Gunther Bodem

Influence of thyroid status on plasma half-life of antipyrine in man.

Abstract The half-life of antipyrine in plasma was studied In four hyperthyroid and four hypothyroid patients before and after thyroid status returned to normal. The half-life (± S.E.M.) was 7.9 ± 1.0 hours In hyperthyroid and 17.3 ± 1.1 hours in hypothyroid patients. After correction of the abnormal thyroid state the half-life values of both groups (12.3 ± 0.7 and 12.0 ± 0.5 hours) were within the normal range. These results suggest that abnormalities of thyroid function can markedly influence human metabolism of some drugs. (N Engl J Med 290:1040–1042, 1974)

Absorption of digoxin from the distal parts of the intestine in man

SummaryIn 12 patients undergoing coloscopy, 0.5 mg digoxin in aqueous alcoholic solution was injected into the transverse colon. The late maximum of the blood level curve at about 2 hours after the administration suggested delayed absorption of the glycoside. However, the 24 hour urinary excretion of 17±3.4% in 8 patients with normal colonic mucosa demonstrated extensive absorption in the distal part of the bowel. The results have been contrasted with the findings in 4 patients with ulcerative colitis who excreted only 1.66±0.6% of the given dose in 24 hours.

Dose-independent pharmacokinetics of digoxin in humans.

Nine healthy male volunteers received single 0.5, 1.0, and 1.5 mg. doses of intravenous digoxin in a randomized three-way crossover study. Multiple venous blood samples were drawn during 35 hours after each dose, and all urine was collected for 6 consecutive days. Concentrations of digoxin in serum and urine were determined by radioimmunoassay. Over-all mean values for kinetic variables were: distribution half-life, 0.35 hours; elimination half-life, 27.9 hours; volume of distribution, 5.46 liters/Kg; total clearance, 2.51 ml./min./Kg. The mean projected cumulative urinary excretion of digoxin was 70.1% of the dose; mean renal clearance of digoxin was 1.71 ml./min./Kg., not significantly different from creatinine clearance (1.50 ml./min./Kg.). None of the identifiable pharmacokinetic variables was significantly influenced by dose, suggesting that digoxin disposition is dose-independent in healthy individuals.

Effect of age and Billroth gastrectomy on absorption of desmethyldiazepam from clorazepate.

The effect of age and Billroth gastrectomy on absorption of desmethyldiazepam (DMDZ) from a single 20‐mg oral dose of its precursor, clorazepate (CZP) dipotassium, was assessed in 24 males. Six were healthy young controls (mean age, 24), 8 were elderly controls (mean age, 66.5 yr) with no gastrointestinal disease, and 10 were patients (mean age, 56) who had undergone Billroth gastrectomy at least 2 yr before. Absent or impaired gastric acid secretion was documented in 6 of the 10 postgastrectomy patients. Weight‐normalized area under the 48‐hr serum DMDZ concentration curve (WtN‐AUC‐48) among elderly controls (mean, 324 units) and gastrectomy patients (401 units) were similar and significantly less than those in young controls (603 units). Peak serum DMDZ concentrations in elderly controls and gastrectomy patients (185 and 216 ng/ml, respectively) were also lower and reached later after the dose (2.2 and 2.3 hr) than in young controls (371 ng/ml; 1.1 hr). Age per se rather than gastrectomy or acid secretion status explained by far most of the overall variability in WtN‐AUC‐48 and peak DMDZ concentration. Thus normal gastric acidity is not essential for absorption of CZP‐derived DMDZ. The appearance of DMDZ in the systemic circulation is reduced in elderly males, irrespective of surgery or gastric acid secretion. This could be explained by age‐related reduction in conversion of CZP to DMDZ or by more extensive distribution of DMDZ in the elderly.

