Unintentional lethal overdose with metildigoxin in a 36-week-old infant--post mortem tissue distribution of metildigoxin and its metabolites by liquid chromatography tandem mass spectrometry.

A massive lethal overdose with beta-metildigoxin in a 36-week-old infant is presented. Determination of beta-metildigoxin and its metabolites digoxin, digoxigenin and digoxigenin-monodigitoxosid is achieved by a liquid chromatographic mass spectrometric (LC-MS/MS) method. Measured concentrations for beta-metildigoxin and digoxin in peripheral blood were 40.2 ng/ml and 25.6 ng/ml, respectively. Tissue distribution showed highest concentrations in kidney tissue and gastric content. The metabolite digoxigenin-monodigitoxosid could be detected in heart blood, duodenal content, gastric content and fat tissue while the metabolite digoxigenin could only be detected in gastric content since the drug was given by a stomach tube.

Impact of ABCB1 (MDR1) gene polymorphism and P-glycoprotein inhibitors on digoxin serum concentration in congestive heart failure patients.

Digoxin, a drug of narrow therapeutic index, is a substrate for common transmembrane transporter, P-glycoprotein, encoded by ABCB1 ( MDR1 ) gene. It has been suggested that ABCB1 polymorphism, as well as co-administration of P-glycoprotein inhibitors, may influence digoxin bioavailability. The aim of the present study was to evaluate the effects of ABCB1 gene polymorphism and P-gp inhibitor co-administration on steady-state digoxin serum concentration in congestive heart failure patients. Digoxin concentrations as well as 3435C > T and 2677G > A,T ABCB1 single nucleotide polymorphisms, were determined in 77 patients administered digoxin (0.25 mg daily) and methyldigoxin (0.50 mg daily), some of them co-medicated with known P-glycoprotein (Pgp) inhibitors. Significant differences were noted in digoxin serum concentrations (C(min,ss)) between patients co-administered and not co-administered P-gp inhibitors: 0.868 +/- 0.348 and 0.524 +/- 0.281 for digoxin (p < 0.002), as well as 1.280 +/- 0.524 and 0.908 +/- 0.358 for methyldigoxin (p < 0.02), respectively. No influence of ABCB1 2677G > A,T and C3435C > T polymorphisms on digoxin concentration was noted. Although some of the previous studies have shown that digoxin pharmacokinetics might be affected by ABCB1 genetic polymorphism, those modest changes are probably clinically irrelevant, and digoxin dose adjustment should include P-gp inhibitor co-administration rather than ABCB1 genotyping.

Role of organic anion transporting polypeptide 2 in pharmacokinetics of digoxin and beta-methyldigoxin in rats.

Recently, we found that potent P-glycoprotein (P-gp) inhibitors, such as verapamil and cyclosporin A, markedly modulated the pharmacokinetics of digoxin in rats, whereas they did not affect beta-methyldigoxin pharmacokinetics significantly. Digoxin is also a substrate of rat organic anion transporting polypeptide 2 (Oatp2). Here, we compared the magnitude of Oatp2-mediated drug interaction of digoxin and beta-methyldigoxin using amiodarone as an Oatp2 inhibitor in rats. Amiodarone (20 mg/kg) given intravenously significantly increased plasma levels and decreased biliary excretion, liver distribution, and intestinal distribution of digoxin administered intravenously at a dose of 10 mug/kg. Amiodarone also significantly decreased biliary excretion and liver distribution of beta-methyldigoxin, but the change in plasma levels of beta-methyldigoxin was quite small. These findings may give a clue in selecting these cardiac glycosides in clinical pharmacotherapy for patients receiving multiple drugs towards escape from Oatp2-mediated drug interactions.

Role of P-glycoprotein in pharmacokinetics and drug interactions of digoxin and beta-methyldigoxin in rats.

