Hydrolysis of digoxin by acid

Gault, M. H.; Charles, John; Sugden, David; Kepkay, David L.

doi:10.1111/j.2042-7158.1977.tb11232.x

Cited by 40 publications

(4 citation statements)

References 14 publications

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“…Our study illustrates that intragastric hydrolysis of digoxin can occur at roughly the same rate as acid hydrolysis in vitro. 12 Mean digoxin remaining 90 min after administration was 13% for all subjects given pentagastrin and mean hydrogen ion activity at 90 min was 56 mM.…”

Section: Discussionmentioning

confidence: 90%

Influence of gastric pH on digoxin biotransformation

Kalra

Ahmed

Kepkay

et al. 1980

Clin Pharmacol Ther

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3H-digoxin-12 alpha and unlabeled digoxin were administered down a nasogastric tube and digoxin, digoxyigenin and its mono- and bis-digitoxosides, and pH were assayed in gastric fluid of 6 healthy subjects at intervals for 90 min each under 4 conditions: pentagastrin infusion 6 micrograms/kg/hr with the subjects ambulatory and supine, and saline infusion ambulatory and supine. Intragastric hydrolysis occurred at roughly the same rate as reported in vitro. At 90 min, an average of 12.5% of the radioactivity that remained in the gastric fluid was recovered as digoxin for the 2 conditions when pentagastrin was infused, compared with 52.5% for th 2 conditions when saline was infused. The main glycosidic metabolite was digoxigenin and the amount correlated closely with the hydrogen ion activity in gastric fluid at 90 min (r = 0.83, p less than 0.01). Only minor differences were found between the supine and ambulatory conditions. The clinical significance of these results remains to be determined.

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Section: Discussionmentioning

confidence: 90%

Influence of gastric pH on digoxin biotransformation

Kalra

Ahmed

Kepkay

et al. 1980

Clin Pharmacol Ther

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“…2, panel B) resulted in immunoreactive fractions with identical retention times as those of the digoxin standards or the digoxin treated with the same acid. Based on the known sequential removal of sugars by acid hydrolysis (26) and the similarity in the retention times observed for the new DLIF fractions and those of the digoxin congeners (digoxigenin, mono-, and bis-digitoxosides), we named the DLIF fractions eluting at 15, 19, 23, and 25 min as DLIF-genin, DLIF-bis, DLIF-mono, and DLIF, respectively. In addition, note the additional immunoreactive DLIFs appearing in fractions corresponding to less polar products of digoxin.…”

Section: Resultsmentioning

confidence: 99%

Deglycosylated Products of Endogenous Digoxin-like Immunoreactive Factor in Mammalian Tissue

Qazzaz

Goudy

Valdes

1996

Journal of Biological Chemistry

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Digoxin-like immunoreactive factor (DLIF) from adrenal cortex is an endogenous molecule with structural features remarkably similar to those of digoxin, a plantderived cardiac glycoside (Shaikh, I. M., Lau, B. W. C., Siegfried, B. A., and Valdes, R., Jr. (1991) J. Biol. Chem. 266, 13672-13678). Two characteristic structural and functional features of digoxin are a lactone ring and three digitoxose sugars attached to a steroid nucleus. Digoxin is known to undergo deglycosylation during metabolism in humans. We now demonstrate the existence of several naturally occurring deglycosylated components of DLIF in human serum. The components are identified as DLIF-genin, DLIF-mono, and DLIF-bis, corresponding to the aglycone, and the aglycone with one and two sugars, respectively. Similar components are produced by acid-induced deglycosylation of DLIF isolated from bovine adrenal cortex. The elution pattern and sequence of DLIF-deglycosylation was identical to that of digoxin suggesting identical sugar stoichiometry. However, analysis of these newly discovered congeners by reverse-phase chromatography, spectrophotometry, antibody reactivity, and kinetics of deglycosylation, demonstrates that subtle structural and physical differences do exist when compared to digoxin. DLIF was chromatographically distinct from digoxin, and interestingly, the mobility of the DLIF-genin was shifted toward increased polarity relative to digoxigenin. DLIF and DLIF-bis, -mono, and -genin congeners have absorbance maxima at 216 nm, whereas digoxin and its congeners absorb at 220 nm. Reaction with specific antibodies directed at the lactone portion of these molecules shows DLIF and its deglycosylated congeners to be 10 3 -fold less reactive than digoxin. Kinetics of sugar removal suggests that DLIF is 8-fold more susceptible to deglycosylation than is digoxin. Two less polar DLIF components produced from the DLIF-genin have max at 196 nm and are 4-fold less immunoreactive than DLIF. Our data suggest that subtle structural differences exist between DLIF and digoxin at or near the lactone ring as well as in the nature of the sugars. The presence of deglycosylated congeners of DLIF in human serum, including the less polar components, suggests in vivo deglycosylation of these factors. This is the first demonstration of the existence of naturally occurring deglycosylated derivatives of DLIF and establishes the likelihood of active metabolism of DLIF in mammals.Endogenous digoxin-like immunoreactive factors (DLIFs)