Intravenous quinidine: pharmacokinetic properties and effects on left ventricular performance in humans

Ten healthy volunteers received 300 mg. of quinidine base as the gluconate salt by 15-minute intravenous infusion. Physiologic variables monitored before, during, and for 24 hours after the infusion were: electrocardiogram, systolic and diastolic blood pressure, echocardiogram, and carotid pulse tracing. During quinidine infusion, mean ventricular rate increased by 18% (67.1 to 79.5 beats per minute) and corrected QT interval increased by 54% (0.44 to 0.68 sec.). QRS duration did not change significantly, nor did systolic or diastolic blood pressure. Ejection fraction (EF) measured by echocardiography did not decrease during quinidine infusion, but rather increased by 12% (0.58 to 0.65). Mean rate of circumferential fiber shortening (Vcf) likewise increased by 22%, from 1.15 to 1.40 per second. Over the 24-hours post-infusion, all monitored physiologic variables fluctuated considerably; in the case of EF and Vcf, apparently random variations over time were as great as those attributable to quinidine infusion. Mean (and range) kinetic variables for quinidine were: volume of distribution, 2.03 (1.47 to 3.00) liter/Kg.; elimination half-life, 6.3 (4.8 to 7.9) hours; total clearance, 3.8 (2.8 to 5.2) ml./min./Kg. Neither total nor unbound serum quinidine concentrations were significantly correlated with physiologic changes. Thus, intravenous quinidine in the doses studied did not have negative inotropic effects in a series of healthy humans.

Single‐ and multiple‐dose kinetics of intravenous digoxin

Nine healthy men received 0.5, 1.0, and 1.5 mg digoxin intravenously in random sequence on occasions separated by at least 4 wk. Digoxin concentrations were measured in serum samples drawn during 36 hr after each dose, and a mean across‐dose kinetic profile was determined for each subject. After a 6‐mo washout period, the same subjects received 0.25 mg digoxin intravenously every 24 hr for 10 consecutive days. Samples were drawn every 12 hr during the first 9 days and at multiple points during 72 hr after the last dose. Mean kinetic variables for the single‐ and multiple‐dose trials were as follows: elimination half‐life (t½), 27.9 and 38.0 hr (r = 0.62); volume of distribution, 5.5 and 7.4 l/kg (r = −0.56); total clearance, 2.50 and 2.49 ml/min/kg (r = 0.19); urinary excretion t½, 40.9 and 37.9 hr (r = −0.14). Mean observed and predicted predose steady‐state serum concentrations were 0.59 and 0.79 ng/ml (r = −0.02). Mean values of accumulation and elimination t½ were nearly identical (27.8 and 27.9 hr), but were not positively correlated (r = −0.64). Multiple‐dose digoxin therapy leads to no systematic change in digoxin clearance. Single‐dose kinetics is poorly predictive of the rate and extent of drug accumulation and of washout kinetics during and after multiple‐dose therapy.

Disease-related alterations in cardiac glycoside disposition.

SummaryThe effects of diseases involving the kidney, gastrointestinal tract, thyroid, and cardiovascular system on the disposition of cardiac glycosides are reviewed.The glycosides ouabain and digoxin are cleared predominantly by renal excretion of the intact drugs. Not surprisingly, total clearance of these two compounds is reduced in patients with reduced Creatinine clearance. Similarly, steady-state serum concentrations of digoxin at any given dose become higher as renal function declines. However, individual variability is considerable, thereby limiting the utility of dosage schemes based on nomograms or equations. A further complication is that tissue distribution of digoxin is altered in renal insufficiency, so that serum concentrations take on u different meaning in patients with renal failure. In the case of digitoxin, renal clearance accounts for only part of the total clearance. A clear relationship between Creatinine clearance and total digitoxin clearance has not yet been established. However, digitoxin protein binding is reduced in renal insufficiency, requiring a change in the clinical interpretation of total (free plus bound) digitoxin serum concentrations in such patients.Although digoxin absorption may be impaired in patients with serious malabsorption syndromes, most studies have demonstrated normal or near normal absorption despite gastrointestinal disease or extensive ablative surgery. Hepatic cirrhosis does not alter the pharmacokinetics of digoxin, but is associated with impaired demethylation of β-methyldigoxin (medigoxin). Although hepatic biotransformation accounts for a substantial fraction of the total clearance of digitoxin, disappearance of digitoxin from the plasma is, if anything, more rapid in patients with liver disease as opposed to healthy controls.Clearance of both digitoxin and digoxin varies in direct relation to thyroid function; clearance is increased and the half-life shortened in thyrotoxicosis, and the reverse is true for hypothyroidism. This may be explained by parallel changes in Creatinine clearance, but further studies are needed to define the mechanism of alterations in glycoside clearance in relation to thyroid function.Continuing refinement of analytical and pharmacokinetic techniques will lead to rapid progress in research in this area, and a need for continuing re-evaluation of the state of the art.