Digoxin and beta-methyldigoxin were evaluated pharmacokinetically in terms of P-glycoprotein (P-gp)-mediated drug interactions in rats. Evaluation was made by measuring the effects of a potent P-gp inhibitor (verapamil, cyclosporin A) on in vitro efflux transport of these compounds across the everted small intestine, on in situ absorption from the small intestine, and on in vivo total plasma clearance (CL(total)) as well as biliary and urinary excretions after intravenous administration. Both the intestinal efflux transport and absorption of beta-methyldigoxin were approximately 1.5-fold greater than those of digoxin, probably due to its higher lipophilicity. Addition of verapamil (300 microM) significantly decreased the intestinal efflux transport and increased the intestinal absorption of digoxin. In contrast, the influence of verapamil on beta-methyldigoxin was small. Intravenous cyclosporin A (30 mg/kg) significantly decreased in vivo CL(total) and biliary excretion of digoxin, but affected little on beta-methyldigoxin clearances. These results suggest that P-gp-mediated drug interactions can easily occur in digoxin, but hardly in beta-methyldigoxin. These findings may give a clue in selecting these digitalis compounds in clinical use, towards escape from P-gp-mediated drug interactions or reduction of interindividual variations.

Pharmacokinetic study of beta-methyldigoxin by enzyme immunoassay using a novel specific antiserum in rats.

We previously showed that enzyme immunoassay (EIA) of beta-methyldigoxin (MDx3) using anti-MDx3 3'-hemisuccinate-bovine serum albumin antiserum (Antiserum-I) was superior to that using commercial anti-digoxin antiserum (Antiserum-II) in terms of specificity and that pretreatment of human serum with phenyl boric acid (PBA) column was effective. In the present study, we examined the precision of EIA using Antiserum-I and the recovery of MDx3 after PBA column treatment in rat serum, and also investigated pharmacokinetic changes of MDx3 in rats. The intra- and inter-assay variations and recovery tests using Antiserum-I were good. The PBA column was effective in selectively separating MDx3 from rat serum containing MDx3 and its metabolites. The recovery tests using Antiserum-I with PBA column showed about 110% and the interference of metabolites of MDx3 was negligible. Serum concentration-time courses of MDx3 by EIA using Antiserum-I with PBA column and Antiserum-I were lower than that using Antiserum-II. The distribution volume at steady state and total body clearance values of MDx3 in these conditions were significantly higher than those using Antiserum-II. The usefulness of PBA column was ascertained, while effects of PBA column on these parameters were not significant. In addition, rapid absorption of MDx3 was observed by EIA using Antiserum-I with PBA column. These results suggest that EIA using Antiserum-I with PBA column for the pretreatment of serum samples should be a more useful and valuable system in therapeutic drug monitoring and pharmacokinetic studies of the unchanged type of MDx3 than Antiserum-II.

P-glycoprotein-mediated transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin.

Digoxin is a drug with a narrow therapeutic index, which is substrate of the ATP-dependent efflux pump P-glycoprotein. Increased or decreased digoxin plasma concentrations occur in humans due to inhibition or induction of this drug transporter in organs with excretory function such as small intestine, liver and kidneys. Whereas particle size, dissolution rate and lipophilic properties have been identified as determinants for absorption of digitalis glycosides, little is known about P-glycoprotein transport characteristics of digitalis glycosides such as digitoxin, alpha-methyldigoxin, beta-acetyldigoxin and ouabain. Using polarized P-glycoprotein-expressing cell lines we therefore studied whether these compounds are substrates of P-glycoprotein. Polarized transport of digitalis glycosides was assessed in P-glycoprotein-expressing Caco-2 and L-MDR1 cells (LLC-PK1 cells stably transfected with the human MDR1 P-glycoprotein). Inhibition of P-glycoprotein-mediated transport of these compounds in Caco-2 cells was determined using the cyclosporine analogue PSC-833 (valspodar) as inhibitor of P-glycoprotein. No polarized transport was observed for ouabain. However, basal-to-apical transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin was greater than apical-to-basal transport in Caco-2 and L-MDR1 cells. In Caco-2 cells net transport rates of these compounds were similar to those of digoxin (digoxin: 16.0+/-4.4%, digitoxin: 15.0+/-3.3%, beta-acetyldigoxin: 16.2+/-1.6%, alpha-methyldigoxin: 13.5+/-4.8%). Furthermore, polarized transport of these compounds could be completely inhibited by 1 microM PSC-833. In summary, these data provide evidence that not only digoxin, but also digitoxin, alpha-methyldigoxin and beta-acetyldigoxin are substrates of P-glycoprotein.

