Serum Digitoxin Concentrations Research Articles

The association of ABCB1 polymorphisms and elevated serum digitoxin concentrations in geriatric patients

Digitoxin is a known substrate of the efflux pump P-glycoprotein (gene name: ABCB1). P-glycoprotein expression was shown to be modulated by single nucleotide polymorphisms in the ABCB1 gene, but it remains unclear whether these polymorphisms influence digitoxin blood levels. Our objective was to examine the association of ABCB1 C3435T genotype and elevated serum digitoxin concentrations (SDC) in a cohort of 77 geriatric patients consecutively admitted to a geriatric department over a 12-month period. The impact of ABCB1 3435 CC, CT, and TT genotypes on SDC and SDC normalized for daily digitoxin dosage and body weight was assessed by multivariate regression analysis. Among participants, 18 (23%) had the CC, 36 (47%) the CT, and 23 (30%) the TT genotype. Adjusting for relevant covariates, no significant association of ABCB1 C3435T genotype and SDC or normalized SDC was detected. Mean SDC was 22.4 ng/ml (95% CI 18.9-25.9) for the TT, 21.8 ng/ml (95% CI 18.1-25.5) for the CT, and 25.7 ng/ml (95% CI 20.6-30.8) for the CC genotype. The means for normalized SDC were 5.2 kg.l(-1) (95% CI 4.3-6.1) for the TT, 6.1 kg.l(-1) (95% CI 4.7-7.5) for the CT, and 6.2 kg.l(-1) (95% CI 4.6-7.7) for the CC genotype. In this sample of frail geriatric patients, the impact of ABCB1 C3435T genotype on serum digitoxin concentration was not of major relevance. Regular monitoring of digitoxin blood levels and surveillance of appropriate drug use remain the best ways to prevent digitoxin intoxications in the elderly.

Falsely elevated serum digitoxin concentrations due to cross-reactivity of water-extractable digitoxin-like immunoreactivity of Chinese medicine Chan SU: elimination of interference by use of a chemiluminescent assay

Chinese medicines are available without prescription in health food stores. One such Chinese preparation, Chan SU, is used as a cardiotonic agent. Digoxin-like immunoreactivity of Chan SU has been reported in the past. In this report we demonstrated significant digitoxin-like immunoreactivity of Chan SU. For example, when a 20-μl aliquot of an aqueous extract of Chan SU (2 mg/ml) was added to drug-free serum, the observed digitoxin-like immunoreactivity was 51.40 ng/ml by the fluorescence polarization assay. In contrast, a new chemiluminescent assay for digitoxin did not show any immunoreactivity. When very small amount of aqueous extract of Chan SU was added into serum containing digitoxin, the observed digitoxin concentrations were falsely elevated when measured by the fluorescence polarization immunoassay (FPIA), but did not change significantly when measured by the chemiluminescent immunoassay (CLIA). Significant digitoxin-like immunoreactivity was also observed (FPIA) in mice after feeding with Chan SU. Because bufalin, cinobufotalin and cinobufagin are major components of Chan SU, digitoxin-like immunoreactivity of these purified compounds was also studied. Bufalin was identified as the major digitoxin-like immunoreactive compound responsible for most of the interference in serum digitoxin measurement using the FPIA.

Digitoxin kinetics and renal excretion in children.

Digitoxin kinetics were investigated in 11 children, three girls and eight boys, with a mean age of 7.1 yr (5.9 to 9.2). Five children received digitoxin, 17.5 to 20 micrograms/kg IV, and six other children received 20 micrograms/kg as an oral solution. Digitoxin was given as a single dose 24 to 48 hr after cardiac surgery, and patients were monitored in an intensive care unit for 24 hr. Serum and urine digitoxin concentrations were determined by radioimmunoassay. Children had larger apparent volumes of distribution (1 l/kg) than adults (0.57 l/kg). Mean serum elimination t 1/2 was 6.4 days in children (3 to 11.2) and 8.2 days in adults (5.9 to 11.3). Total body clearance was much greater in children (0.085 ml X min-1 X kg-1) than in adults (0.036 ml X min-1 X kg-1). This was because of an increase in metabolic clearance, although there was no difference in renal clearance in children and adults. Absolute oral bioavailability, measured by comparing serum AUCs after intravenous and oral doses, was complete. Peak serum concentrations of 23 to 50 ng/ml developed 90 to 120 min after the oral dose. A single digitalization dose of 20 micrograms/kg was well tolerated and did not induce arrhythmias.

