Comparative pharmacokinetics and biodistributions of mebendazole from cosolvent and nanoemulsion formulations in nude athymic mice

Abstract

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Objective: Mebendazole (Mbz), Methyl 5-benzoyl-2-benzimidazole carbamate, exerts growth inhibition in culture and tumor bearing nu/nu mice against NSCLC cell lines. The antineoplastic activity of MBZ is also evident in colorectal carcinoma and melanoma. A nanoemulsion (37 nm) formulation (PM1) of Mbz has been developed in our laboratory for potential parental delivery. This study was to comparatively characterize pharmacokinetics and biodistributions of Mbz from cosolvent formulation and PM1 in nude athymic mice.

Method: Mbz was administrated by i.v. bolus to the mice (30-35 gm) at 5 mg/kg for cosolvent system and 2.5 mg/kg for PM1. Concentrations of Mbz in plasma and five organs (heart, lung, liver, spleen, and kidney) were monitored by HPLC assays up to 6 hours post dose. The pharmacokinetic and tissue distribution profiles were constructed and pharmacokinetic parameters were derived using the WinNonlin.

Results: The plasma concentration-time profiles of Mbz from cosolvent and PM1 systems followed a two-compartment model with dose normalized AUCs of 2.46 and 2.38 μg·min/ml per μg dose, respectively. The clearance (CL) was 0.41 ml/min for cosolvent and 0.42 ml/min for PM1. The apparent volume distributions at steady-state (Vss) for cosolvent and PM1 were 42.8 ml and 38.8 ml, respectively. Different tissue distribution patterns between the two formulations were observed. For cosolvent, Mbz peak concentrations in different organs were reached in 5 minutes after injection. The highest peak concentration was 76.41 ng/g tissue/μg dose in liver, in contrast to 224.42 ng/g/μg in lung at 2 hr post dose for PM1. Mbz in cosolvent yielded the highest exposure in liver with AUC of 8.24 ug·min/g/ug dose, followed by kidney of 6.67 ug·min/g/ug. However, for PM1, AUC in lung (63.57 ug·min/g/ug) was the highest, which was about 20 folds of that from cosolvent (3.24 ug·min/g/ug), followed by those in liver (5.56 ug·min/g/ug) and kidney (5.22 ug·min/g/ug). For cosolvent, the elimination half-lives were 80, 72, 91, 84 and 98 min in heart, lung, liver, spleen, and kidney, respectively. For PM1, the elimination half-lives were substantially prolonged than those from cosolvent, 96, 172, 193, 123 and 131 min in heart, lung, liver, spleen, and kidney, respectively.

Conclusion: Mbz in cosolvent and PM1 systems exhibit similar plasma pharmacokinetics, but distinct tissue distributions. PM1 yields higher Mbz concentrations and prolonged exposures in organs than cosolvent, especially in lung, which may have potential value for lung cancer therapy.