Drugs online research references
Drug Metab Dispos. 1988 May-Jun;16(3):392-6.
Differential renal handling of angiotensin-converting enzyme inhibitors enalaprilat and lisinopril in rats.
Lin JH, Chen IW, Ulm EH, Duggan DE.
Department of Drug Metabolism, Merck Sharp and Dohme Research Laboratories, West Point, PA 19486.
Enalaprilat, the active metabolite of enalapril, and its lysine analogue lisinopril are potent nonsulfhydryl angiotensin-converting enzyme inhibitors. Earlier studies from our laboratories demonstrated that neither drug is significantly metabolized, and both are almost exclusively eliminated by renal excretion. This report compares the renal excretory mechanisms for these structurally related compounds in the rat. After an iv, 1-mg/kg dose, ratios of renal clearance (CLR) of unbound drug to glomerular filtration rate (GFR) for enalaprilat and lisinopril were 2.72 +/- 0.70 and 1.01 +/- 0.18, respectively, suggesting that enalaprilat, but not lisinopril, was actively secreted by the kidneys. Treatment with probenecid and p-aminohippuric acid, potent competitive inhibitors for the renal anionic transport system, caused a profound decrease in the renal clearance of enalaprilat to the level of GFR. The CLR/fu.GFR, where fu is the unbound fraction, became 1.10 +/- 0.09 and 1.25 +/- 0.25, respectively. These results and the fact that quinine, a potent inhibitor for the cationic transport system, had little effect on the renal clearance of enalaprilat indicated that enalaprilat is secreted by the organic anion transport system. On the other hand, probenecid, p-aminohippuric acid, and quinine had no effect on the renal clearance of lisinopril, suggesting that lisinopril is eliminated exclusively by glomerular filtration.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2900730&dopt=Abstract
word match zestril online literature
J Biol Chem. 1985 Mar 10;260(5):2952-62.
Inhibition of rabbit lung angiotensin-converting enzyme by N alpha-[(S)-1-carboxy-3-phenylpropyl]L-alanyl-L-proline and N alpha-[(S)-1-carboxy-3-phenylpropyl]L-lysyl-L-proline.
Bull HG, Thornberry NA, Cordes MH, Patchett AA, Cordes EH.
Two novel peptide analogs, N alpha-[(S)-1-carboxy-3-phenylpropyl]L-alanyl-L-proline and the corresponding L-lysyl-L-proline derivative, have been demonstrated to be potent competitive inhibitors of purified rabbit lung angiotensin-converting enzyme: Ki = 2 and 1 X 10(-10) M, respectively, at pH 7.5, 25 degrees C, and 0.3 M chloride ion. Second-order rate constants for addition of these inhibitors to enzyme under the same conditions are in the range 1-2 X 10(6) M-1 s-1; first-order rate constants for dissociation of the EI complexes are in the range 1-4 X 10(-4) s-1. The association rate constants are similar to those measured for D-3-mercapto-2-methylpropanoyl-L-proline, captopril, but the dissociation rate constants are severalfold slower and account for the higher affinity of these inhibitors for the enzyme. The dissociation constant for the EI complex containing N alpha-[(S)-1-carboxy-3-phenylpropyl]L-alanyl-L-proline is pH-dependent, and reaches a minimum at approximately pH 6: Ki = 4 +/- 1 X 10(-11) M. The pH dependence is consistent either with a model for which the protonation state of the secondary nitrogen atom in the inhibitor determines binding affinity, or one for which ionizations on the enzyme alone influence affinity for these inhibitors. The affinity of this inhibitor for the zinc-free apoenzyme is 2 X 10(4) times less than for the zinc-free apoenzyme is 2 X 10(4) times less than that for the holoenzyme. If considered as a "collected product" inhibitor, N alpha-[(S)-1-carboxy-3-phenylpropyl]L-alanyl-L-proline appears to derive an additional factor of 375 M in its affinity for the enzyme compared to that of the two products of its hypothetical hydrolysis, a consequence of favorable entropy effects.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2982845&dopt=Abstract
word match zestril online literature
J Biol Chem. 1985 Mar 10;260(5):2963-72.
Purification of angiotensin-converting enzyme from rabbit lung and human plasma by affinity chromatography.
Bull HG, Thornberry NA, Cordes EH.
Lisinopril (N alpha-[(S)-1-carboxy-3-phenylpropyl]L-lysyl-L-proline), a potent angiotensin-converting enzyme inhibitor, is an exceptionally selective affinity chromatography ligand for this enzyme. Affinity chromatography furnishes electrophoretically homogeneous enzyme directly from crude homogenates of rabbit lung tissue, a 1,000-fold purification; also, it affords a 100,000-fold enrichment of the more rare human plasma enzyme in a single step. The affinity of angiotensin-converting enzyme for the Sepharose-spacer-lisinopril matrix (Ki matrix = 1 X 10(-5) M) is weak compared to its affinity for free lisinopril (Ki = 1 X 10(-10) M). The capacity of the affinity column is described quantitatively as a function of Ki matrix, lisinopril, and enzyme concentrations. The recovery of bound enzyme is low in chromatography of crude tissue samples (10-40%), although it approaches a reversible process (70-100%) with pure enzyme. The holoenzyme is converted to Zn2+-free apoenzyme to effect removal of lisinopril. In this process, the rate constant for spontaneous dissociation of Zn2+ from free enzyme is 1 X 10(-2) s-1 (t 1/2 = 1 min), which places a lower limit of 3 X 10(-10) M on the dissociation constant of Zn2+ at neutral pH from angiotensin-converting enzyme. The exceptional selectivity of lisinopril as an affinity chromatography ligand for angiotensin-converting enzyme suggests it is among the most specific inhibitors designed for any enzyme.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2982846&dopt=Abstract
word match zestril online literature
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