Digitoxin accumulation.

1 Nine healthy volunteers received single 1 mg intravenous doses of digitoxin, following which serum digitoxin concentrations were measured at multiple points in time over the next 14 days. 2 Mean kinetic variables for digitoxin were: volume of distribution, 0.76 l/kg; elimination half-life, 8 days; total clearance, 0.049 ml min-1 kg-1. 3 After a drug-free interval of at least 4 months, subjects took 0.07 mg of oral digitoxin daily for 28 consecutive days. Serum digitoxin concentrations were measured during the period of dosage and in the 21 day post-dosage washout. 4 Digitoxin accumulation was slow, proceeding with a mean half-life (7.9 days) that was nearly identical to the single-dose half-life. However, the two were not significantly correlated. 5 Mean observed steady-state serum concentrations (15.4 ng/ml) also were nearly identical to those predicted from the single-dose study (15.3 ng/ml), but again the two were not significantly correlated. 6 Steady state is very slowly attained after initiation of maintenance therapy with digitoxin. The kinetic data suggest that a loading dose on the average should be 12 times the maintenance dose.

Digitoxin elimination reduced during quinidine therapy.

Elevated serum digoxin concentrations and clinical toxicity have been reported in patients receiving quinidine. The present study was undertaken to ascertain whether a similar interaction occurs between quinidine and another cardiac glycoside, digitoxin, and if so to evaluate the pharmacokinetic basis in five healthy volunteers. In the presence of quinidine the serum digitoxin concentration was elevated, the mean digitoxin elimination half-life was increased from 87.8 +/- 11.6 to 218.3 +/- 20.6 h (mean +/- SEM) (p < 0.01), and mean total body clearance was reduced from 5.01 +/- 1.18 to 1.87 +/- 0.20 mL/h x kg (p < 0.052). No change was observed in the apparent volume of distribution or in the volume of the central compartment for digitoxin. The data suggest that the mechanism for this interaction is a reduction in elimination and not displacement of digitoxin from tissue binding sites.

Correlation between pharmacokinetics and intropic and electrophysiologic responses to digitoxin in the intact dog.

We attempted to correlate inotropic and eletrophysilogic digitoxin effects with serum digitoxin concentrations during 8 hr after a single dose. Eight pentobarbital-anesthetized Labrador dogs were given 2.0 mg digitoxin intravenously. Left heart catheterization and His bundle registration were performed. acing and programed electrical stimulation were used to determine heart rate-independant changes in dP/dt, intra-atrial, atrioventricular (AV), His-Purkinje, and intraventricular conduction velocity. The effective (A-ERP) and functional (A-FRP) refractory periods of the atrium and the functional nodal refractory period (AV-FRP) were measured. Serum digitoxin concentrations were determined by radioimmunoassay. Median serum digitoxin half-time was 5.7 hr. The dP/dt increased after digitoxin, with maximum values after 2 hr. Digitoxin concentration correlated with the inotropic response after 4 hr. Heart rate fell significantly within 2 min and remained below control values for the 8 hr observation period concimitant with an increase in AV-nodal conduction time and AV-ERP increased significantly in the late elimination phase, while A-FRP increased slightly initially and remained high. No consistent correlation was found between the electrophysilogic variables and serum concentrations. We conclude that the two main effects of digitoxin, the inotropic and electrophysiologic, are dissociated in the elimination phase after a single dose.