[Therapeutic drug monitoring in perioperative period--management of atrial fibrillation in a patient with bradycardia due to relative overdose of digitalis].

We reported a 79 year old man with preoperative bradycardia due to relative overdose of digitalis prior to undergoing subtotal gastrectomy. The patient had received metildigoxin 0.2 mg.day-1 for atrial fibrillation preoperatively and severe bradycardia of 35-41 bpm was found on the preoperative ECG examination. Serum digoxin level was detected to be 1.91 ng.ml-1 on the day before surgery. We thought this serum level must be toxic for him, even though it was within normal limits for the majority. As we thought that his bradycardia had been caused by relative overdose of digitalis, he was withheld to receive metildigoxin on the day before surgery and thereafter. Heart rate on arrival at the operating theater was around 40-45 bpm, and therefore the patient was placed on a temporary pacemaker catheter before the anesthetic induction to prevent aggravating bradycardia during anesthesia and surgery. Heart rate during procedure was 50-70 bpm and hemodynamics was stable. Intravenous digoxin was restarted on the 2nd postoperative day because of decrease in serum digoxin level to 0.84 ng.ml-1 and it was converted to metildigoxin 0.1 mg.day-1 when he was permitted to take pills per os. Our experience demonstrates that perioperative therapeutic drug monitoring is clinically important for anesthesiologists to make proper pharmacological management of surgical patients who have received digitalis.

New and simple method for estimating metildigoxin dosing regimens by multiple trough screen analysis.

The pharmacokinetics of digitalis glycosides were studied using routine therapeutic drug monitoring data to evaluate the role of patient characteristics for estimating metildigoxin dosing regimens. The 232 serum glycoside concentration data at steady-state after repetitive oral administration in 144 hospitalized patients was analyzed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. Pharmacokinetic analysis of digitalis glycosides was described using a simple steady-state pharmacokinetic model. The effect of a variety of developmental and demographic factors on glycoside clearance was investigated. NONMEM estimates indicated that this digitalis glycoside clearance was influenced by the demographic variables of age, total body weight, serum creatinine, gender, daily dose and the coadministration of spironolactone. An elderly patient was expected to have a lower rate of clearance than a young patient of equal body weight and serum creatinine. The interindividual variability in glycoside clearance was modelled with proportional error with an estimated coefficient of variation of 19.7% and the residual variability was 21.8% The dosing method based on glycoside clearance value obtained by NONMEM analysis allowed the prediction of the minimum steady-state glycoside concentration as a function of metildigoxin maintenance dose with acceptable error for therapeutic drug monitoring.

[Digoxin-like immunoreactivity in newborn infants--a pitfall of digoxin therapy?]. / Digoxin-ähnliche Immunoreaktivität bei Neugeborenen--eine Falle bei der Digoxintherapie?

Endogenous digoxin-like immunoreactive substances (DLIS) show crossreactions with different immunoassays used for digoxin drug monitoring. In 61 blood samples of 47 eutrophic healthy newborns with jaundice, digoxin serum concentrations were measured during examination of serum bilirubin using a digoxin polarisation immunoassay. Although there was no digoxin therapy in any case, we found positive serum digoxin immunoreactivity (> or = 0.2 ng/ml) in 86% of serum samples. The mean DLIS-concentration was 0.43 +/- 0.19 ng/ml with a maximum of 0.9 ng/ml. We found a significant indirect correlation (rs = -0.34; p = 0.05) between age and serum DLIS concentration. A case report demonstrates the possibility of DLIS interference on digoxin drug monitoring.

Pharmacokinetics of beta-methyldigoxin in subjects with normal and impaired renal function.

