The Significance of Combined Therapy in Pulmonary Arterial Hypertension (PAH)
Pulmonary arterial hypertension (PAH) is a severe and progressive disease characterized by high blood pressure in the pulmonary arteries, which ultimately leads to heart failure if left untreated. Modern therapeutic approaches frequently involve combination treatments using drugs like tadalafil, a phosphodiesterase-5 (PDE-5) inhibitor, and macitentan, an endothelin receptor antagonist (ERA). Combining these drugs can target multiple pathogenic pathways simultaneously, offering improved outcomes compared to monotherapy. However, accurately monitoring these drugs in biological systems remains analytically challenging due to their differing chemical properties and concentrations in plasma.
Historically, analytical methods available for tadalafil and macitentan have been either costly or cumbersome, thus highlighting the need for reliable, cost-effective methods capable of simultaneously quantifying these drugs. Recognizing this analytical gap, the present study aimed to develop and validate a robust, eco-friendly LC-MS/MS method for simultaneous estimation of tadalafil and macitentan in rat plasma. This innovative approach aligns with green chemistry principles, ensuring minimal environmental impact while delivering precise and reliable data for pharmacokinetic analyses.
Optimizing the Analytical Method: A Green and Efficient Approach
The LC-MS/MS method was optimized through a structured experimental design approach (Box-Behnken Design), focusing on critical parameters like organic phase composition, flow rate, and pH. This statistical approach enabled identification of optimal conditions (50% acetonitrile, flow rate of 1.0 mL/min, and pH 3.2), ensuring precise chromatographic separation with short retention times: 4.13 min for tadalafil, 5.32 min for macitentan, and 7.89 min for ritonavir (internal standard).
Following optimization, method validation adhered strictly to regulatory guidelines. Linearity was confirmed across broad concentration ranges (20–400 ng/mL for tadalafil and 5–100 ng/mL for macitentan), achieving impressive correlation coefficients (>0.9997). Precision and accuracy were consistently excellent, with intra- and inter-day variability below 15%, underscoring the reliability and reproducibility of the method. Drug recovery rates exceeded 98%, highlighting the method’s analytical efficiency.
Pharmacokinetics: Unveiling Drug Behavior in Biological Systems
The developed LC-MS/MS method was effectively applied in pharmacokinetic studies involving male Wistar rats. Following a single dose administration (tadalafil: 0.0033 mg/kg; macitentan: 0.0003 mg/kg), distinct absorption and elimination profiles were observed. Tadalafil demonstrated rapid absorption, achieving a peak plasma concentration (Cmax) of 164.2 ng/mL within 1.5 hours, and exhibited a relatively short half-life of approximately 5 hours, suggesting quick systemic clearance. Conversely, macitentan showed slower absorption, with a Cmax of 43.8 ng/mL at 2 hours, yet maintained prolonged systemic exposure with a half-life extending to 15 hours.
These pharmacokinetic profiles underscore the importance of tailored dosing strategies for tadalafil and macitentan. Specifically, the rapid clearance of tadalafil supports its suitability for situations demanding rapid onset and short duration of action, whereas macitentan’s sustained systemic presence aligns with chronic therapeutic needs.
Green Chemistry: A Commitment to Sustainability
Incorporating green analytical chemistry principles, the study evaluated the environmental impact of the developed method using multiple eco-assessment tools, including ComplexGAPI, AGREE, Analytical Eco-Scale, and BAGI. The method scored highly across these assessments, particularly for its low solvent consumption, reduced toxicity, and overall sustainability. With an Analytical Eco-Scale score of 76 and an AGREE score of 0.70, the method demonstrates exceptional environmental responsibility without compromising analytical quality.
Such eco-friendly methodologies not only safeguard environmental health but also promote long-term sustainable practices within analytical chemistry, making this LC-MS/MS approach particularly valuable for future pharmacokinetic and clinical research applications.
This study successfully introduced a reliable, validated LC-MS/MS method capable of simultaneously quantifying tadalafil and macitentan in biological matrices. Its precision, accuracy, and eco-friendly attributes make it highly suitable for routine pharmacokinetic studies and potential clinical monitoring. By integrating rigorous method validation and green analytical principles, researchers and clinicians alike gain access to a powerful tool for accurately assessing these critical PAH treatments, ultimately facilitating safer and more effective patient management.
Frequently Asked Questions (FAQ)
1. Why is it essential to simultaneously measure tadalafil and macitentan?
Simultaneous measurement ensures accurate pharmacokinetic profiling when these drugs are used in combination therapy, improving therapeutic outcomes in PAH patients.
2. What makes this LC-MS/MS method “green” and sustainable?
This method reduces environmental impact by minimizing solvent use, employing less toxic reagents, and optimizing energy efficiency, aligning with modern sustainability standards.
3. How does the pharmacokinetic difference between tadalafil and macitentan influence clinical use?
Tadalafil’s rapid absorption and elimination are beneficial for acute needs, whereas macitentan’s prolonged systemic presence supports its use in chronic therapy, allowing tailored dosing strategies for patients.
Sravanthi Gandu, Kumaraswamy Gandla, Lalitha Repudi
Department of Pharmacy, Chaitanya (Deemed to be University), Gandipet Himayath Nagar (Vill), Hyderabad, 500075, Telangana, India
