Indacrinone (MK196)
(Synonyms: 茚达立酮; MK-196; Indacrynic acid) 目录号 : GC31582
Indacrinone (MK196) (MK196) 是一种研究性利尿剂，在大鼠和狗中具有明显的利尿作用，在黑猩猩中也具有排尿酸和利尿作用。
Cas No.:56049-88-8
Sample solution is provided at 25 µL, 10mM.
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Animal experiment: | Sixteen mice are administered Indacrinone-14C. Four mice, 2 male and 2 female, are dosed orally with 10 mg/kg of drug and four additional mice (2M, 2F) are given the drug i.v. via the tail vein. In similar fashion eight additional mice are dosed with 1 mg/kg Indacrinone-14C either orally or intravenously.The animals are housed in separate metabolism cages, 2 mice of same sex per cage.The animals are fasted overnight prior to drug administration. Urine and feces are collected for the 24-hour period post drug. Animals are allowed free access to water. Urine specimens are also obtained from mice which receive Indacrinone orally at doses of 10 and 20 mg/kg/day for 9 days. On day 9 the mice are dosed and placed in metabolism cages; two cages are used per sex per group. Urine is collected during the five-hour period post last dose. A total of nineteen mice are dosed with 10 mg/kg and 18 mice are dosed with 20 mg/kg of drug[1]. |
References: [1]. A.G. ZACCHEI, et al. THE PHYSIOLOGICAL DISPOSITION | |
Indacrinone (MK196) is an investigational diuretic which has pronounced saluretic activity in the rat and dog as well as both uricosuric and saluretic activity in the chimpanzee.
As the dose increasing from 1 to 10 mg/kg, the amount excreted via the urine decreased from 20 to 11% of administered dose. The amount excretes via the feces is 2-fold higher at the lower dose. At the 10 mg/kg dose the Indacrinone (MK-196)/1 ratio is 0.8 and 5 for the urine and feces, respectively. The urinary ratio of Indacrinone/1 decrease as dose increasing from 10 mg/kg (0.5) to 20 mg/kg (0.2)[1].
[1]. A.G. ZACCHEI, et al. THE PHYSIOLOGICAL DISPOSITION
| Cas No. | 56049-88-8 | SDF | |
| 别名 | 茚达立酮; MK-196; Indacrynic acid | ||
| Canonical SMILES | O=C(O)COC1=CC2=C(C(C(C3=CC=CC=C3)(C)C2)=O)C(Cl)=C1Cl | ||
| 分子式 | C18H14Cl2O4 | 分子量 | 365.21 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.7382 mL | 13.6908 mL | 27.3815 mL |
| 5 mM | 0.5476 mL | 2.7382 mL | 5.4763 mL |
| 10 mM | 0.2738 mL | 1.3691 mL | 2.7382 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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2.
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Studies on the mechanism and characteristics of action of a uricosuric diuretic, indacrinone (MK-196)
1 The renal action of indacrinone (MK-196), a phenoxyacetic acid derivative with diuretic and uricosuric properties, has been studied in fifteen male subjects. 2 Increasing single doses of up to 60 mg of oral indacrinone produced a linear increase in urinary volume and excretion of Na+ and Cl-, whilst the responses of urinary K+, Ca2+, Mg2+ and uric acid excretion, rose to a plateau at the 40 mg dose. 3 Indacrinone evoked a rapid diuretic response which reached a maximum of 2-4 h and was largely complete at 8-12 h after administration. 4 During maximal hydration, indacrinone produced a substantial fall in fractional free water clearance (CH2O), from 8.89% to 5.83% of the filtered load of water, associated with an increase in osmolal clearance, from 1.38% to 5.78% of the filtered load of solute. The reduction in CH2O was of the same order as that produced by a dose of ethacrynic acid with comparable saluretic activity and significantly greater than that produced by an equi-saluretic dose of hydrochlorothiazide. These findings imply an action of indacrinone upon solute transport in the diluting segments of the distal tubule. 5 At the time of maximal indacrinone-induced saluresis, which amounted to an increase from 0.48% to 4.61% of the filtered load of NaCl, fractional urate clearance increased from 5.16% to 12.24% of the filtered load of uric acid. 6 Indacrinone is a long acting diuretic, sharing some properties in common with both loop diuretics and benzothiadiazines. The results are discussed in relation to structure-activity amongst derivatives of phenoxyacetic acid.
Ototoxicity of indacrinone is stereospecific
Indacrinone (MK-196) is a loop diuretic which consists of a racemic mixture. The purpose of this study was to evaluate the individual enantiomers in the chinchilla model to determine whether these compounds affect auditory function and whether a difference in ototoxic potency exists. Very little change of endocochlear potential (EP) or compound action potential (CAP) was noted in animals receiving the (+)-enantiomer. On the other hand, chinchillas injected with the (-)-enantiomer were found to have a dose related reduction in both CAP and EP. These findings suggest the possibility that the diuretic receptor in the kidney and the receptor mediating ototoxicity in the cochlea, may have similar steric requirements for interacting with loop diuretics.
