Pharmacokinetics of alpha-naphthyl isothiocyanate in rats
1Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, New York 14260, USA.
Abstract:
Many naturally occurring and synthetic isothiocyanates can inhibit chemical carcinogenesis in animal models. Recently, we found that alpha-naphthyl isothiocyanate (1-NITC) inhibited P-glycoprotein- and multidrug resistance associated protein 1-mediated efflux, indicating the potential application of 1-NITC as a chemosensitizing agent for cancer chemotherapy. The objective of this study was to explore the pharmacokinetic characteristics of 1-NITC in rats. A single dose of 10, 25, 50, or 75 mg/kg of 1-NITC was administered intravenously or orally to female Sprague-Dawley rats (n = 4 for each group). Dose-normalized concentration-time profiles were not superimposable following intravenous or oral dosing, indicating that the disposition of 1-NITC in rats was nonlinear. As doses increased from 10 to 75 mg/kg following iv administration, the total clearance decreased from 2.2 +/- 0.9 to 0.8 +/- 0.3 L/h/kg; oral availability averaged 0.46 for oral doses of 10-75 mg/kg. A nonlinear two-compartment open model with capacity-limited absorption and capacity-limited elimination from the central compartment best fit the data, based on goodness-of-fit criteria. The mechanism underlying the nonlinear elimination of 1-NITC in rats is most likely due to the capacity-limited metabolism of 1-NITC. This study represents the first report of the pharmacokinetics of 1-NITC.
Insights
Alpha-naphthyl isothiocyanate (1-NITC) shows potential as a cancer chemotherapy sensitizer. This study reveals its nonlinear pharmacokinetics in rats, likely due to limited metabolism, impacting drug development.
Area of Science:
- Pharmacology
- Toxicology
- Drug Metabolism
Background:
- Isothiocyanates, including alpha-naphthyl isothiocyanate (1-NITC), can inhibit chemical carcinogenesis.
- 1-NITC has demonstrated potential as a chemosensitizing agent by inhibiting drug efflux pumps.
Purpose of the Study:
- To investigate the pharmacokinetic characteristics of 1-NITC in a rat model.
- To understand the absorption, distribution, metabolism, and excretion (ADME) profile of 1-NITC.
Main Methods:
- Single intravenous or oral administration of 1-NITC (10-75 mg/kg) to female Sprague-Dawley rats.
- Analysis of dose-normalized concentration-time profiles to assess linearity.
- Nonlinear pharmacokinetic modeling (two-compartment open model) to characterize disposition.
Main Results:
- 1-NITC exhibited nonlinear pharmacokinetics following both intravenous and oral administration.
- Total clearance decreased significantly with increasing doses (from 2.2 to 0.8 L/h/kg).
- Oral bioavailability averaged 0.46, and data best fit a model with capacity-limited absorption and elimination.
Conclusions:
- The nonlinear elimination of 1-NITC in rats is likely attributed to capacity-limited metabolism.
- These pharmacokinetic findings are crucial for understanding 1-NITC's behavior and potential therapeutic applications.
- This study provides the foundational pharmacokinetic data for 1-NITC.