Beta-methyldigoxin (beta-MD) was administered orally (0.2 mg) to 24 patients with various degrees of renal function, to investigate its pharmacokinetic characteristics related to renal function. Serum and urine collected until 120 hours after dosing were assayed for beta-MD and digoxin by high-performance liquid chromatography and fluorescence polarization immunoassay method. The steady-state volume of distribution decreased proportionately as creatinine clearance (CLCR) decreased, although steady-state volume of distribution of hemodialysis patients had large interindividual variability, and their mean value was not different from that of patients with normal renal function. Both renal clearance of beta-MD and digoxin were significantly correlated with CLCR (r = .820, P < .001 and r = .822, P < .01, respectively), and the slope of regression line for beta-MD was only 44% that for digoxin. Significantly reduced urinary excretion of total drug (beta-MD plus digoxin) was shown in patients with CLCR below 50 mL/minute/1.48 m2. This study suggests that the dosage modification is not necessary until CLCR decreases to below 50 mL/minute/1.48 m2, but careful attention should be given in the use of beta-MD in patients with CLCR below this value.

Influence of food on the absorption of beta-methyldigoxin.

Nine healthy subjects received 0.2 mg of beta-methyldigoxin (beta-MD) orally in the fasting state, 30 minutes after and before a standard breakfast. The time-to-peak serum glycoside concentration was delayed and the peak concentration was lower in the postprandial state compared with the other regimens (P less than .01). The absorption rate constant was significantly reduced when beta-MD was given after a meal (1.55 +/- 1.75 hr-1) than before a meal (5.54 +/- 2.16 hr-1) and in the fasting state (5.22 +/- 3.06 hr-1)(P less than .01). Although the area under the serum glycoside concentration-time curve and the cumulative urinary excretion (CUE) of beta-MD, digoxin, and total drug (beta-MD plus digoxin) was not significantly different between three regimens, the CUE infinity tended to be smaller in the postprandial state compared with before a meal. The results indicate that the timing of drug administration in relation to a meal is an important factor leading to the fluctuations of serum glycoside concentration after oral beta-MD, which might be of some clinical importance.

[Serum digoxin in children treated with beta methyl digoxin]. / Concentraciones séricas de digoxina en niños tratados con beta metil digoxina.

Concentrations of serum digoxin were measured by the polarized immunofluorescence Abbot TDx11 method in 59 samples from 53 children under treatment with mean beta methyl digoxin doses of 8.9 +/- 2.0 micrograms.kg.day. The therapeutic range for serum digoxin concentration was estimated to be 0.9 to 2.25 ng/ml. Simultaneous Na, K and creatine serum concentrations were measured. In 36 samples mean serum digoxin level was 1.52 +/- 0.45 ng/ml -within therapeutic range- and in only one of these cases clinical evidence of toxicity was apparent. In 15 samples digoxin level was above the therapeutic range and 11 patients of this group (73%) showed clinical signs of toxicity, consisting in arrythmias (six cases: supraventricular in 5 patients, ventricular in one child) and gastrointestinal symptoms (eight patients). Six patients with digoxin levels over therapeutic range and signs of digitalis toxicity had coincidental acute renal failure, which in 4 cases was subclinical--in 2 of these late it was pre-renal- and, in spite of this, all were inadvertently given the usual dosage of beta methyl digoxin. Almost invariably there was clinical evidence of toxicity when digoxin serum levels were above 2.4 ng/ml, so established maximal therapeutic level at 2.25 ng/ml seems adequate. Signs of digitalis toxicity must be looked on systematically in children treated with such drugs. In the critically ill or in children with acute renal failure it is necessary to monitor serum digoxin concentration. Among the clinical signs of toxicity, gastrointestinal symptoms are more frequent in children. An oral dose from 7 to 10 micrograms.kg.day of beta methyl digoxin in recommended.

[Maintenance therapy with beta-methyldigoxin in the elderly. A study of 40 patients]. / Terapia di mantenimento con beta metildigossina nell'anziano. Studio su 40 pazienti.

The efficacy of beta methyldigoxin was examined in a group of 40 elderly patients who had been hospitalised due to congested heart decompensation. A good clinical response was obtained in 95.5% of cases with the presence of slight toxic phenomena in 2 cases only (4.5%). The paper underlines the excellent pharmacokinetic pattern of the substance used in the steady state. Steady state digitalemic values were within the acceptable range in 83.76% of cases, whereas underdosage and overdosage phenomena were observed in 6.87% and 9.37% of patients respectively.