Studies on digitalis. 23. Blood‐brain barrier of digitoxin in humans

AbstractData on the cerebrospinal fluid concentrations of digitoxin in man have been lacking. Aim of the present study was to investigate serum and cerebrospinal fluid concentrations of digitoxin. Eleven patients with normal cerebrospinal fluid composition, normal serum albumin values, normal renal and hepatic function and normal hematologic tests were given a single dose of 0.6 mg digitoxin. Serum and cerebrospinal fluid were collected 16 h after the dose, and assayed by radio‐immunoassay, serum digitoxin protein binding was measured with equilibrium dialysis.Mean serum digitoxin concentration was 12.4 ng/ml (SD 2.6) and mean CSF concentration 0.84 ng/ml (SD 0.22) giving a CSF/serum ratio of 0.07 (SD 0.03). Serum digitoxin protein binding was 97.4% (SD 0.4) and the calculated CSF/free serum digitoxin ratio was thus 2.94 (SD 1.43).Free serum digitoxin concentrations are more relevant for pharmacologic effect than total serum digitoxin concentrations and also for passage into the central nervous system. Using free drug concentrations the ratio between digitoxin in serum and CSF is lower than reported values for digoxin indicating a higher penetrance of digitoxin into the central nervous system. This corresponds well with the higher lipid solubility of digitoxin. Post mortem studies have shown that concentrations are higher in cerebral tissue than in CSF for digoxin. Determination of CSF concentrations thus probably underestimates the penetrance of digitalis glycosides into the central nervous system, but may serve as a useful indicator of variance among digitalis glycosides.

Effect of hemoperfusion on the pharmacokinetics of digitoxin in dogs.

Abstract To determine the pharmacokinetics of digitoxin, five dogs were given 0.15 mg/kg digitoxin intravenously. Serum digitoxin concentrations were measured by 125 l RIA. Pharmacokinetic analysis was performed with a three-compartment model. The mean Vd was 0.81 ± 0.27 (S.D.) L/kg, mean t12 was 6.60 ± 1.97 hr, and mean Clt was 27 ± 11 ml/min. Another five dogs received the same amount of digitoxin and were hemoperfused at a flow of 108 ml/min for 4 hr with a 300 gm Amberlite XAD-4 column. Vd, t12, and Clt values before perfusion were 0.66 ± 0.27 L/kg, 7.09 ± 3.52 hr, and 34 ± 20 ml/min, not significantly different from the values of the first five dogs. In two dogs, digitoxin concentrations became undetectable within 15 min of starting perfusion, and 58.5 μg of digitoxin were recovered from the columns. In the remaining three dogs, the plasma clearance of digitoxin by the columns was 25 ±7 ml/min, and 233 ± 55 μg of digitoxin were recovered. Mean hemoperfusion clearance calculated from the total amount recovered was 19.7 ± 3.9 ml/ min. After perfusion there was an increase in the serum digitoxin concentration. Once the new pseudo-steady state was reached, the serum digitoxin concentration was from 5 to 44 ng/ml less than if hemoperfusion had not been done. The increase in serum digitoxin concentration after hemoperfusion occurred because the central compartment, depleted of digitoxin during hemoperfusion, was refilled from peripheral compartments. In conclusion, 4 hr of resin hemoperfusion nearly doubled the rate of removal of digitoxin from dogs, and a multicompartmental pharmacokinetic model explains the postperfusion increase in serum digitoxin concentrations.

Effect of cardiopulmonary bypass with heparin administration on digitoxin pharmacokinetics, serum electrolytes, free fatty acids, and renal function.

In 14 patients investigated before, during, and after extracorporeal circulation, serum digitoxin concentration fell significantly during bypass but returned to preoperative values within 24 hr. Both changes occurred in parallel with changes in hematocrit. Serum magnesium concentration fell markedly just before and during bypass and returned to preoperative values on the third and fourth postoperative days. Urine digitoxin concentration fell on the day of operation and remained low in the postoperative period, with a concomitant reduction in the renal excretion of digitoxin. Creatinine and digitoxin clearances decreased on the day of operation and returned slowly to control values during the postoperative period. In 5 other patients, serum digitoxin protein binding decreased significantly during bypass due to heparinization and was normalized by administration of protamine sulfate. Free fatty acids increased significantly immediately before bypass and returned to normal toward its end. The marked changes in digitoxin serum levels during cardiopulmonary bypass can be explained by hemodilution. Acute deterioration of renal function does not lead to accumulation of digitoxin. Heparin administration causes major changes in free fatty acids and serum digitoxin protein binding without important changes in the free digitoxin concentration. Digitoxin can thus be safely administered to patients undergoing cardiac surgery with extracorporeal circulation.

