Pharmacokinetic-hemodynamic studies of the enantiomers of isoidide dinitrate in conscious rats.
Our objective was to determine the pharmacokinetic properties of the D- and L-enantiomers of isoidide dinitrate (IIDN) in relation to their hemodynamic effects. Conscious male Sprague-Dawley rats were administered a bolus i.v. dose of 2 mg.kg-1 D- or IIDN and simultaneous blood samples and blood pressure recordings were taken at various times. The elimination half-life of D-IIDN was significantly shorter than that of L-IIDN (10 vs. 16 min) owing to a larger Vd area of the L-enantiomer (5.8 vs. 3.8 L.kg-1). The plasma clearance of either enantiomer was approximately 250 mL.min-1.kg-1, a value equal to plasma cardiac output. The pharmacokinetic data indicates that IIDN is distributed extensively and that significant extrahepatic biotransformation of the drug occurs. After intravenous administration of D-IIDN, there was an initial decrease in mean arterial pressure (MAP) of 29% compared with 15% for L-IIDN (p less than 0.05). For L-IIDN, the decrease in MAP was short lived (less than 2 min), while for D-IIDN, MAP remained significantly decreased for up to 60 min. The oral bioavailability of both enantiomers was low (ca. 7%). However, decreases in MAP occurred after oral administration of D-IIDN, suggesting that the mononitrate metabolite of IIDN was pharmacologically active. We conclude that, despite a faster rate of elimination from the central compartment, D-IIDN exhibits a greater vasodilator effect in the intact animal compared to L-IIDN. This is consistent with previous observations of a 10-fold greater potency of D-IIDN for relaxation of isolated vascular smooth muscle.
Bennett
B M
BM
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ont., Canada.
Kempenaar
J W
JW
Hayward
L D
LD
Baur
R
R
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013402:Sugar Alcohols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*
D013402:Sugar Alcohols; D014665:Vasodilator Agents; C002589:isoidide dinitrate