Aerosol Pirfenidone Pharmacokinetics after Inhaled Delivery in Sheep:a Viable Approach to Treating Idiopathic Pulmonary Fibrosis

Inhaled delivery of pirfenidone to the lungs of patients with idiopathic pulmonary fibrosis holds promise to eliminate oral-observed side effects while enhancing efficacy. This study aimed to comprehensively describe the pulmonary pharmacokinetics of inhaled aerosol pirfenidone in healthy adult sheep.Pirfenidone concentrations were evaluated in plasma, lung-derived lymph and epithelial lining fluid (ELF) with data subjected to non-compartmental pharmacokinetic analysis.Compartmental pharmacokinetic evaluation indicated that a 49\ua0mg lung-deposited dose delivered an ELF Cmax of 62 ± 23\ua0mg/L, and plasma Cmax of 3.1 ± 1.7\ua0mg/L. Further analysis revealed that plasma pirfenidone reached Tmax faster and at higher concentrations than in lymph. These results suggested inhaled pirfenidone was cleared from the alveolar interstitium via blood faster than the drug could equilibrate between the lung interstitial fluid and lung lymphatics. However, the data also suggested that a 'reservoir' of pirfenidone feeds into lung lymph at later time points (after it has largely been cleared from plasma), prolonging lung lymphatic exposure.This study indicates inhaled pirfenidone efficiently deposits in ELF and is cleared from the lungs by initial absorption into plasma, followed by later equilibrium with lung interstitial and lymph fluid

Detection of multiple H(3) receptor affinity states utilizing [(3)H]A-349821, a novel, selective, non-imidazole histamine H(3) receptor inverse agonist radioligand

1. A-349821 is a selective histamine H(3) receptor antagonist/inverse agonist. Herein, binding of the novel non-imidazole H(3) receptor radioligand [(3)H]A-349821 to membranes expressing native or recombinant H(3) receptors from rat or human sources was characterized and compared with the binding of the agonist [(3)H]N-α-methylhistamine ([(3)H]NαMH). 2. [(3)H]A-349821 bound with high affinity and specificity to an apparent single class of saturable sites and recognized human H(3) receptors with 10-fold higher affinity compared to rat H(3) receptors. [(3)H]A-349821 detected larger populations of receptors compared to [(3)H]NαMH. 3. Displacement of [(3)H]A-349821 binding by H(3) receptor antagonists/inverse agonists was monophasic, suggesting recognition of a single binding site, while that of H(3) receptor agonists was biphasic, suggesting recognition of both high- and low-affinity H(3) receptor sites. 4. pK(i) values of high-affinity binding sites for H(3) receptor competitors utilizing [(3)H]A-349821 were highly correlated with pK(i) values obtained with [(3)H]NαMH, consistent with labelling of H(3) receptors by [(3)H]A-349821. 5. Unlike assays utilizing [(3)H]NαMH, addition of GDP had no effect on saturation parameters measured with [(3)H]A-349821, while displacement of [(3)H]A-349821 binding by the H(3) receptor agonist histamine was sensitive to GDP. 6. In conclusion, [(3)H]A-349821 labels interconvertible high- and low-affinity states of the H(3) receptor, and displays improved selectivity over imidazole-containing H(3) receptor antagonist radioligands. [(3)H]A-349821 competition studies showed significant differences in the proportions and potencies of high- and low-affinity sites across species, providing new information about the fundamental pharmacological nature of H(3) receptors