Regioisomeric aromatic dihydroxylation of propranolol. Synthesis and identification of 4,6- and 4,8-dihydroxypropranolol as metabolites in the rat and in man.
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.
D000368:Aged; D000818:Animals; D001711:Biotransformation; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007536:Isomerism; D008297:Male; D008875:Middle Aged; D011433:Propranolol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
C056309:4,8-dihydroxypropranolol; C056308:4,6-dihydroxypropranolol; D011433:Propranolol