Distribution to and elimination from tissues following a single or repeated administration of 14C-(+-)-3-(benzyl-methylamino)-2,2-dimethylpropyl methyl 4-(2-fluoro-5-nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedica rbo xylate hydrochloride in rats.
A newly synthesized calcium antagonist, TC-81((+-)-3-benzylmethylamino)-2,2-dimethylpropyl methyl-4-(2-fluoro-5-nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5- pyridinedicarboxylate hydrochloride, CAS 96515-74-1) was administered to adult male rats, pregnant and lactating rats with a single oral dose or with repeated doses of 0.3 mg/kg for 2 weeks. The distribution to tissues, placental transfer and secretion of the radioactive drug into milk was studied using whole body autoradiography methods and quantitative determination of total radioactivity after autopsy. 14C-TC-81 was distributed rapidly but disproportionately to the tissues after single administration. The highest concentration of radioactivity was observed in the liver. The radioactivity in the various tissues declined slowly comparing to the plasma but at 96 h after dosing the radioactivity was detected only in the liver. The radioactivity penetrated the blood-placental barrier to a low extent after oral administration of 14C-TC-81 to pregnant rats. When 14C-TC-81 was administered to lactating rats, the radioactivity was secreted into the milk with the maximum concentration of radioactivity, 86% of the corresponding plasma concentration. Following 14-day oral treatments of male rats the equivalent concentration in the plasma was increased 1.5 fold as compared to the single treatment. In all tissues, the AUC0-24 h after 1, 7, and 14 days treatment were gradually increased, but these increases were almost the same as or even less than the rise observed in the plasma. After the last dosing, the radioactivity declined slowly with time in most of the tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
Matsunaga
T
T
Pharmacological Research Department, 2nd Bio-Medical Research Laboratories, Teijin Limited, Tokyo, Japan.
Tanabe
H
H
Mochizuki
T
T
Okabe
K
K
Ishii
S
S
Sato
J
J
Kiyoki
M
M
Takeshita
T
T
D000818:Animals; D001345:Autoradiography; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004095:Dihydropyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D008297:Male; D008892:Milk / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C074351:TC 81