Pharmacokinetics of Stereomeric 1,4:3,6-Dianhydrohexitol Mononitrates in Rats

Abstract

The pharmacokinetics and urinary recoveries of four isomeric mononitrates, L-isoidide mononitrate (L-IIMN), isosorbide-2-mononitrate (IS-2-MN), isomannide mononitrate (IMMN), and isosorbide-5-mononitrate (IS-5-MN), were investigated at an intravenous dose of 2 mg/kg in rats. All four compounds exhibited monoexponential kinetics at this dose. The volumes of distribution were similar for all four isomers and were estimated at about 1.0 liter/kg. The systemic clearances of L-IIMN, IMMN, IS-2-MN, and IS-5-MN were 65.1 ± 13.0, 32.7 ± 12.0, 11.0 ± 2.3, and 8.23 ± 1.82 ml/min/kg, respectively (P < 0.05, all pairwise comparisons). Free mononitrate in the urine accounted for 0.306 to 4.56% of the administered dose, while the recovery in conjugated forms (after glusulase hydrolysis) accounted for 42.8% of the IMMN dose and 7.70 to 14.5% of the dose of the remaining three isomers. The dose-dependent pharmacokinetics of three of the mononitrates were explored at selected higher doses which cause equivalent vasodilator responses, L-IIMN (22 mg/kg), IS-2-MN (100 mg/kg), and IS-5-MN (300 mg/kg). The clearances of L-IIMN, IS-2-MN, and IS-5-MN at these higher doses were 42.3 ± 5.7, 6.38 ± 0.59, and 3.33 ± 0.62 ml/min/kg, respectively, all significantly less than those found at the 2 mg/kg dose. Typical Michaelis–Menten-type curvatures were observed in the concentration–time curves after IS-2-MN and IS-5-MN dosing. The pharmacokinetics of L-IIMN were also dose dependent, but they could not be described by simple Michaelis–Menten kinetics.