Metabolism of a bisphosphonate ester (PNU-91638) in rat.
1. Metabolites of the cyclic bisphosphonate ester, 4-[2,2'-bis-(5,5- dimethyl-1,3,2-dioxaphosphorinan-2-yl)] butanoyl-3-fluoro-benzene (PNU-91638) in bile or urine of the male Sprague-Dawley rat were characterized by mass spectrometry. The chronically bile duct/duodenal-cannulated male rats received a single oral dose of 100 mg/kg [13C] [14C]PNU-91638. Bile and urine samples were analysed for radioactivity and profiled by hplc with radiometric and UV detection. 2. The 0-28-h bile and urine accounted for 46.0 and 19.7% of dose respectively. The structures of radioactive peaks were investigated by ionspray and liquid secondary ion mass spectrometry (LSIMS) and LSIMS/MS analysis. 3. Major metabolites in urine included two regioisomeric phenol glucuronides, a gem methyl hydroxylated metabolite of the bisphosphonate heterocycle, a phenol metabolite, parent drug and a benzylic alcohol metabolite. Additional metabolites in bile included an unstable phenol/glutathione adduct (from a putative epoxide intermediate) with several minor isobaric regioisomers, and a carboxylic acid derived from the gem methyl hydroxylated bisphosphonate ring. 4. The structures proposed have not been confirmed by nmr due to discontinuation of the development of PNU-91638.
Slatter
J G
JG
Drug Metabolism Research, Pharmacia & Upjohn Co., Kalamazoo, MI 49007, USA.
Feenstra
K L
KL
Hauer
M J
MJ
Sanders
P E
PE
Vrbanac
J J
JJ
Scott
G
G
Speed
W
W
D000818:Animals; D018501:Antirheumatic Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D001646:Bile / Q000378:metabolism; D001659:Biliary Tract / Q000378:metabolism; D002250:Carbon Radioisotopes; D002853:Chromatography, Liquid; D004164:Diphosphonates / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D004355:Drug Stability; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D017207:Rats, Sprague-Dawley
D018501:Antirheumatic Agents; D002250:Carbon Radioisotopes; D004164:Diphosphonates; C110479:PNU 91638