RT Journal Article
SR Electronic
T1 Regioisomeric aromatic dihydroxylation of propranolol. Synthesis and identification of 4,6- and 4,8-dihydroxypropranolol as metabolites in the rat and in man.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 212
OP 216
VO 16
IS 2
A1 R E Talaat
A1 W L Nelson
YR 1988
UL http://dmd.aspetjournals.org/content/16/2/212.abstract
AB The formation of the three prominent dihydroxylated propranolol [(HO)2-P] metabolites, 4,6-, 4,8-, and 3,4-(HO)2-Ps, was investigated in vivo in rat and in man. Authentic O,O-dibenzyl ethers of 4,6- and 4,8-(HO)2-P were synthesized from the corresponding dihydroxy-l-naphthaldehydes. The l-carboxyaldehyde group was used as the latent side chain l-naphthol ether available by Baeyer-Villiger oxidation and subsequent side chain elaboration. The benzyl ethers were cleaved, and the resulting dihydroxynaphthalenes were immediately derivatized with bis-N,O-(trimethylsilyl)trifluoroacetamide. After ip administration of P-3,3-d2 (20 mg/kg) to rats, 4,6-, 5,6-, 3,7-, 3,4-, and 4,8-(HO)2-Ps were identified by GC/MS as urinary metabolites. After administering pseudoracemic propranolol [(2R)-P-d0/(2S)-P-3,3-d2] ip to rats (20 mg/kg), parent ions of the (HO)2-Ps as trimethylsilyl derivatives were monitored by GC/MS. While 4,6- and 3,4-(HO)2-P arose stereoselectively from (2S)-propranolol, 4,8-, 4,7-, and 5,6-(HO)2-P arose stereoselectively from (2R)-propranolol. About 3.3% of the dose was converted to (HO)2-Ps. Three (HO)2-Ps, 4,6-, 4,8-, and 3,4-(HO)2-P, were identified as urinary metabolites of propranolol in man after a single oral dose of 80 mg of P-3,3-d2. Less than 1% of this dose was converted to urinary (HO)2-Ps in 24 hr.