F A Fitzpatrick — Page 8

PubMedDate not supplied

In vivo disposition of prostaglandin E1 via pharmacokinetic characterization of its pulmonary metabolite.

Prostaglandin E1 (PGE1) was administered intravenously to conscious beagles and the plasma concentrations of its pulmonary metabolite 13,14-dihydro-15-keto-PGE1 were quantitated at various times after dosing. Pharmacokinetic parameters were calculated for four experimental designs including single-dose bolus injections (30, 10, and 3 micrograms PGE1/kg): single-dose, 4-h continuous infusions (20 and 320 ng/kg/min): multiple-dose continuous infusions (5, 20, 80, and 320 ng/kg/min); and single-dose, 30-day chronic infusions (100 ng/kg/min). 13,14-Dihydro-15-keto-PGE1 plasma concentrations were proportional to the dose in all experiments and they declined biexponentially with a terminal half-life ranging from 25 to 34 min. Typical clearance values were 10-14 ml/kg/min. Pharmacokinetic characterization of 13,14-dihydro-15-keto-PGE1 provides a useful index to monitor, indirectly, the in vivo disposition of PGE1 under clinically and toxicologically relevant circumstances. The factors that prevent accurate or meaningful measurement of intact drug, namely instantaneous and comprehensive pulmonary metabolism, contribute to and simplify the measurement and pharmacokinetic characterization of 13,14-dihydro-15-keto-PGE1.

Alprostadil↗

PubMedDate not supplied

Receptor antagonism of leukotriene B4 myotropic activity by the 2,6 disubstituted pyridine analog U-75302: characterization on lung parenchyma strips.

Leukotriene B4 constricts guinea pig lung parenchyma strips in a concentration-dependent manner. The LTB4 structural analog U-75302, 6-(6-[3-hydroxy-1E,5 Z-undecadienyl]-2-pyridinyl)-1,5-hexanediol, was a partial agonist in this system with a potency 300-1000 times less than LTB4. U-75302 constricted lung parenchyma strips only at concentrations greater than 0.3 microM. At concentrations lacking agonist activity U-75302 was an effective antagonist, displacing the LTB4 dose-response curve. Half-maximal responses required 0.10 microM LTB4 in the presence of 0.3 microM U-75302 and 0.01-0.02 microM LTB4 in its absence. The maximal force of contraction was unaffected at this concentration. Concurrent with antagonism of the myotropic response, U-75302 inhibited the LTB4-dependent release of thromboxane B2 from lung parenchyma. This effect was attributable to receptor antagonism, not enzymatic inhibition of phospholipase, cyclooxygenase, or thromboxane synthase. For instance, 0.3 microM U-75302 did not inhibit thromboxane B2 formation by lung parenchyma stimulated with calcium ionophore A23187 and it did not inhibit thromboxane B2 formation by human platelets stimulated with arachidonic acid. U-75302 selectively antagonized the activity of LTB4 and not other myotropic agonists including the thromboxane A2 mimetic U-46619, LTC4, LTD4, AGEPC, PGF2 alpha, and histamine. Receptor antagonists of leukotriene B4 may have multiple beneficial effects on asthmatic or respiratory disorders. These include (i) direct antagonism of LTB4 myotropic actions; (ii) antagonism of LTB4-dependent mediator release; and (iii) antagonism of LTB4 chemotactic action associated with leukocyte infiltration during anaphylactic late phase reactions.

Animals↗