Hydrolysis of bimatoprost (Lumigan) to its free acid by ocular tissue in vitro.
We determined whether bimatoprost, which has been reported to act via putative prostamide receptors, could be hydrolyzed to its free acid (17-phenyl-PGF(2 alpha)), a potent FP receptor agonist, by human ocular tissue in vitro. We developed a gas chromatography/mass spectrometric method to measure 17-phenyl-PGF(2 alpha) levels at sub-picomolar levels. We then analyzed the amount of 17-phenyl-PGF(2 alpha) present after incubation of 50 microl Lumigan (0.03% bimatoprost) with eye tissue using this assay. We found that cornea, sclera, iris, and ciliary body, all rapidly hydrolyzed bimatoprost to 17-phenyl-PGF(2 alpha) with linear kinetics at a rate of 6.3, 2.0, 2.8, and 1.5 pmol mg tissue(-1) hr(-1), respectively. For cornea, sclera, and ciliary body, this linear rate of hydrolysis continued over a period of at least three hours, while iris-induced hydrolysis did not continue beyond one hour. Our findings suggest that bimatoprost can act as prodrug for FP receptor activation and questions the concept of a "prostamide receptor" agonist.
Davies
Sean S
SS
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Ju
Won-Kyu
WK
Neufeld
Arthur H
AH
Abran
Daniel
D
Chemtob
Sylvain
S
Roberts
L Jackson
LJ
D000577:Amides; D000818:Animals; D000069580:Bimatoprost; D002924:Ciliary Body / Q000378:metabolism; D003008:Cloprostenol / Q000031:analogs & derivatives; D003315:Cornea / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D005123:Eye / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007498:Iris / Q000378:metabolism; D007700:Kinetics; D050356:Lipid Metabolism; D008055:Lipids; D011355:Prodrugs / Q000378:metabolism*; D012590:Sclera / Q000378:metabolism; D013552:Swine; D013997:Time Factors
D000577:Amides; D008055:Lipids; D011355:Prodrugs; D003008:Cloprostenol; C027042:17-phenylprostaglandin F2alpha; D015237:Dinoprost; D000069580:Bimatoprost