Objectives-(i) determine if montelukast undergoes carrier mediated uptake; (ii) classify the carrier protein(s) responsible for uptake; (iii) identify specific transporters that mediate transport of montelukast; (iv) evaluate whether variation in the gene encoding the transport protein(s) influences the pharmacokinetics and pharmacodynamics of montelukast.Methods-In vitro permeability studies of montelukast are conducted using Caco-2 cell culture, a standard model of human intestinal drug transport. In vivo plasma concentrations of montelukast in an asthmatic population are determined by HPLC, and genotyping of transport proteins is by LightTyper analysis.Results-Permeability of montelukast has an activation energy of 13.7±0.7 kcal/mol, consistent with carrier mediated transport. Permeability is saturable at high concentrations of montelukast and follows Michaelis-Menten kinetics. Permeability is subject to competition by sulfobromophthalein, estrone 3-sulfate, pravastatin, taurocholic acid, and cholic acid (p<0.05, % of control; 72±7 -86±7) and is inhibited by 5-10% citrus juice (p<0.05, maximal inhibition % of control; 31±2). An MDCKII cell line expressing OATP2B1 (coded for by the SLCO2B1 gene) displays significantly increased permeability of montelukast (p<0.05, % of control; 140±20). A nonsynonymous polymorphism in SLCO2B1, (rs12422149; SLCO2B1{NM_007256.2}:c.935G>A) associates with significantly reduced plasma concentration in subjects measured on the morning after an evening dose (p<0.025, square root mean transformed plasma concentration ± SE; c. Conclusions-Together these observations suggest that the genetics of SLCO2B1 may be an important variable in determining the pharmacokinetics and the pharmacodynamics of montelukast.

BackgroundAnti-inflammatory drug development efforts for lung disease have been hampered in part by the lack of noninvasive inflammation biomarkers and the limited ability of animal models to predict efficacy in humans. We used 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in a human model of lung inflammation to assess whether pioglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, and zileuton, a 5-lipoxygenase inhibitor, reduce lung inflammation.MethodsFor this single center, single-blind, placebo-controlled cohort study, we enrolled healthy volunteers sequentially into the following treatment cohorts (N = 6 per cohort): pioglitazone plus placebo, zileuton plus placebo, or dual placebo prior to bronchoscopic endotoxin instillation. 18F-FDG uptake pre- and post-endotoxin was quantified as the Patlak graphical analysis-determined Ki (primary outcome measure). Secondary outcome measures included the mean standard uptake value (SUVmean), post-endotoxin bronchoalveolar lavage (BAL) cell counts and differentials and blood adiponectin and urinary leukotriene E4 (LTE4) levels, determined by enzyme-linked immunosorbent assay, to verify treatment compliance. One- or two-way analysis of variance assessed for differences among cohorts in the outcome measures (expressed as mean ± standard deviation).ResultsTen females and eight males (29±6 years of age) completed all study procedures except for one volunteer who did not complete the post-endotoxin BAL. Ki and SUVmean increased in all cohorts after endotoxin instillation (Ki increased by 0.0021±0.0019, 0.0023±0.0017, and 0.0024±0.0020 and SUVmean by 0.47±0.14, 0.55±0.15, and 0.54±0.38 in placebo, pioglitazone, and zileuton cohorts, respectively, p<0.001) with no differences among treatment cohorts (p = 0.933). Adiponectin levels increased as expected with pioglitazone treatment but not urinary LTE4 levels as expected with zileuton treatment. BAL cell counts (p = 0.442) and neutrophil percentage (p = 0.773) were similar among the treatment cohorts.ConclusionsEndotoxin-induced lung inflammation in humans is not responsive to pioglitazone or zileuton, highlighting the challenge in translating anti-inflammatory drug efficacy results from murine models to humans.Trial registrationClinicalTrials.gov NCT01174056.

Although luteinizing hormone-releasing hormone (LH-RH) agonists have been administered successfully by other than systemic routes (oral, intranasal (i.n.) and vaginal), there is no evidence that inhibitory analogues may be used in any form other than injectable. In the present study, we compared the effect of two routes of administration: subcutaneous (s.c.), 0.5, 0.2 and 1 mg; and i.n., 0.2, 1 and 5 mg of an LH-RH antagonist, ORG 30276 ([N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10]-LH-RH) on gonadotropin levels in oophorectomized monkeys. One hour after s.c. administration, FSH and LH values exhibited a dose-dependent fall that lasted for up to 12 h. After s.c. administration, the maximum inhibition of serum FSH and LH was 29 and 41% (0.2 mg dose) and 41 and 58% (1 mg dose), respectively. After i.n. administration, maximum inhibition of serum FSH and LH was 19 and 40% (1 mg) and 32 and 53% (5 mg), respectively. These decreases were dose-related and lasted for up to 12 h. Analysis of the data revealed that the bioavailability of the i.n. route versus the s.c. route ranged from 16 to 26%. This high effectiveness of the i.n. route in terms of bioavailability is markedly greater than that previously reported for LH-RH agonists (1%) and is probably due to a resistance to enzymatic hydrolysis in the nasal mucosa. These results show for the first time that antagonists of LH-RH can be administered by routes other than parenteral, increasing their potential clinical use in conditions in which inhibition of gonadotropins is desired, as in contraception and in therapy for endometriosis, precocious puberty, and hormone-dependent neoplasms.