title: Hydroxylation of pentamidine by rat liver microsomes.
abstract: The antiprotozoal/antifungal drug pentamidine [1,5-bis(4-amidinophenoxy)pentane] has been recently shown to be metabolized by rat liver fractions to at least six putative metabolites as detected by high-performance liquid chromatography. Two minor metabolites have been previously identified as N-hydroxypentamidine and N,N'-dihydroxypentamidine. In this study, the two major microsomal metabolites have been identified as the 2-pentanol and 3-pentanol analogs of pentamidine [1,5-di(4-amidinophenoxy)-2-pentanol; and 1,5-bis(4-amidinophenoxy)-3-pentanol]. As well, a seventh putative metabolite has been discovered and identified as para-hydroxybenzamidine, a fragment of the original drug. Whereas the cytochromes P-450 have been demonstrated as the enzyme system responsible for pentamidine metabolism, hydroxylation of the drug was not inducible by phenobarbital, beta-naphthoflavone, clofibrate, isosafrole, pregnenolone-16 alpha-carbonitrile, ethanol or pentamidine pretreatment of rats. The kinetics of the production of the two major microsomal metabolites has been determined as Km = 56 +/- 19 microM and Vmax = 126 +/- 21 pmol/min/mg microsomal protein for the 2-pentanol analog, and Km = 28 +/- 0.28 microM and Vmax = 195 +/- 2.4 pmol/min/mg microsomal protein for the 3-pentanol analog. Therefore, the mixed-function oxidases readily convert pentamidine to hydroxylated metabolites, but exactly which isozyme(s) of cytochrome P-450 is responsible is not clear.
authors.affiliation: Department of Parasitology and Laboratory Practice, School of Public Health, University of North Carolina, Chapel Hill.
authors.forename: B J
authors.initials: BJ
authors.lastname: Berger
authors.forename: V V
authors.initials: VV
authors.lastname: Reddy
authors.forename: S T
authors.initials: ST
authors.lastname: Le
authors.forename: R J
authors.initials: RJ
authors.lastname: Lombardy
authors.forename: J E
authors.initials: JE
authors.lastname: Hall
authors.forename: R R
authors.initials: RR
authors.lastname: Tidwell
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D010419:Pentamidine / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D010419:Pentamidine; D003577:Cytochrome P-450 Enzyme System