflammatory conditions are often co-administered in clinical practice. The simultaneous estimation of DAS and ERY helps in understanding the pharmacokinetics and drug-drug interactions. In this respect, we presented novel, sensitive, and validated bio-analytical LC-ESI-MS/MS method for simultaneous estimation of DAS and ERY in CD-1 mice plasma. The LLOQ was 2.0 ng/mL with an S/N ratio of 15. This validated method was used to study the PK of DAS and ERY in mice following intravenous and oral administration. The DAS was administered at 5 mg/kg via both oral and intraveneous route, whereas ERY was administered at 50 mg/kg orally and 5 mg/kg intraveneousaly. Following intravenous dosing, DAS showed high clearance and distribution, while ERY exhibited high clearance and distribution. The oral bioavailability was 64% for DAS and 21% for ERY. When co-administered orally at 5 mg/kg for DAS and 50 mg/kg of ERY, the AUC and Cmax of DAS were unchanged. However, the systemic exposure (w.r.t AUC and Cmax) of ERY was slightly higher (2.4-fold) in the presence of DAS, which may be attributed because of the CYP3A4 inhibition potential.
Insights
A new LC-ESI-MS/MS method accurately measures dasatinib (DAS) and erythromycin (ERY) in mice plasma. Co-administration showed DAS had no effect on ERY pharmacokinetics, but DAS exposure slightly increased ERY systemic exposure.
Area of Science:
- Pharmacology
- Analytical Chemistry
- Biochemistry
Background:
- Dasatinib (DAS) and erythromycin (ERY) are frequently co-administered.
- Understanding their pharmacokinetic interactions is crucial for safe and effective clinical practice.
Purpose of the Study:
- To develop and validate a sensitive bio-analytical LC-ESI-MS/MS method for simultaneous quantification of DAS and ERY in mice plasma.
- To investigate the pharmacokinetic profiles and potential drug-drug interactions between DAS and ERY in mice.
Main Methods:
- A novel, sensitive, and validated liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method was employed.
- The method's lower limit of quantification (LLOQ) was established at 2.0 ng/mL with an S/N ratio of 15.
- Pharmacokinetic studies were conducted in CD-1 mice following intravenous and oral administration of DAS and ERY, both individually and in combination.
Main Results:
- The validated LC-ESI-MS/MS method demonstrated high sensitivity and accuracy for simultaneous DAS and ERY estimation.
- Following intravenous administration, both DAS and ERY exhibited high clearance and distribution.
- Oral bioavailability was determined to be 64% for DAS and 21% for ERY.
- Co-administration of DAS (5 mg/kg) and ERY (50 mg/kg) orally did not alter DAS pharmacokinetics (AUC and Cmax).
- However, ERY's systemic exposure (AUC and Cmax) increased by 2.4-fold in the presence of DAS.
Conclusions:
- The developed LC-ESI-MS/MS method is suitable for pharmacokinetic studies of DAS and ERY.
- Co-administration of DAS and ERY may lead to increased ERY systemic exposure, potentially due to DAS-induced CYP3A4 inhibition.
- Further investigation into the clinical implications of this interaction is warranted.
