Digoxin bioavailability: Formulations and rates of infusions

Marcus, Frank I.; Dickerson, Janet; Pippin, Susan; Stafford, Marvin; Bressler, Rubin

doi:10.1002/cpt1976203253

Cited by 25 publications

(9 citation statements)

References 1 publication

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“…This phenomenon has been reported previously in relation to digoxin bioavailability studies (Greenblatt, Duhme, Koch-Weser & Smith, 1974;Marcus, Dickerson, Pippin, Stafford & Bressler, 1976), and may be due to alterations in clearance which are dependent on the precise mode of administration. Marcus et al (1976) reported that 21% more digoxin was excreted in the urine over 6 days after a 3 h intravenous infusion than after a 1 h infusion. Greenblatt et al (1974) also observed this effect when they found a greater 6 day urinary excretion of digoxin after a 1 h infusion compared with a rapid intravenous injection.…”

Section: Discussionsupporting

confidence: 72%

“…An interesting discrepancy revealed by the results was the significant difference in the bioavailability fraction calculated from serum and from urinary excretion data, the latter giving higher values. This phenomenon has been reported previously in relation to digoxin bioavailability studies (Greenblatt, Duhme, Koch-Weser & Smith, 1974;Marcus, Dickerson, Pippin, Stafford & Bressler, 1976), and may be due to alterations in clearance which are dependent on the precise mode of administration. Marcus et al (1976) reported that 21% more digoxin was excreted in the urine over 6 days after a 3 h intravenous infusion than after a 1 h infusion.…”

Section: Discussionsupporting

confidence: 72%

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Disopyramide serum and pharmacologic effect kinetics applied to the assessment of bioavailability.

Bryson¹,

Whiting²,

Lawrence³

1978

Brit J Clinical Pharma

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I Serum, urine and pharmacologic effect (prolongation of the QT interval) kinetics of the antiarrhythmic disopyramide have been investigated in eight volunteers after intravenous administration (2 mg/kg) and oral administration (300 mg) of the two commercially available preparations, Rythmodan (Roussel Laboratories) and Norpace (Searle Laboratories). 2 An open one compartment body model adequately described the kinetics of disopyramide in serum and urine. 3 After intravenous administration, the following average pharmacokinetic parameters were found: biological half-life, 7.8 h; total clearance, 95 ml/min; renal clearance, 54 ml/min; apparent volume of distribution, 60 litres. 4 After oral Rythmodan and Norpace, serum concentration profiles and urinary excretion data revealed significant differences in rates of absorption, times required to achieve peak serum concentrations and biological half-lives. These differences were largely due to the relatively slow absorption characteristics of Norpace. SThe absence of hysteresis in plots of QT prolongation against disopyramide serum concentration after oral administration indicated that serum and pharmacologic effect kinetics were indistinguishable within a kinetically equivalent compartment. 6 Analysis of both serum and urine data showed that while Norpace had a significantly higher degree of bioavailability (P< 0.005), the 5-15% difference between the two formulations should not normally be of any clinical significance.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionsupporting

confidence: 72%

Disopyramide serum and pharmacologic effect kinetics applied to the assessment of bioavailability.

Bryson¹,

Whiting²,

Lawrence³

1978

Brit J Clinical Pharma

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“…Our data (Table IV) show that 6 day urinary excretion after rapid iv injection, 67.5% of the dose, was significantly greater than after 1 hr infusion, 50% of the dose, and the coefficient of variation, 6.53%, after rapid iv injection was much less than the corresponding value of 22.4% following 1 hr infusion. So far as ratios are concerned, results obtained in our study agreed with those reported by Marcus et al (2). They reported that 60, 70, and 51% of the dose (ratios of 1.0, 1.17, and 0.85) were excreted in the urine in 6 days following 1 hr infusion, 3 hr infusion and oral solution, respectively; whereas in our study, the corresponding values (row 2 of Table IV) were 50, 58, and 36% of the dose (ratio 1.0, 1.16 and 0.72) for the same routes of administration, respectively.…”

Section: Discussionsupporting

confidence: 93%

“…Marcus et al (2) administered 0.4 mg doses of digoxin to five normal volunteers both as a constant rate infusion over 1 hr and as an infusion over 3 hr with 0.1 mg of the digoxin being infused during the first hour, 0.2 mg being infused during the second hour, and 0.1 mg being infused during the third hour. They reported: "The most striking finding in our study was that the 6 day urinary excretion of digoxin after a 3 hr infusion was 21% more than after the same dose of drug given during the 1 hr infusion.…”

