Use of physicochemical calculation of pKa and CLogP to predict phospholipidosis-inducing potential: a case study with structurally related piperazines.
Several cationic amphiphilic compounds are known to induce phospholipidosis, a condition primarily characterized by excessive accumulation of phospholipids in different cell types, giving the affected cells a finely foamy appearance. Excessive storage of lamellar membranous intralysosomal inclusion bodies is the hallmark for phospholipidosis on the electron microscopic level. In case of alveolar phospholipidosis, foamy macrophages accumulate within the alveolar spaces of the lung. Based on such findings in a one-year toxicity study with gepirone in rats, we studied the molecular properties of this compound and compounds suspected of being phospholipidosis inducers by means of physicochemical calculations. Physicochemical molecular calculations of molecular weight, ClogP (partition coefficient octanol/water), logD at pH 7.4, and pKa were performed, for the cationic amphiphilic compounds chlorpromazine, amiodarone, imipramine, propranolol and fluoxetine, and for the structurally related compounds 1-phenylpiperazine (1-PHP), gepirone (and its major metabolites, 3-OH-gepirone and 1-pyrimidinylpiperazine [1-PP]), and buspirone. ClogP and calculated pKa cluster differently for the amphiphilic drugs compared to the chemical series of piperazines. In line with this analysis, lamellar inclusion bodies were found in an in vitro validation experiment in the human monoblastoid cell line U-937, incubated for 96 h at 10 microg/mL with cationic amphiphilic drugs (amiodarone, imipramine, or propranolol). No such lamellar inclusion bodies were seen for any of the compounds from the chemical series of piperazines including gepirone and its metabolites. The data presented support the use of simple physicochemical calculations of ClogP and pKa to discriminate rapidly between compounds suspected of being phospholipidosis inducers. Finally, the discriminative power of these physicochemical ClogP and pKa calculations to predict phospholipidosis-inducing potential was further validated by extension of the set of compounds.
Ploemen
Jan-Peter H T M
JP
NV Organon, Toxicology & Drug Disposition, Oss, The Netherlands. jan-peter.ploemen@organon.com
Kelder
Jan
J
Hafmans
Theo
T
van de Sandt
Han
H
van Burgsteden
Johan A
JA
Saleminki
Paul J M
PJ
van Esch
Eric
E
D000284:Administration, Oral; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004032:Diet; D004305:Dose-Response Relationship, Drug; D005260:Female; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008064:Lipidoses / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010743:Phospholipids / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018675:Toxicity Tests; D020298:U937 Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
D000928:Antidepressive Agents; D010743:Phospholipids; D011743:Pyrimidines; C039979:gepirone