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“…Digoxin is known to be converted metabolically to digoxigenin bis-digitoxoside, digoxigenin mono-digitoxoside and digoxigenin by cleavage of the sugar moiety. 1,2) In addition, it is metabolized to dihydrodigoxin by reduction of the double bond in the lactone ring.3)The analysis of digoxin in biological fluids can be performed by immunoassays. The antisera used for these immunoassays are produced by immunization with a haptencarrier protein conjugate, which is coupled to the terminal digitoxose of digoxin using periodate oxidation.…”

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confidence: 99%

Development of Radioimmunoassay for Measurement of Serum Digoxin in Digitalized Patients Using Novel Anti-digoxin Antiserum.

Ikeda

Araki

Takimoto

et al. 2002

Biological & Pharmaceutical Bulletin

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Digoxin is the most widely used cardiac glycoside for the treatment of congestive heart failure and atrial fibrillation. Digoxin is known to be converted metabolically to digoxigenin bis-digitoxoside, digoxigenin mono-digitoxoside and digoxigenin by cleavage of the sugar moiety. 1,2) In addition, it is metabolized to dihydrodigoxin by reduction of the double bond in the lactone ring.3)The analysis of digoxin in biological fluids can be performed by immunoassays. The antisera used for these immunoassays are produced by immunization with a haptencarrier protein conjugate, which is coupled to the terminal digitoxose of digoxin using periodate oxidation. 4,5) These antisera show high cross-reactivity with metabolites formed by the successive cleavage of the digitoxose residues. [6][7][8] In the radioimmunoassay (RIA) for determining digoxin concentrations in serum, 3 H-and 125 I-labeled digoxin derivatives have been widely used. [8][9][10] We recently reported the preparation and antigenic properties of digoxin-bovine serum albumin (BSA) conjugates linked at the digitoxose C-3Ј and C-3Љ positions. 11,12) The properties of the antisera were characterized by RIA for [ 3 H]-digoxin. Although the antiserum elicited by digoxin 3Ј-hemisuccinate-BSA conjugate possesses high specificity for digoxin, it still lacks the sensitivity needed for measurement of digoxin concentrations in serum. The sensitivity of RIA increases using a tracer whose specific radioactivity is high. In the present study, we describe development of a type of RIA of digoxin 3Ј-hemisuccinyl-[ 3 H]leucine using the antiserum elicited by digoxin 3Ј-hemisuccinate-BSA conjugate for measuring digoxin in serum from digitalized patients, and compare its performance with commercially available anti-digoxin BSA serum and monoclonal anti-digoxin. , and Dextran T-70 from Pharmacia Fine Chemicals (Uppsala, Sweden). Norit SX and other general reagents were supplied by Wako Pure Chemical Industries (Osaka, Japan). Digoxigenin, and its mono-and bis-digitoxosides were prepared by hydrolysis of digoxin according to the methods of Kaiser and his colleagues. MATERIALS AND METHODS Materials 13)RIA was performed in phosphate saline buffer (pH 7.4) containing K 2 HPO 4 (0.696 g), NaH 2 PO 4 · H 2 O (0.138 g), NaCl (4.39 g), and BSA (1.0 g) in H 2 O (500 ml). A dextrancoated charcoal suspension was prepared by continuously stirring Norit SX (500 mg) and Dextran T-70 (50 mg) in cold phosphate saline buffer (40 ml) for 10 min prior to use.The antiserum (antibody (A)) was prepared by immunizing rabbit with digoxin 3Ј-hemisuccinate-BSA conjugate. 12)The commercial anti-digoxin BSA serum (antibody (B)) and monoclonal anti-digoxin (antibody (C)) were supplied by BioMakor Co. (Rehovot, Israel).Apparatus The melting point was determined with a Yanagimoto micro hot-stage apparatus and is uncorrected. Optical rotation was measured with a JASCO DIP-370 digital polarimeter. FAB-MS measurement was made on a JEOL HX-100 instrument equipped with a FAB ion source using glycerol and NaCl as th...

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Hydrolysis of digoxin by acid

Cited by 40 publications

References 14 publications

Influence of gastric pH on digoxin biotransformation

Influence of gastric pH on digoxin biotransformation

Deglycosylated Products of Endogenous Digoxin-like Immunoreactive Factor in Mammalian Tissue

Development of Radioimmunoassay for Measurement of Serum Digoxin in Digitalized Patients Using Novel Anti-digoxin Antiserum.

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