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Human Aqueous Humor Concentrations of Bimatoprost and Bimatoprost Free Acid Following Topical Ocular Dosing of Lumigan (Bimatoprost (17–Phenyl–Trinor–PGF₂) 0.03% Ophthalmic Solution)

¹ Pharmacokinetics, Alcon Research Ltd, Fort Worth, TX
² Glaucoma Consultants of Colorado PC, Littleton, CO
³ Wills Eye Hospital, Philadelphia, PA
⁴ Sall Eye Research Medical Center, Bellflower, CA
⁵ Dept of Ophthalmology, UT Southwestern Medical Center at Dallas, Dallas, TX
⁶ Alta Analytical Laboratory Inc, El Dorado Hills, CA

Commercial Relationships: D.C. Dahlin, Alcon Res E; E.R. Craven, Alcon Res F; M. Moster, Alcon Res F; K. Sall, Alcon Res F; J.T. Whitson, Alcon Res F; R. Betham, Alcon Res F; M. Curtis, Alcon Res E; R. Faulkner, Alcon Res E; S. Orr, Alcon Res E.

Grant Identification: none

Abstract

Purpose: To measure the concentrations of bimatoprost (B) and bimatoprost free acid (BFA) (17–phenyl–trinor–PGF₂ ) in the aqueous humor (AH) following bilateral topical ocular administration of Lumigan® once daily for at least 21 days prior to cataract surgery. Methods: In an open–label, multiple–dose study, 26 glaucoma patients with cataracts were randomized to receive Lumigan bilaterally once daily in the morning for 21 days prior to cataract surgery, and 0.5, 1, 2 or 3 hrs prior to AH sampling on the morning of surgery. At the time of surgery approximately 0.15 mL of AH was collected using a tuberculin syringe and immediately placed in a storage container on dry ice. The samples were stored at –70°. Samples were assayed by an independent bioanalytical laboratory using a validated LC–MS/MS method. The lower limit of quantitation was 0.20 ng/mL for both B and BFA. The mean AH concentrations of B and BFA were determined using at least 5 values at each time point. The chemical structure of BFA in the sampled AH was confirmed based on the intensity ratios of 5 select fragment ions relative to a 6th intense fragment ion (ratios ± 10%) between samples and an authentic standard. Results: AH levels of BFA were quantifiable in all samples at all time points. The mean (± SD) C_max of BFA was 35.5 ± 42.2 nM (12.0 ± 14.3 ng/mL) and was reached at 2 hrs post–dose. Mean concentrations of B were lower than BFA at all time points, and peaked at 1 hr post–dose at 8.90 ± 4.18 nM (3.01 ± 1.41 ng/mL). Conclusions: BFA (17–phenyl–trinor–PGF ₂ is present in the AH from patients dosed with Lumigan. The concentration is sufficient to activate human ciliary muscle and trabecular meshwork FP prostanoid receptors^7,8 and to account for the IOP lowering effect of Lumigan. ⁷Sharif, NA et al, Human ciliary muscle responses to FP–class prostaglandin analogs: phosphoinositide hydrolysis, intracellular Ca²⁺ mobilization and MAP kinase activation. J. Oc Pharm & Ther 19:437–455 (2003). ⁸Sharif, NA et al. Ocular hypotensive FP prostaglandin (PG) analogs: PG receptor subtype binding affinities and selectivities, and agonist potencies at FP and other PG receptors in cultured cells. J. Oc Pharm & Ther (in press).

Keywords: pharmacology • anterior chamber • aqueous

© 2004, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. For permission to reproduce any part of this abstract, contact the ARVO Office at arvo{at}arvo.org.