Captopril disulfide conjugates may act as prodrugs: Disposition of the disulfide dimer of captopril in the rat

doi:10.1016/0006-2952(84)90138-2

Biochemical Pharmacology

Volume 33, Issue 22, 15 November 1984, Pages 3567-3571

https://doi.org/10.1016/0006-2952(84)90138-2 Get rights and content

Abstract

The absorption and metabolism of the disulfide dimer conjugate of captopril has been studied in the rat following both oral and intravenous dosing and compared with that of the active monomer, captopril. Metabolism of the dimer to captopril has been shown after both oral and intravenous administration of the dimer (10 mg/kg) with peak plasma levels of captopril (154 ng/ml) occurring at 1 hr post dose. By contrast the peak plasma level of captopril after oral administration of captopril (10 mg/kg) at the same dose was much higher at 678 ng/ml and also occurred at 1 hr post dose. Plasma captopril disulfide species were much higher than the plasma levels of captopril after the administration of either dimer or captopril and tended to persist for much longer than for monomeric captopril particularly after administration of the dimer. Both the dimer and its pharmacologically active product captopril were found in relatively large amounts in lung, kidney and liver following the oral administration of the dimer.

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Cited by (30)

The slow molecular mobility in amorphous captopril and captopril disulfide: A DSC and TSDC study
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Citation Excerpt :
There is also indirect evidence suggesting that the disulfide may play a role in the maintenance of the hypotensive action of captopril by acting as a pool of drug capable of reduction back to captopril. In this context, the possibility of using captopril disulfide as a means of delivering captopril as a prodrug can be considered [10]. We thus synthetized captopril disulfide and found that the amorphous solid state was readily prepared by cooling from the equilibrium melt.
The slow molecular mobility in the amorphous pharmaceutical drug captopril is studied by differential scanning calorimetry (DSC) and thermally stimulated depolarization currents (TSDC). The general kinetic features of the secondary relaxations and of the main relaxation were determined by TSDC. The dynamic fragility of captopril is obtained by DSC and TSDC, and the values compared with that obtained by dielectric relaxation spectroscopy (DRS). The local motional modes of the fast secondary relaxation were found to be slightly aging sensitive, even at temperatures lower than 100° below T_g, which was ascribed to the intermolecular hydrogen bond network that is reported to exist in the amorphous solid state of captopril. Captopril disulfide, a metabolite product of captopril, was synthetized and characterized by DSC and TSDC. Compared to captopril, it behaves as a stronger glass forming liquid.
The use of experimental design in the development of an HPLC-ECD method for the analysis of captopril
2011, Talanta
Citation Excerpt :
Hydrodynamic voltammetric (HDV) studies were used to determine the optimum working electrode potentials. CPT undergoes oxidation to form the dimer, captopril disulfide [26,27]. Amide hydrolysis has also been reported in aqueous solution [27] and it has been shown that oxidation of CPT is predominant in the pH range 2–5.6 and becomes an increasingly important consideration as the pH increases.
An accurate, sensitive and specific high performance liquid chromatography–electrochemical detection (HPLC–ECD) method that was developed and validated for captopril (CPT) is presented. Separation was achieved using a Phenomenex^® Luna 5 μm (C₁₈) column and a mobile phase comprised of phosphate buffer (adjusted to pH 3.0): acetonitrile in a ratio of 70:30 (v/v). Detection was accomplished using a full scan multi channel ESA Coulometric detector in the “oxidative-screen” mode with the upstream electrode (E₁) set at +600 mV and the downstream (analytical) electrode (E₂) set at +950 mV, while the potential of the guard cell was maintained at +1050 mV. The detector gain was set at 300. Experimental design using central composite design (CCD) was used to facilitate method development. Mobile phase pH, molarity and concentration of acetonitrile (ACN) were considered the critical factors to be studied to establish the retention time of CPT and cyclizine (CYC) that was used as the internal standard. Twenty experiments including centre points were undertaken and a quadratic model was derived for the retention time for CPT using the experimental data. The method was validated for linearity, accuracy, precision, limits of quantitation and detection, as per the ICH guidelines. The system was found to produce sharp and well-resolved peaks for CPT and CYC with retention times of 3.08 and 7.56 min, respectively. Linear regression analysis for the calibration curve showed a good linear relationship with a regression coefficient of 0.978 in the concentration range of 2–70 μg/mL. The linear regression equation was y = 0.0131x + 0.0275. The limits of detection (LOQ) and quantitation (LOD) were found to be 2.27 and 0.6 μg/mL, respectively. The method was used to analyze CPT in tablets. The wide range for linearity, accuracy, sensitivity, short retention time and composition of the mobile phase indicated that this method is better for the quantification of CPT than the pharmacopoeial methods.
