Cardioselectivity of alpha-tocopherol analogues, with free radical scavenger activity, in the rat.
MDL74270 (6-acetyloxy-3,4-dihydro-N,N,N,2,5,7, 8-heptamethyl-2H-1-benzopyran-2-ethanaminium, 4-methylbenzenesulfonate) is a quaternary amine analogue of alpha-tocopherol with free radical scavenger properties. Rats were injected iv with [14C]MDL74270 (0.91 mg/kg), and whole blood and heart tissue were sampled. Five min after drug, the heart tissue/blood ratio (T/B) of radioactivity was 3.5, whereas at 1 hr it was 20.1 and remained at this value up to at least 6 hr. After iv administration the t 1/2 of radioactivity in blood was 6.3 hr, but po blood levels could not be quantified. The 0- to 96-hr urinary elimination of radioactivity was 39.9 +/- 5.7% of the dose after iv and only 1.2 +/- 0.4% after po administration, conversely, 44.7 +/- 5.2% was excreted in feces after iv and 79.1 +/- 17.4% after po administration. These results confirmed poor oral absorption of the compound. Tissue distribution of [14C]MDL74270 was compared with that of its tertiary amine analogue [14C]MDL74366 in rat heart, skeletal muscle, brain, and whole blood, after iv administration (1 mg/kg). The heart T/B was above 20, 1-6 hr after [14C]MDL74270, whereas it was less than 2 after [14C]MDL74366. Over the 1- to 6-hr time interval, skeletal muscle T/B varied from 1.8 to 5 compared with 1.5 to 0.6 for [14C] MDL74366. Brain T/B was higher after the tertiary amine compound. Results showed marked cardioselectivity of radioactivity after [14C] MDL74270. Differential centrifugation of heart homogenates showed that radioactivity was equally distributed between the major subcellular fractions studied.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Clinical Biochemistry and Drug Metabolism, Marion Merrell Dow, Strasbourg, France.
J
J
Dow
M A
MA
Petty
J M
JM
Grisar
E R
ER
Wagner
K D
KD
Haegele
D000818:Animals; D001578:Benzopyrans / Q000097:blood / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D016166:Free Radical Scavengers; D008297:Male; D009132:Muscles / Q000378:metabolism; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution; D014810:Vitamin E / Q000031:analogs & derivatives*
D001578:Benzopyrans; D002250:Carbon Radioisotopes; D016166:Free Radical Scavengers; C064728:MDL 74270; C069478:MDL 74366; D014810:Vitamin E