Cardiovascular & hematological disorders drug targets · 2026
Pharmacokinetic Studies and Toxicity Assessment of Nisoldipine and Cilnidipine Analogues for Drug Development.
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Krosuri Pavankumar, Mohan Mothilal
Аннотация
INTRODUCTION: Nisoldipine and Cilnidipine are dihydropyridine calcium channel blockers used in cardiovascular therapy. Their clinical utility is limited by low oral bioavailability and rapid metabolism. This study evaluates the pharmacokinetic profiles and acute oral toxicity of selected analogues from the Zinc database, comparing pure drugs, unformulated analogues, and optimized oral disintegrating tablet (ODT) formulations.
METHODS: Acute toxicity was assessed in Swiss albino mice (n=3/group) per OECD 423 guidelines at oral doses from 5-2000 mg/kg. Pharmacokinetic studies were conducted in New Zealand rabbits (n=6/group) with human-equivalent dosing. Non-compartmental analysis was used to determine Cmax, Tmax, AUC₀-t, AUC₀-∞, t½, MRT, and relative bioavailability. Plasma drug concentrations were measured by validated HPLC. Data were analysed by ANOVA with Tukey's post hoc test (p<0.05).
RESULTS: Both compounds exhibited toxicity dependent on the dose, with no mortality at 5 mg/kg and complete mortality at 2000 mg/kg. Improvements were observed in the pharmacokinetics of ODT formulations. The relative bioavailability of Nisoldipine Analogue (NC3) was 165%. The relative bioavailability of Cilnidipine Analogue (CC5) was 180%, and Tmax 0.50 h and t½ 3.80 h indicate rapid absorption and faster action.
DISCUSSION: The optimized formulations facilitated superior solubility and a significant enhancement in metabolic stability, leading to improved oral bioavailability and reduced Tmax without affecting acute safety. Rapid disintegration supports immediate-release dosing and better patient compliance.
CONCLUSION: More rapid absorption and action may offer quicker control of blood pressure and relief of symptoms in acute angina or hypertensive crises. The short elimination half-life (t½) observed indicates that multiple dosing and/or modified-release formulations may be required to maintain clinical benefit. The Nisoldipine and Cilnidipine ODT analogues show potential for further preclinical cardiovascular drug development.
METHODS: Acute toxicity was assessed in Swiss albino mice (n=3/group) per OECD 423 guidelines at oral doses from 5-2000 mg/kg. Pharmacokinetic studies were conducted in New Zealand rabbits (n=6/group) with human-equivalent dosing. Non-compartmental analysis was used to determine Cmax, Tmax, AUC₀-t, AUC₀-∞, t½, MRT, and relative bioavailability. Plasma drug concentrations were measured by validated HPLC. Data were analysed by ANOVA with Tukey's post hoc test (p<0.05).
RESULTS: Both compounds exhibited toxicity dependent on the dose, with no mortality at 5 mg/kg and complete mortality at 2000 mg/kg. Improvements were observed in the pharmacokinetics of ODT formulations. The relative bioavailability of Nisoldipine Analogue (NC3) was 165%. The relative bioavailability of Cilnidipine Analogue (CC5) was 180%, and Tmax 0.50 h and t½ 3.80 h indicate rapid absorption and faster action.
DISCUSSION: The optimized formulations facilitated superior solubility and a significant enhancement in metabolic stability, leading to improved oral bioavailability and reduced Tmax without affecting acute safety. Rapid disintegration supports immediate-release dosing and better patient compliance.
CONCLUSION: More rapid absorption and action may offer quicker control of blood pressure and relief of symptoms in acute angina or hypertensive crises. The short elimination half-life (t½) observed indicates that multiple dosing and/or modified-release formulations may be required to maintain clinical benefit. The Nisoldipine and Cilnidipine ODT analogues show potential for further preclinical cardiovascular drug development.