Physicochemistry, pharmacokinetics, and pharmacodynamics of S- nitrosocaptopril crystals, a new nitric oxide donor
1999, Journal of Pharmaceutical Sciences
S‐nitrosocaptopril (CapNO) has been proposed as a compound possessing capacities of both a nitric oxide (NO) donor and an inhibitor of angiotensin converting enzyme (ACE). In the present study, we characterized the physicochemical, pharmacokinetic, and pharmacological properties of the crystalline CapNO. The novel stable crystals are in a red flake form. Spectroscopic analyses of CapNO revealed its UV/visible λ_max and the corresponding extinction coef‐ ficients, and characteristic infrared frequencies for the N-O and S–N stretch. The NMR signals corresponding to the protons attached to the carbon (C–S) and the carbon itself were remarkably shifted downfield upon S‐nitrosylation. Mass and HPLC analyses, solubility, and melting point of CapNO were determined. Simultaneous on‐line analyses of pharmacodynamic and pharmacokinetic profiles of CapNO in catheterized awake rats of spontaneous hypertension (SHR) showed acute decreases in mean arterial pressure (MAP), concomitant with the corresponding increases in plasma levels of CapNO after po or iv administration. The pharmacokinetic parameters for CapNO, i.e., t_1/2, T_max, C_max, V_d, AUC, and oral bioavailability were analyzed to understand the dose‐dependent potency and effective period of CapNO. The highest concentrations of oral CapNO distributed in tissues were found in kidney, liver, lung, and small intestine. CapNO was excreted predominantly via urine, and second via feces in the detectable forms of thiols and nitrogen oxide although a small portion of CapNO was found in bile. The results provide the evidence of in vivo cleavage of the S–N bond and biotransformation of CapNO.
Stability and in vitro absorption of captopril, enalapril and lisinopril across the rat intestine
1994, Biochemical Pharmacology
In vitro absorption of three angiotensin converting enzyme (ACE) inhibitors, captopril, enalapril and lisinopril, and their stabilities in aqueous buffer as well as their resistance to intestinal and dermal tissue homogenates were investigated. The results demonstrate that the spontaneous oxidation of captopril, enalapril and lisinopril followed first-order degradation kinetics in McIlvaine's citrate-phosphate buffer. The degradation rates for enalapril and lisinopril were much slower than that for captopril. With the former two ACE inhibitors, the first-order rate constants of breakdown in the presence of dermal homogenate were not significantly different from the control values. Intestinal homogenate increase the decomposition of both of these inhibitors when compared to the enzyme-free control systems. On the other hand, the first-order rates of disapperance of captopril in the presence of both dermal and intestinal homogenates were lower than in the enzyme-free system. The extent of reduction was proportional to the amount of homogenate added. This suggests that tissue homogenates prevent the oxidation of captopril to its disulphide dimer. Transport experiments show that the amounts of ACE inhibitors transferred from solution on the mucosal side increased linearly with incubation time over the 2 hr of study. The rates of transfer from the mucosal side to the serosal side had the following rank order: captopril > enalapril > lisinopril roughly in the ratio 1:1.13:1.27. Addition of harmaline caused a significant reduction in the transfer rate of captopril compared to the control system, which strongly suggests that captopril is transported by a sodium-dependent carrier-mediated process across intestinal tissue.
Nuclear magnetic resonance studies of thiol/disulfide chemistry. I. Kinetics and equilibria of the reduction of captopril disulfide and captopril-glutathione mixed disulfide by glutathione
1989, Bioorganic Chemistry
The kinetics and equilibria of the reduction of captopril disulfide (CpSSCp) and captopril-glutathione mixed disulfide (GSSCp) by glutathione (GSH) have been studied by ¹H and ¹³C NMR. Reduction takes place by thiol/disulfide exchange: . Equilibrium constants were determined as a function of pH for the two reactions; at physiological pH, the equilibrium constants for the first and second reactions are 1.46 and 0.300, respectively. The equilibrium constant for the overall reaction is 0.436, which corresponds to a difference in formal electrode potential for the two half reactions ( $E_{GSSGGSH}^{o} ′ - E_{CpSSCpCpSH}^{o} ′$ ) of 0.011 V; i.e., CpSH is more strongly reducing than GSH. Rate constants were determined as a function of pD for the forward and reverse reactions of both steps. The results indicate that, at physiological pH, the rate predicted for the in vivo reduction of CpSSCp by endogenous thiols is much slower than that oberved experimentally, which supports previous conclusions that reduction of CpSSCp to CpSH involves both enzymatic and nonenzymatic, i.e., thiol/disulfide exchange, processes.
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Captopril disulfide conjugates may act as prodrugs: Disposition of the disulfide dimer of captopril in the rat

Abstract

Am. J. Cardiol.

Biochem. Pharmac.

Biochem. Pharmac.

J. Chromatogr.

J. biol. Chem.

Biochem. Pharmac.

J. Pharm. Sci.

J. Pharmac. pharm. Sci.

Clin. pharmac. Ther.

Clin. pharmac. Ther.