Pharmacokinetics and pharmacodynamics of intravenous digoxin and digitoxin

SummaryHealthy volunteers received single 1.0-mg doses of intravenous digoxin (n=10) or digitoxin (n=12). Glycoside pharmacokinetics were determined from multiple plasma samples drawn over the 48 hours (for digoxin) or 14 days (for digitoxin) after the dose. Electrocardiogram, echocardiogram, and blood pressure were recorded at multiple time points 24 h after the dose. To control for nonspecific cardiovascular changes, pharmacodynamic measurements were repeated on a second occasion for 8 hours after an intravenous injection of saline. Mean (±S.E.) kinetic variables for digoxin were: volume of distribution (Vd), 8.3 (±0.6) l/kg; elimination half-life (t1/2), 49 (±5) h; clearance 2.1 (±0.2) ml/min/kg. Changes in blood pressure, ventricular rate, and corrected QT-interval attributable to digoxin were small. However, echocardiographically-determined mean rate of circumferential fibre shortening (mVcf) and ejection fraction (EF) increased significantly following digoxin when compared to saline infusion. Changes were maximal at 4–6 h after dosage, and were highly correlated with plasma digoxin concentration. mVcf and EF returned to baseline by 24 h post-dosage. Mean kinetic variables for digitoxin were: Vd, 0.63 (±0.03) l/kg; t1/2, 7.3 (±0.4) days; clearance, 0.043 (±0.003) ml/min/kg. Like digoxin, digitoxin infusion produced minimal change in blood pressure, ventricular rate, or QT-interval. However, mVcf and EF increased significantly when compared to saline control. Changes were maximal at 4–8 h after infusion, and were correlated with plasma digitoxin concentration; at 24 h post-dosage, mVcf and EF were still increased over baseline. Thus, digoxin and digitoxin significantly increase myocardial contractility in healthy humans, but without important change in heart rate and blood pressure. Changes in contractility are of slow onset, probably due to slow distribution of glycoside to sites of pharmacologic activity.ZusammenfassungGesunde Versuchspersonen erhielten eine einmalige Gabe von 1,0 mg Digoxin (n=10) oder Digitoxin (n=12). Die Kinetik der Glykoside wurde anhand der Plasma-Konzentrationszeitkurve über 48 h (Digoxin) oder 14 Tage (Digitoxin) analysiert. Während der ersten 24 h nach der Glykosidapplikation erfolgten in häufigen Zeitabständen die Registrierung von EKG, Echokardiogramm und Blutdruck. Um unspezifische kardiovaskuläre Änderungen auszuschließen, wurden die pharmakodynamischen Parameter nach Kochsalzinjektion erneut bestimmt. Die kinetischen Variablen (±SE) für Digoxin lauteten: Verteilungsvolumen (Vd) 8,3±0,6 l/kg Körpergewicht, Eliminationshalbwertzeit (Elt 1/2) 49±5 h, Clearance 2,1±0,2 ml/min/kg Körpergewicht. Die Digoxingabe führte nur zu geringen Änderungen von Blutdruck, Herzfrequenz und korrigiertem QT-Intervall. Dagegen nahm die echokardiographisch bestimmte zirkumferentielle Faserverkürzungsgeschwindigkeit und Ejektionsfraktion nach Digoxin im Vergleich zu Placebo signifikant zu. Das Maximum der Inotropie-Änderung wurde 4–6 h nach Digoxin-Applikation registriert. Die Änderungen von mVcf und EF korrelierten signifikant mit den Plasma-Digoxinkonzentrationen. 24 h nach Digoxin-Injektion waren die Ausgangswerte von mVcf und EF wieder erreicht. Die kinetischen Variablen für Digitoxin lauteten: Vd 0,63±0,03 l/kg; Elt 1/2 7,3±0,4 Tage; Clearance 0,043±0,003 ml/min/kg. Wie die Gabe von Digoxin führte die Digitoxininfusion nur zu geringfügigen Änderungen von Blutdruck, Herzfrequenz und QT-Intervall. Dagegen nahmen mVcf und EF im Vergleich zur Kochsalzinfusion signifikant zu. Die maximalen Änderungen wurden 4–8 h nach der Digitoxin-Infusion gemessen und korrelierten mit den Plasma-Digitoxinkonzentrationen. Somit steigern Digoxin und Digitoxin die myokardiale Kontraktilität gesunder Versuchspersonen im Vergleich zu einer Placebo-Gabe, jedoch ohne Herzfrequenz und Blutdruck zu beeinflussen. Das Maximum der Kontraktilitätsänderung ist erst nach ca. 4 h erreicht und hängt wahrscheinlich mit der langsamen Verteilung der Glykoside zusammen.

