RESUMEN
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.
Asunto(s)
Nitratos/farmacocinética , Alcoholes del Azúcar/farmacocinética , Vasodilatadores/farmacocinética , Animales , Inyecciones Intravenosas , Dinitrato de Isosorbide/análogos & derivados , Dinitrato de Isosorbide/sangre , Dinitrato de Isosorbide/farmacocinética , Dinitrato de Isosorbide/orina , Masculino , Nitratos/sangre , Nitratos/orina , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Alcoholes del Azúcar/sangre , Alcoholes del Azúcar/orina , Vasodilatadores/sangre , Vasodilatadores/orinaRESUMEN
Single oral doses of 20 mg of the carbon-14 labelled form of the antianginal drug isosorbide 5-mononitrate (5-ISMN, Elantan) were essentially completely absorbed and excreted fairly rapidly in the urine. Means of 24, 52, 78, 93 and 96% dose were excreted during 6, 12, 24, 48 and 120 h, respectively. Concentrations of 14C reached peak levels at about 1-2 h when about 86% of the 14C was associated with the parent drug, 5-ISMN (peak mean level 430 ng/ml), and the remainder mainly with the pharmacologically-inactive denitrated product isosorbide. Because the plasma (and urinary) half-life of isosorbide was longer (about 8-9 h) than that of 5-ISMN (about 4.5 h), the proportions of the former in plasma increased relative to the latter. Concentrations of 14C in whole-blood and plasma were similar, implying that 5-ISMN diffused into blood cells. Concentrations of 5-ISMN in saliva and plasma were almost identical, presumably because of the almost negligible plasma protein binding of the drug (less than 5%). At least five metabolites of 5-ISMN were detected in urine - these were isosorbide (about 37% dose), conjugated material (about 25% dose) presumably mainly 5-ISMN-glucuronide, sorbitol (about 7% dose), the parent drug 5-ISMN (about 2% dose) and two unidentified metabolites (about 7 and 4% dose, respectively). The conjugated material was excreted in the urine relatively more rapidly than the denitrated product, isosorbide.
Asunto(s)
Dinitrato de Isosorbide/análogos & derivados , Adulto , Biotransformación , Cromatografía en Capa Delgada , Humanos , Isosorbida/sangre , Isosorbida/metabolismo , Isosorbida/orina , Dinitrato de Isosorbide/sangre , Dinitrato de Isosorbide/metabolismo , Dinitrato de Isosorbide/orina , Masculino , Espectrometría de Masas , Saliva/metabolismo , Factores de TiempoRESUMEN
This paper describes a sensitive method for the determination of 2-isosorbide mononitrate and 5-isosorbide mononitrate as metabolites of isosorbide dinitrate at concentrations down to 2 ng/ml of 2-isosorbide mononitrate in both plasma and urine, and 5 ng/ml and 10 ng/ml of 5-isosorbide mononitrate in plasma and urine, respectively. The two mononitrate metabolites are extracted at basic pH into ethyl acetate, which is then evaporated to dryness. The residue is dissolved in a basic aqueous solution, which is washed with heptane and then re-extracted into ethyl acetate. The metabolites are quantitated by gas chromatography, using a 63Ni electron-capture detector. Conjugates of 2- and 5-isosorbide mononitrate are determined in urine after enzymatic hydrolysis.