2005-06-01·Journal of Clinical Pharmacology3区 · 医学
The effect of ketoconazole on the pharmacokinetics of a selective α1A-adrenoceptor antagonist
3区 · 医学
作者: Winchell, Gregory A. ; Mistry, Goutam C. ; Kari, Prasad P. ; Marbury, Thomas ; Miller, Jutta L. ; Simpson, Richard C. ; Rodrigues, A. David ; Gottesdiener, Keith M. ; Wagner, John A.
The effect of a clin. relevant dosing regimen of ketoconazole on the single-dose pharmacokinetics of L-771,688, a potent and highly selective α1A-adrenoceptor antagonist was studied. Plasma concentrations of L-771,688 were significantly higher when a single-dose of L-771,688 was administered during a multiple-dose regimen of ketoconazole. The terminal half-life of L-771,688 was only moderately longer in the presence of ketoconazole. The moderate change in half-life is consistent with the prediction that metabolic clearance would be limited by liver blood even in the presence of substantial inhibition. Qual., the results suggest that ketoconazole primarily affected the first-pass elimination, and therefore bioavailability, of L-771,688 and had only a minor effect on the systemic clearance of L-771,688. The magnitude of the interaction implies that the bioavailability of L-771,688 in humans is well below 5% in the absence of ketoconazole.
2000-12-15·European Journal of Pharmacology3区 · 医学
In vitro studies on L-771,688 (SNAP 6383), a new potent and selective α1A-adrenoceptor antagonist
3区 · 医学
作者: Chang, R. S. L. ; Chen, T.-B. ; O'Malley, S. S. ; Pettibone, D. J. ; DiSalvo, J. ; Francis, B. ; Bock, M. G. ; Freidinger, R. ; Nagarathnam, D. ; Miao, S. W. ; Shen, Q. ; Lagu, B. ; Murali Dhar, T. G. ; Tyagarajan, S. ; Marzabadi, M. R. ; Wong, W. C. ; Gluchowski, C. ; Forray, C.
L-771,688 (SNAP 6383, methyl(4S)-4-(3, 4-difluorophenyl)-6-[(methyloxy)methyl]-2-oxo-3-[(¿3-[4-(2-pyridin yl)-1-piperidinyl]propyl¿amino)carbonyl]-1,2,3, 4-tetrahydro-5-pyrimidine carboxylate) had high affinity (Ki less than or = 1 nM) for [3H]prazosin binding to cloned human, rat and dog alpha1A-adrenoceptors and high selectivity (>500-fold) over alpha1B and alpha1D-adrenoceptors. [3H]Prazosin / (+/-)-beta-[125I]-4-hydroxy-phenyl)-ethyl-aminomethylteralone ([125I]HEAT) binding studies in human and animal tissues known to contain alpha1A and non-alpha1A-adrenoceptors further demonstrated the potency and alpha1A-subtype selectivity of L-771,688. [3H]L-771,688 binding studies at the cloned human alpha1A-adrenoceptors and in rat tissues indicated that specific [3H]L-771,688 binding was saturable and of high affinity (Kd=43-90 pM) and represented binding to the pharmacologically relevant alpha1A-adrenoceptors. L-771,688 antagonized norepinephrine-induced inositol-phosphate responses in cloned human alpha1A-adrenoceptors, as well as phenylephrine or A-61603 (N-[5-4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7, 8-terahydro-naphthlen-1-yl] methanesulfonamide hydrobromide) induced contraction in isolated rat, dog and human prostate, human and monkey bladder neck and rat caudal artery with apparent Kb values of 0.02-0.28 nM. In contrast, the contraction of rat aorta induced by norepinephrine was resistant to L-771,688. These data indicate that L-771,688 is a highly selective alpha1A-adrenoceptor antagonist.