Beta-methyl digoxin: a better absorbable digoxin.

Since Megges and Repke [1961] showed that acetylation of the hydroxyl groups in the aglycone or the sugar side chain of the digitalis molecule results in a derivative with enhanced and more complete absorption from the gastrointestinal tract, several new compounds resulting from acetylation or methylation of digoxin molecule have been developed. Beta-methyl digoxin (beta-methyl digoxin) is a methyl derivative (methyl group in position 4 of the digitoxose residue) of digoxin. Enhanced and more complete gastrointestinal absorption of tritium labeled beta-methyl digoxin [Rennekamp et al. 1972] has been confirmed. Weiss et al. [1975], based on the serum levels following oral administration, calculated that to achieve comparable levels, digoxin dose would have to be increased by 1.55 times compared to that of beta-methyl digoxin. These and other studies supported an earlier notion that beta-methyl digoxin was a better and desirable cardiotropic agent than the digoxin. Comparison of cardiac effects using equivalent doses of the two compounds however, showed no difference [Das et al. 1977]. Following oral administration, the serum glycoside levels to beta-methyl digoxin indeed were significantly greater than those with digoxin. However, these differences in serum levels were not of sufficient magnitude to influence detectable cardiac inotropic effects, hence, the search for a better digoxin should continue.

[Use of beta-methyldigoxin preparations medilazine and bemecor in patients with congestive heart failure]. / Primenenie preparatov beta-metildigoksina medilazina i bemekora u bo'lnykh s zastoinoi serdechnoi nedostatochnos'tiu.

The two agents beta-methyldigoxin (medixin), a Soviet medilazide, and bemecor (digicor), a foreign analogue (LEK, Yugoslavia) were comparatively evaluated. An equal high (85%) clinical efficacy of the drugs was found in 81 patients with varying stages of heart failure. A positive therapeutic effect was accompanied by lower heart rate, higher diuresis and natri-and kaliuresis, decreased systolic and diastolic pressures in the pulmonary artery. The incidence of adverse reactions and the causes of their occurrence are analyzed.

[Tissue concentrations of beta-methyl-digoxin in children]. / Concentraciones tisulares de beta-metil-digoxina en el niño.

Beta-methyl-digoxin concentrations in adipose, skeletal muscle and myocardial tissues, were studied in 8 patients undergoing by-pass surgery because of congenital heart disease. Correlation between doses/kg, plasmatic and tissue concentrations were analysed. We found statistically correlation between doses/kg and plasmatic concentrations; doses/kg and skeletal muscle concentrations (p less than 0.01); plasmatic and skeletal muscle concentrations (p less than 0.05). Concentrations was significantly greater in myocardial than adipose tissue before extracorporeal circulation (p less than 0.01); and significantly greater than adipose (p less than 0.01) and skeletal muscle (p less than 0.05) tissues after extracorporeal circulation. Extracorporeal circulation lessens adipose and skeletal muscle concentrations, but increases myocardial concentrations significantly (p less than 0.05). It is concluded, that the behaviour of beta-methyl-digoxin, in relation with tissue concentrations, is similar to digoxin.

[Course of chronic life-threatening digitalis poisoning in infancy with immunopharmacologic treatment using antidigoxin Fab of sheep]. / Verlauf einer chronischen lebensbedrohlichen Digitalis-Intoxikation im Säuglingsalter unter immunpharmakologischer Behandlung mit Antidigoxin Fab vom Schaf.

A 2 months old girl was given a tenfold increased dosage of Beta-Methyldigoxin for 2 weeks and subsequently developed severe symptoms of glycoside intoxication. In hospital she was treated by digoxin-specific Fab antibody fragments. 18 hours later the symptoms had totally disappeared. However, 48 hours from the beginning of the treatment free digoxin levels rose again to toxic ranges. In chronic intoxications the rediffusion of glycosides from tissues and interstitial space seems to be much more pronounced than in acute intoxications, and there is a higher risk of reintoxication.