Pharmacokinetics and metabolism of a 4'-methylthio derivative of propranolol in the dog.
The purpose of this study was to examine the effect of a methylthio substituent in the metabolically most active position of propranolol, i.e. the 4'-position, on the pharmacokinetics and metabolism of this drug in the dog. The kinetics of 4'-methylthiopropranolol (MTP) were compared to those of propranolol following simultaneous iv doses of labeled drug and oral doses of unlabeled drug. MTP had a significantly larger volume of distribution and a longer half-life, and demonstrated a greater accumulation by red blood cells and cardiac conductile tissue than propranolol, effects which presumably are due to a higher lipophilicity of MTP. The greatest effect was on the oral clearance, which was substantially lower for MTP (1.6 vs. 5.5 liters/min) with an associated higher bioavailability (23.1 vs. 10.9%). Studies of MTP metabolism using radiolabeled drug showed that MTP, like propranolol, was eliminated entirely by metabolism. About 70% of the urinary radioactivity was extractable into ethyl acetate at pH 9.8 and pH 2.0. The extractable metabolites were separated by HPLC and identified by GC/MS, direct probe MS, and comparison with authentic compounds. Eleven metabolites were identified as sulfoxides and, in particular, sulfones of MTP and its N-dealkylated and subsequently deaminated glycollic and lactic acid metabolites. The nonextractable urinary radioactivity (30%) was isolated by DEAE-Sephadex chromatography and identified by HPLC/MS as four glucuronic acid conjugates. In contrast to propranolol, there was no evidence of aromatic carbon oxidation for MTP. These observations suggest that the markedly decreased oral clearance of MTP compared to propranolol is due to qualitatively altered metabolism from a highly efficient aromatic carbon oxidation for propranolol to a less efficient sulfur oxidation for MTP.
Bai
S A
SA
Department of Anatomy, North Carolina State University.
Easterling
D E
DE
Wilson
M J
MJ
Walle
U K
UK
Haney
C A
CA
Peet
N P
NP
Pruett
J K
JK
Walle
T
T
D000818:Animals; D002845:Chromatography; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005243:Feces / Q000032:analysis; D005260:Female; D005965:Glucuronates / Q000652:urine; D006329:Heart Conduction System / Q000378:metabolism*; D007275:Injections, Intravenous; D008297:Male; D011433:Propranolol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011690:Purkinje Fibers / Q000187:drug effects / Q000378:metabolism*; D014556:Urine / Q000032:analysis
D005965:Glucuronates; D011433:Propranolol