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)
Dow
J
J
Department of Clinical Biochemistry and Drug Metabolism, Marion Merrell Dow, Strasbourg, France.
Petty
M A
MA
Grisar
J M
JM
Wagner
E R
ER
Haegele
K D
KD
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