Pharmacokinetics of diltiazem and a new analogue, LR-A/113, in the conscious rat.
Pharmacokinetics and metabolism of diltiazem and a new analogue, LR-A/113, have been studied in the rat. Conscious rats, with the jugular vein cannulated, received the compounds by intravenous (3 mg/kg body weight) or oral (50 mg/kg body weight) route. Parent compounds and their N-demethyl and N-deacetyl metabolites were assayed at serial times in blood. Half-life of elimination of diltiazem was significantly shorter than that of LR-A/113, both after oral (37 +/- 9 vs 59 +/- 26 min) and intravenous (29 +/- 12 vs 57 +/- 16 min) administration. N-deacetyl-diltiazem concentrations after oral administration were higher than the parent compound and N-demethyldiltiazem; LR-A/113 blood concentrations were higher than those of its two metabolites. Metabolites were measurable only in traces after intravenous administration. Oral bioavailability was very low, 3.5% for diltiazem and 4.2% for LR-A/113. In conclusion, the substitution of a methyl by an isopropyl group appears to slow in vivo elimination of the analogue of diltiazem, LR-A/113.
Bernasconi
R
R
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Caliari
S
S
Latini
R
R
Leopaldi
D
D
Porzio
S
S
Salimbeni
A
A
D000818:Animals; D003243:Consciousness; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006207:Half-Life; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
C085176:siratiazem; D004110:Diltiazem