Studies on Digitalis

In a prospective study on digitalis intoxication, low serum magnesium was found in 90 patients, while 388 patients had values above 1.5 mEq/l. Hypomagnesemia was more frequent in women than in men, in those with low body weight and in those with advanced heart failure. More patients with hypomagnesemia than those without had nausea, anorexia, fatigue, flickering of vision and atrial tachycardia with block. Patients with hypomagnesemia also had lower serum potassium than normomagnesemic patients. There was, however, no significant difference in the prevalence of digitalis intoxication or in serum digitoxin concentration. Nor was there any correlation between serum digitoxin and serum magnesium levels.

Serum digitoxin levels in the aged

radioimmunoassay により digitoxin 維持量投与中の患者118人 (男81人, 女37人) の血清 digitoxin 濃度を測定 (のべ262回) し, その臨床的意義につき検討した. さらに従来老齢者にジギタリス中毒が多いといわれているのでこの点に注目して血清濃度の面より検討を加えた. その結果,1) 中毒群の血清濃度は平均35.5ng/ml, 非中毒群のそれは平均18.4ng/mlであり両群間で明らかな有意差 を示した (P<0.0001).2) 中毒群と非中毒群の臨床所見, 検査所見を検討し, 両群間で心胸廓比, GOT, GPTに有意差が認められた.3) 血清濃度は維持量の増加に比例して dose-dependent に増加し, 回帰直線を求めると, y(濃度)=194x(投与量)+4.87であった. 血清濃度35.0ng/ml以上は全例中毒症状を示し, 24.5ng/ml未満では中毒例は認められず, 24.5～35.0ng/mlのレベルで中毒と非中毒例が overlap していた.4) 老齢者群 (60歳以上) と若年者群 (59歳以下) の2群に分けて同一維持量で比較すると老齢者群の血清濃度は統計学上有意に高く (P<0.001) 回帰直線を計算するとそれぞれ, y=231x+3.91, y=148x+5.39であった. なお中毒症状を示した症例は若年者群53人中3人 (5.6%), 老齢者群62人中21人 (34.0%) と圧倒的に老齢者に多かった.5) 両群間の検査所見を比較すると血清総蛋白は老齢者で有意に低く, また24時間内因性クレアチニン・クリアランスが低下すると中毒例が増加する傾向が認められた.老齢者で血清 digitoxin 濃度が高くなる理由の一つの因子として加齢に伴う腎機能低下が示唆された. その他薬物代謝系活性の低下など種々の因子を列挙して考察を加えた.老齢者では維持量0.1mg投与では過剰となる場合も少くなく, 投与量の慎重な配慮と注意深い経過観察が必要である. また臨床的所見, 心電図記録は当然のことであるが, さらに血清濃度を経過中頻回に測定することは臨床上ジギタリス中毒の早期発見に極めて有用である.

Serum digitoxin concentrations in infants and children.

Serum digitoxin levels were measured in 18 infants (under two years) and in 23 children (aged 2-13 years) receiving maintenance therapy. Digitalization was carried out because of heart failure in 17 infants and 13 children and for control of dysrhythmia in one infant and 10 children. Mean maintenance dosage for infants was 0.0042 plus or minus 0.0008 (sd) mg/kg/day and for children was 0.0031 plus or minus 0.0012 mg/kg/day. The mean serum digitoxin level was not significantly different in infants (30 plus or minus 10 ng/ml, range 14-58) from that found for children (34 plus or minus 11 ng/ml, range 19-61). Both values were significantly different (P smaller than 0.001) from those determined in this laboratory for adults (mean 24 plus or minus 7 ng/ml, range 5-39). In four infants with electrocardiographic or other evidence of toxicity, the mean serum level was 71 plus or minus 2 ng/ml (range 68-72), and in four children with electrocardiographic or other evidence of toxicity, the mean serum level for digitoxin was 72 plus or minus 14 ng/ml (range 53-84). The data suggest that infants and children tolerate a higher serum digitoxin concentration without any evidence of toxicity and may require more digitoxin (mg/kg) for therapeutic effect than do adults. Serum digitoxin levels may serve as an important guide in determining the adequacy of digitalization and in the recognition and management of digitalis toxicity.