The Hydrolysis of the Prostaglandin Analog Prodrug Bimatoprost to 17-Phenyl-trinor PGF_2α by Human and Rabbit Ocular Tissue

Abstract

Bimatoprost (Lumigan), the ethyl amide derivative of the potent prostaglandin FP agonist 17-phenyl-trinor PGF(2alpha), has been reported to be a member of a pharmacologically unique class of ocular hypotensive agents. To confirm that bimatoprost, which is intrinsically active as an FP prostaglandin agonist, is also a prostaglandin analog prodrug, the hydrolysis of bimatoprost by ocular tissues was studied by incubating solutions containing bimatoprost with either human or rabbit ocular tissue. The ethyl amide group of bimatoprost was hydrolyzed by rabbit and human cornea, iris/ciliary body and Thasclera to produce the expected carboxylic acid product, 17-phenyl-trinor PGF(2alpha). The rate of hydrolysis by human and rabbit cornea and iris/ciliary body is similar, whereas the rate of hydrolysis by the sclera is slower in humans than in rabbits. These studies show that human and rabbit ocular tissue (cornea, iris/ciliary body and sclera) can convert bimatoprost to the potent prostaglandin FP agonist 17-phenyl-trinor PGF(2alpha). Separate in vitro studies clearly show that both bimatoprost and 17-phenyl-trinor PGF(2alpha) have affinity for and are agonists at the human FP receptor. Taken together, the data strongly suggests that the ocular hypotensive effect of bimatoprost can be attributed to its activity as a prostaglandin receptor agonist either directly or through its role as a prostaglandin agonist prodrug.

Effects of Prostaglandin F2αon Adipocyte Biology Relevant to Graves' Orbitopathy

“…The inhibitory actions on proliferation and differentiation were obtained in the range of 10 -8 to 10 -6 M PGF 2a , and even the most concentrated is 3 orders of magnitude less than the 0.03% used in eye drops, although this is a prodrug. The prodrug, 17-phenyl trinor PGF 2a ethyl amide, needs to be converted by an amidase enzyme present in the human cornea, to the corresponding free acid, 17-phenyl trinor PGF 2a (33,34). The latter free acid compound, which we used in these experiments to negate the requirement of the amidase enzyme, is a potent FP receptor agonist but has a short half-life, as illustrated by the rapid recovery of 3T3-L1 proliferation and OF adipogenesis when the agent was withdrawn, and indicates that daily administration would be required.…”

Prodrugs—from Serendipity to Rational Design

“…The first prodrug to improve ocular absorption was the dipivalyl diester of epinephrine (adrenaline), dipivefrin (Propine; Allergan, Inc.), introduced to the market over 15 years ago to lower the intraocular pressure in glaucoma ( RATIONALE FOR PRODRUG DESIGN ivefrin penetrates the human cornea 17 times more rapidly than epinephrine and is therefore not only more effective but also has fewer systemic adverse effects (Hussain and Truelove, 1976;Kaback et al, 1976;Mandell et al, 1978;Kohn et al, 1979). Some recently marketed counterparts of dipivefrin are the prostaglandin analogs latanoprost (Xalatan; Pfizer Health AB, Stockholm, Sweden), bimatoprost (Lumigan; Allergan, Inc.), travoprost (Travatan; Alcon, Inc., Hü nenberg, Switzerland), and unoprostone isopropyl (Rescula; Sucampo AG, Zug, Switzerland) (Netland et al, 2001;Susanna et al, 2002;Hellberg et al, 2003).…”

Intraocular Pressure–Lowering Activity of NCX 470, a Novel Nitric Oxide–Donating Bimatoprost in Preclinical Models

“…22 It is known, however, that rabbits, more than higher species, rapidly hydrolyze bimatoprost to bimatoprost acid. 21 In our study, the levels of bimatoprost in rabbit AH, CR, and ICB were equally low following NCX 470 or bimatoprost dosing, making any meaningful conclusion on the contribution of this molecule in the overall IOP-lowering activity of these compounds in our experimental conditions difficult. On the other hand, the levels of bimatoprost acid were measurable and were found slightly increased in target ocular tissues of rabbits exposed to NCX 470 compared to equimolar concentrations of bimatoprost.…”

“…18,20 The IOP-lowering activity of NCX 470 depends on the concomitant release of bimatoprost and bimatoprost acid as well as of NO in target ocular tissues. Bimatoprost and bimatoprost acid (the latter being released from bimatoprost via the action of amidopepdidase 21 ) are also the active molecular species following bimatoprost treatment. 22 It is known, however, that rabbits, more than higher species, rapidly hydrolyze bimatoprost to bimatoprost acid.…”