Clinical implications of serum digoxin concentrations.

SummaryFactors influencing serum digoxin concentrations, and the relation of these levels to classical electrocardiographic (ECG) and clinical manifestations of toxicity, were assessed in a series of 463 consecutively hospitalized patients of mean age 58 years. The majority of patients were receiving beta-acetyldigoxin or beta-methyldigoxin. Age, sex, creatinine clearance, and weight-corrected dose collectively explained less than 7% of overall variability in serum digoxin concentrations; creatinine clearance, which declined significantly with age (r=−0.36,p<0.001) was the most important of these determinants. ST-segment depression was present in the majority of patients and became more common at higher serum digoxin concentrations. However, PR interval, QRS duration, QT interval, or the presence of AV block were not associated with serum levels. Among 75 patients with atrial fibrillation, ventricular rate did not decline with increasing digoxin concentrations. The presence of gastrointestinal, neuromuscular, or psychiatric symptoms classically attributed to digitalis toxicity was not associated with serum digoxin concentration. Serum levels of digoxin appear to be of limited value in assessing the degree of digitalization.ZusammenfassungBei 463 chronisch digitalisierten Patienten, die während eines Jahres zur stationären Aufnahme kamen, konnten prospektiv verschiedene Faktoren, die die Serum-Digoxin-Konzentration zu beeinflussen vermögen, untersucht werden. Die meisten Patienten nahmen β-Acetyl- oder β-Methyldigoxin ein. Mit Alter, Geschlecht, Kreatinin-Clearance sowie gewichtskorrigierter Dosis ließen sich weniger als 7% der Gesamtvariabilität der Serum-Digoxinkonzentration erklären. Von diesen Parametern war die Kreatinin-Clearance, die mit zunehmendem Alter signifikant abfiel (r=−0,36;p<0,001), der bedeutendste Faktor. Eine ST-Streckensenkung bestand bei der Mehrzahl der Patienten; sie wurde mit höherer Digoxin-Konzentration deutlicher. Dagegen konnte keine Beziehung zwischen QT- und PR-Intervall, QRS-Dauer oder AV-Zeit im EKG und den Digoxinspiegeln abgeleitet werden. Bei 75 Patienten mit Vorhofflimmern nahm die Ventrikelfrequenz mit höheren Digoxin-Konzentrationen zu. Gastrointestinale, neuromuskuläre oder zentralnervöse Symptome, die mit einer Digitalis-Überdosierung zu vereinbaren sind, wiesen keine signifikante Korrelation mit den Glykosid-Spiegeln auf. Serumdigoxinkonzentrationen sind isoliert betrachtet nur von begrenztem Wert und sollten nur im Kontext mit dem klinischen Bild interpretiert werden.

Effect of dose on bioavailability of oral digoxin

SummaryNine healthy volunteers received single 0.25, 0.5, 1.0, 1.5, and 2.0 mg doses of oral digoxin tablets in random sequence on five occasions separated by at least 4 weeks. Urinary excretion of immunoassayable digoxin was determined from 8 consecutive 24 h urine samples collected after each dose. Mean values of cumulative urinary excretion of digoxin at the 5 doses were: 40.9, 35.6, 36.4, 34.1, and 33.5% of the dose (F=0.64; d. f.=4.32; N. S.). Mean values of urinary excretion half-life were: 2.48, 2.03, 2.20, 2.07, and 1.87 days (F=2.87; d. f.=4.32;p=0.05). Thus, the bioavailability of orally administered digoxin tablets in healthy volunteers is dose-independent over an 8-fold range of doses.