Section: Introductionmentioning

confidence: 99%

Evidence of nonlinearity in digoxin pharmacokinetics

Wagner

Popat

Das

et al. 1981

Journal of Pharmacokinetics and Biopharmaceutics

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Six normal male volunteers received 0.5 mg label doses of digoxin as (a) a bolus intravenous injection over 2 min, (b) a constant rate intravenous infusion over 1 hr, (c) a constant rate intravenous infusion over 3 h, and (d) a solution in 5% dextrose given orally. Plasma concentrations of digoxin were measured by radioimmunoassay for a 4 day period and urinary excretion for a 6 day period after the single doses. The mean (coefficient of variation) total areas under the plasma concentration-time curves per 0.5 mg of digoxin were (a) 35.55 (14.8%), (b) 30.20 (27.7%), (c) 25.80 (35.5%), and (d) 15.47 (49.9%); the means differed significantly (0.01 greater than p greater than 0.005). The mean (coefficient of variation) total amounts excreted in the urine as a fraction of the dose were (a) 0.689 (6.31%), (b) 0.517 (20.4%), (c) 0.588 (16.8%), and (d) 0.374 (23.4%); the means differed significantly (p less than 0.001). Both the total clearance and the nonrenal clearance of digoxin differed significantly with the method of intravenous administration. The slower the rate of input of digoxin to the body, the greater were both the total clearance and the nonrenal clearance of the drug, which strongly suggests nonlinear pharmacokinetics.

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“…Transporter DDI for Glecaprevir and Pibrentasvir by renal excretion, and does not undergo significant enterohepatic circulation (Marcus et al, 1976;Lloyd et al, 1978). Thus, the digoxin AUC may only be increased a maximum of 25%-67% by inhibition of intestinal efflux, which affects bioavailability, not clearance-increases up to 150% have been reported upon coadministration with dronedarone and likely reflect additive inhibition of digoxin renal tubular secretion (Hori et al, 1993;Vallakati et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Translation of In Vitro Transport Inhibition Studies to Clinical Drug-Drug Interactions for Glecaprevir and Pibrentasvir

Kosloski

Bow

Kikuchi

et al. 2019

J Pharmacol Exp Ther

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Glecaprevir and pibrentasvir are oral direct-acting antiviral agents approved in combination for treatment of chronic hepatitis C viral infection. In vitro studies identified the combination as potentially clinically relevant inhibitors of the efflux transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Glecaprevir inhibited P-gp, BCRP, OATP1B1, and OATP1B3 with IC 50 values of 0.33, 2.3, 0.017, and 0.064 mM, respectively. Pibrentasvir inhibited P-gp, BCRP, and OATP1B1 with IC 50 values of 0.036, 14, and 1.3 mM, respectively. Neither agent inhibited organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, OAT3, multidrug and toxin extrusion (MATE) 1, or MATE2K. Openlabel phase 1 clinical drug-drug interaction studies were conducted in healthy subjects to evaluate interaction potential of glecaprevir/ pibrentasvir and coadministered selective substrates for P-gp (digoxin, dabigatran etexilate, and sofosbuvir), BCRP (rosuvastatin and sofosbuvir), and OATP1B1/3 (pravastatin and rosuvastatin). The pharmacokinetic maximum plasma concentration (C max) and area under the concentration-time curve (AUC) parameters were evaluated for probe substrates alone and in combination with glecaprevir/ pibrentasvir. The C max central values increased by 72%, 105%, 123%, 462%, and 66% for digoxin, dabigatran, pravastatin, rosuvastatin, and sofosbuvir, respectively, and the AUC central values increased by 48%, 138%, 130%, 115%, and 125% for digoxin, dabigatran, pravastatin, rosuvastatin, and sofosbuvir, respectively. Exposure of sofosbuvir metabolite GS-331007 (nucleoside analog) was similar with or without glecaprevir/pibrentasvir. The outcomes of the clinical drug-drug interaction studies confirmed clinically relevant inhibition of P-gp, BCRP, and OATP1B1/3, and were used to provide dosing guidance for the concomitant use of glecaprevir/pibrentasvir with relevant transporter substrates.

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Digoxin bioavailability: Formulations and rates of infusions

Cited by 25 publications

References 1 publication

Disopyramide serum and pharmacologic effect kinetics applied to the assessment of bioavailability.

Disopyramide serum and pharmacologic effect kinetics applied to the assessment of bioavailability.

Evidence of nonlinearity in digoxin pharmacokinetics

Translation of In Vitro Transport Inhibition Studies to Clinical Drug-Drug Interactions for Glecaprevir and Pibrentasvir

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