ABSTRACT:The pulmonary and hepatic expression and catalytic activities of phase I and II drug-metabolizing enzymes were compared using human lung and liver tissue, and lung parenchymal cells (LPCs) and cryopreserved hepatocytes. Cytochrome P450 gene expression was generally lower in lung than in liver and CYP3A4 expression in lung was negligible. Esterase gene expression was similar in lung and liver. Expression of all sulfotransferase isoforms in lung was similar to or higher than that in liver. Lung tissue expressed low levels of UGT. However, the expression of UGT2A1 in lung was higher than that in liver. There was a range of catalytic activities in LPCs, including cytochrome P450, esterase, and sulfation pathways. Phase I activities were generally less than 10% of those determined in hepatocytes. Rates of ester hydrolysis and sulfation in LPCs were similar to those in hepatocytes. When measurable, glucuronidation in LPCs was present at very low levels, reflecting the gene expression data. The metabolism of salbutamol, formoterol, and budesonide was also investigated. Production of salbutamol-4-O-sulfate and budesonide oleate was observed in LPCs from at least two of three donor preparations studied. Formoterol sulfate and low levels of formoterol glucuronide were detected in one of three donors. In general, drug-metabolizing capability of LPCs is low compared with liver, although some evidence for substantial sulfation and deesterification capacity was observed. Therefore, these data support the use of this cell-based system for the investigation of key routes of xenobiotic metabolism in human lung parenchyma.
Purpose: Two features define the future of glaucoma therapeutics: (1) greatly improved ocular hypotensive efficacy and (2) a delivery method that improves patient convenience and compliance. A highly efficacious and extraordinarily long-acting ocular hypotensive agent PGN 9856-isopropyl ester represents a potential nextgeneration anti-glaucoma drug. A new periorbital drug delivery route was also investigated. Methods: PGN 9856-isopropyl ester pharmacology was determined by employing human cells, including prostanoid receptor transfectants, and FLIPr or cellular dielectric spectroscopy technology. Intraocular pressure (IOP) was measured in conscious cynomolgus monkeys trained to accept pneumatonometry when under gentle restraint. For periorbital application, the compound was applied radially using a roller-ball device connected to a cylindrical reservoir. Pharmacokinetic data were obtained using LC/MS/MS instrumentation. Results: Single doses of PGN 9856-isopropyl ester, administered over a 0.001%-0.01% dose range, produced profound decreases in monkey IOP that persisted for at least 5 days, which was long after the drug was detectable in ocular tissues. It was not uncommon for a single eye drop to reduce IOP to the level of 4-7 mm Hg. Drug application to the periorbital dermis of ocular normotensive monkeys produced a similarly profound reduction in IOP, which was well maintained. Conclusions: PGN 9856-isopropyl ester appears to possess efficacy and duration of action properties unmatched by currently prescribed anti-glaucoma agents and by those currently undergoing clinical evaluation. In addition, application to the periorbital skin using a roller-ball device offers a more convenient method of ophthalmic drug delivery than eye drops and is noninvasive, unlike other ''dropless'' technologies.
Background and Purpose Lasmiditan is a novel selective 5‐HT1F receptor agonist, recently approved for acute treatment of migraine. 5‐HT1F receptors are widely expressed in the CNS and trigeminovascular system. Here, we have explored the therapeutic effects of 5‐HT1F receptor activation in preclinical models of migraine and cluster headache. Experimental Approach Electrical stimulation of the dura mater or the superior salivatory nucleus in anaesthetised rats evoked trigeminovascular or trigeminal–autonomic reflex activation at the level of the trigeminocervical complex. Additionally, cranial autonomic manifestations in response to trigeminal–autonomic reflex activation were measured, via anterior choroidal blood flow alterations. These responses were then challenged with lasmiditan. We explored the tissue distribution of mRNA for 5‐HT1F receptors in human post‐mortem tissue and of several 5‐HT1 receptor subtypes in specific tissue beds. Key Results Lasmiditan dose‐dependently reduced trigeminovascular activation in a preclinical model of migraine. Lasmiditan also reduced superior salivatory nucleus‐evoked activation of the trigeminal–autonomic reflex, but had no effect on cranial autonomic activation. mRNA profiling in human tissue showed expression of the 5‐HT1F receptor in several structures relevant for migraine and cluster headache. Conclusion and Implications Our data suggest that lasmiditan acts, at least in part, as an anti‐migraine agent by reducing trigeminovascular activation. Furthermore, our results highlight a clear action for lasmiditan in a preclinical model of cluster headache. Given the proven translational efficacy of this model, our data support the potential utility of lasmiditan as a therapeutic option for the acute treatment of cluster headache attacks. LINKED ARTICLES This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc
Background and PurposeProstanoid EP2 receptor agonists exhibit several activities including ocular hypotension, tocolysis and anti‐inflammatory activity. This report describes the affinity and selectivity of a structurally novel, non‐prostanoid EP2 receptor agonist, PGN‐9856, and its therapeutic potential.Experimental ApproachThe pharmacology of a series of non‐prostanoid EP2 receptor agonists was determined according to functional and radioligand binding studies, mostly using human recombinant prostanoid receptor transfectants. The selectivity of PGN‐9856, as the preferred compound, was subsequently determined by using a diverse variety of non‐prostanoid target proteins. The therapeutic potential of PGN‐9856 was addressed by determining its activity in relevant primate cell, tissue and disease models.Key ResultsPGN‐9856 was a selective and high affinity (pKi ≥ 8.3) ligand at human recombinant EP2 receptors. In addition to high affinity binding, it was a potent and full EP2 receptor agonist with a high level of selectivity at EP1, EP3, EP4, DP, FP, IP and TP receptors. In cells overexpressing human recombinant EP2 receptors, PGN‐9856 displayed a potency (pEC50≥ 8.5) and a maximal response (increase in cAMP) comparable to that of the endogenous agonist PGE2. PGN‐9856 exhibited no appreciable affinity (up 10 μM) for a range of 53 other receptors, ion channels and enzymes. Finally, PGN‐9856 exhibited tocolytic, anti‐inflammatory and long‐acting ocular hypotensive properties consistent with its potent EP2 receptor agonist properties.Conclusions and ImplicationsPGN‐9856 is a potent, selective and efficacious prostanoid EP2 receptor agonist with diverse potential therapeutic applications: tocolytic, anti‐inflammatory and notably anti‐glaucoma.
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