Pharmacokinetics and metabolism of the methyl-branched fatty acid (BMIPP) in animals and humans

The aim of this study was to further characterize the major metabolite of 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP). Methods: Radioactive components of 131 I-BMIPP were evaluated in Langendorff-perfused rat hearts, as well as in blood samples from 20 patients after injection of 123 I-BMIPP. Rat hearts were perfused with pH 7.4 Krebs-Henseleit buffer with or without 0.4 mmol/L bovine serum albumin (BSA) or 0.4 mmol/L palmitate. Lipids were Folch extracted and hydrolyzed from samples of the outflow, as well as from homogenized hearts. Radioactive components were determined by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) analyses. The major metabolite of BMIPP was then further characterized by electrospray mass spectrometry. Results: The rat heart perfusate showed one major polar metabolite observed by TLC (R f = 0.35; solvent = benzene-dioxane-acetic acid 80:18:2). The addition of BAS/palmitate to the perfusate buffer significantly increased backdiffusion of BMIPP (R f = 0.55), as well as reduced BMIPP uptake and metabolism. The major metabolite was identified by mass spectral analysis as 2-(p-iodophenyl)acetic acid (IPC 2 ). From TLC and HPLC analyses of the serum lipids obtained from patients, the same metabolite could be identified with levels increasing over time (0%, 5.2% and 11.8% of the injected dose; 3 min, 20 min and 3 h postinjection, respectively). In addition to the identification of unmetabolized BMIPP (53.9%), the rat heart lipid hydrolysate also contained α-methyl-14-(p-iodophenyl)tetradecanoic acid (20.8%), 12-(p-iodophenyl)-substituted-dodecanoic (17.1%), -hexanoic acid (5.2%) and IPC 2 (1.1%). Conclusion: The animal results show the complexity of uptake, metabolism and release of BMIPP from which a part is metabolized through α- and subsequent β-oxidation to the final IPC 2 metabolite as confirmed by mass spectral analysis. The results from patient studies suggest that the slow myocardial washout observed in vivo after intravenous administration of BMIPP may represent a similar process, because both unmetabolized BMIPP and the final metabolite were also identified in serum samples.