Stereo-specificity of diuretic receptors in the nephron: a study of the enantiomers of indacrinone (MK-196) in man
Urinary clearance techniques have been employed to compare the renal sites of action of three phenoxyacetic acid diuretics in man: ethacrynic (etacrynic) acid and the two enantiomers of indacrinone (MK-196). The effects of these compounds on fractional free-water clearance and reabsorption during maximal hydration and hydropenia, respectively, indicate that whilst ethacrynic acid and (-)-indacrinone have their natriuretic site of action in the medullary portion of the thick ascending limb of Henle's Loop, the (+)-enantiomer of indacrinone acts in the 'cortical diluting segment' or early distal tubule. The natriuretic potencies of all three agents are different as is their effect on the renal handling of uric acid. Ethacrynic acid produces minor urate retention whilst both enantiomers of indacrinone produce uricosuria and hypouricaemia. The apparent difference in the renal sites of action of the enantiomers of indacrinone is discussed in relation to our current knowledge of stereo-selectivity in other pharmacological systems.
Opposite effects of indacrinone (MK-196) on sodium and chloride conductance of amphibian skin
Indacrinone, a drug chemically related to ethacrynic acid, usually stimulated reversibly short circuit current and sodium influx when applied to the epithelial surface of amphibian skin. Concomitantly, transepithelial conductance, gt, decreased, provided chloride was the main anion in the incubation fluid. Electrophysiological analysis including microelectrode impalement indicated that the drug increased the sodium-conductance at the apical border of the impaled (most likely granular) cells. The decrease in gt thus points at shunt conductance being reduced with indacrinone, sometimes drastically. Decrease of transepithelial chloride flux with the drug as well as lack of effect of the drug on gt in the absence of chloride on the epithelial side demonstrate the influence of indacrinone on a chloride specific pathway. Whether this is along a paracellular route or through a cellular compartment not coupled to granular cells (mitochondria-rich cells?) cannot be decided on the basis of the present data.
Membrane potential, anion and cation conductances in Ehrlich ascites tumor cells
The fluorescence intensity of the dye 1,1'-dipropylox-adicarbocyanine (DiOC3-(5] has been measured in suspensions of Ehrlich ascites tumor cells in an attempt to monitor their membrane potential (Vm) under different ionic conditions, after treatment with cation ionophores and after hypotonic cell swelling. Calibration is performed with gramicidin in Na+-free K-/choline-media, i.e., standard medium in which NaCl is replaced by KCl and cholineCl and where the sum of potassium and choline is kept constant at 155 mM. Calibration by the valinomycin "null point" procedure described by Laris et al. (Laris, P.C., Pershadsingh, A., Johnstone, R.M., 1976, Biochim, Biophys. Acta 436:475-488) is shown to be valid only in the presence of the Cl- -channel blocker indacrinone (MK196). Distribution of the lipophilic anion SCN- as an indirect estimation of the membrane potential is found not to be applicable for the fast changes in Vm reported in this paper. Incubation with DiOC3-(5) for 5 min is demonstrated to reduce the Cl permeability by 26 +/- 5% and the NO3- permeability by 15 +/- 2%, while no significant effect of the probe could be demonstrated on the K+ permeability. Values for Vm, corrected for the inhibitory effect of the dye on the anion conductance, are estimated at -61 +/- 1 mV in isotonic standard NaCl medium, -78 +/- 3 mV in isotonic Na+-free choline medium and -46 +/- 1 mV in isotonic NaNO3 medium. The cell membrane is depolarized by addition of the K+ channel inhibitor quinine and it is hyperpolarized when the cells are suspended in Na+-free choline medium, indicating that Vm is generated partly by potassium and partly by sodium diffusion. Ehrlich cells have previously been shown to be more permeable to nitrate than to chloride. Substituting NO3- for all cellular and extracellular Cl- leads to a depolarization of the membrane, demonstrating that Vm is also generated by the anions and that anions are above equilibrium. Taking the previously demonstrated single-file behavior of the K+ channels into consideration, the membrane conductances in Ehrlich cells are estimated at 10.4 microS/cm2 for K+, 3.0 microS/cm2 for Na+, 0.6 microS/cm2 for Cl- and 8.7 microS/cm2 for NO3-. Addition of the Ca2+-ionophore A23187 results in net loss of KCl and a hyperpolarization of the membrane, indicating that the K+ permeability exceeds the Cl- permeability also after the addition of A23187. The K+ and Cl- conductances in A23187-treated Ehrlich cells are estimated at 134 and 30 microS/cm2, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)