The metabolic disposition of an orally active pyridyl thiadiazinone cardiotonic agent (MPTD) in rat and baboon.
1. Oral absorption and bioavailability of the orally active cardiotonic agent, (6RS)-6-methyl-5-(pyrid-4-yl)-3H,6H-1,3,4-[6-14C]thiadiaz in-2-one (MPTD) (5 mg/kg), in rat and baboon were high. Peak blood concentrations of MPTD and total radioactivity were reached by 1.5-4 h when MPTD accounted for 60-70% of total radioactivity. In both species, elimination of MPTD from blood was rapid (t 1/2 = 3-4 h), although total nonspecific radioactivity was eliminated more slowly. 2. Radioactivity was rapidly eliminated by both species mainly into urine. In rat, about 3% dose was collected as 14CO2 and 2% remained in the carcass after 4 days. Recovery from baboon was incomplete (78-86%). 3. Examination of urine indicated extensive metabolism of MPTD showing a marked species difference. In baboon, MPTD was metabolized largely by glucuronidation at the pyridyl nitrogen to yield a quaternary ammonium conjugate and only about 1% of the dose was excreted unchanged. In rat, the major urinary component was unchanged MPTD and no glucuronide conjugate was found. Both species formed the pyridine N-oxide of MPTD as well as a number of unidentified minor components. 4. Distribution of radioactivity in rat was rapid and extensive. In general, elimination from tissues was also rapid, although radioactivity was eliminated much more slowly from the nasal and bronchiolar epithelium and from the preputial gland.
McKillop
D
D
Safety of Medicines Department, ICI Pharmaceuticals, macclesfield, Cheshire, UK.
Pickup
K J
KJ
Swaisland
A J
AJ
Holmes
B F
BF
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D008297:Male; D010215:Papio; D011725:Pyridines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D013045:Species Specificity; D013829:Thiadiazines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D013843:Thiazines / Q000378:metabolism*; D014018:Tissue Distribution; D015262:Xenobiotics / Q000378:metabolism
D002316:Cardiotonic Agents; D011725:Pyridines; D013829:Thiadiazines; D013843:Thiazines; D015262:Xenobiotics; C060733:ICI 170777