Digoxin, in plasma

ER Garrett, PH Hinderling. Pharmacokinetics of beta methyl digoxin in healthy humans part 4 comparisons of radioimmunoassays total radioactivity and specific assays of beta methyl digoxin and digoxin in plasma. J Pharm Sci 66 806, 1977. 

The LCEC method in conjunction with the optimal assay parameters resulted in a very sensitive immunoassay for digoxin in plasma throughout its therapeutic range, with a detection limit of 50 pg/ml. A standard curve is shown in Fig. 7. The relative standard deviation of ip obtained for any given digoxin standard ranged from 4% to 12% on various days and is comparable to results ordinarily obtained by other heterogeneous enzyme immunoassays. Approximately 20 samples can be injected per hour. 

Fig. 6. Heterogeneous enzyme immunoassay with LCEC detection for a series of digoxin standards in plasma solutions. Concentration of digoxin in plasma samples (A), 5.0, (B) 2.0, (C) 1.0, (D) 0.5, and (E) 0 ng/ml. Assay conditions 10 pg/ml antibody coating concentration, 1/125 digoxin-alkaline phosphatase conjugate dilution, 4 h antigen/antibody incubation interval, and 40 min substrate reaction time. (Reprinted with permission from Wehmeyeretal., 1986. Copyright 1986, American Chemical Society.)...

Because digitoxin is a nonpolar, lipophilic glycoside, absorption from the GI tract is complete. About 90% of the dmg in plasma is tightly bound to protein. It is metabolized in the Hver to many metaboHtes, including digoxin which is the only pharmacologically active metaboHte. The dmg is excreted via the bile into feces. The elimination half-life of digitoxin is seven to nine days (87). 

Digoxin is rapidly absorbed from the gut in the fasting subject and reaches a peak concentration in plasma after 30-60 minutes. When taken with food absorption of digoxin is delayed and peak plasma levels occim around 120 minutes after ingestion (W8). Steady-state levels are reached 4-6 hours after the last oral dose. In patients receiving long-term therapy plasma digoxin levels fall slowly with a plasma half-life of about 34 hours (D8). 

Digoxin in the blood is virtually conflned to the plasma where, in the therapeutic range, only a relatively small percentage (30%) is protein-bound (P7). After a single intravenous injection of digoxin only 3% remains in the blood after 1 hour in normal subjects (M6). Since only 30% is excreted during the first 24 hours after injection, the data indicate a large volume of distribution. 

Correlation between the daily dose of digoxin and plasma digoxin levels in randomly selected patients (E8) is poor, but it is improved if only those with normal renal function are considered (C4, R4). The difference is consistent with the primary role played by the kidneys in the excretion of digoxin and the likelihood that many patients treated with digoxin are elderly and infirm and have impaired renal function (B6). 

The majority of authors agree that plasma digoxin levels in adequately digitalized but nontoxic patients are lower than those in whom toxic symptoms are present and prominent, but there is considerable overlap. Moreover, precise limits for therapeutic effectiveness and toxicity are, for reasons already discussed difficult or impossible to define. Few patients derive much benefit from digoxin at plasma levels below 0.7 ng/ml, and toxic symptoms do not become unduly frequent until plasma digoxin levels exceed 2 ng/ml. 

F2. Fogelman, A. M., La Mont, J. T., Finkelstein, S., Rado, E., and Pearce, M. L., Fallibility of plasma-digoxin in differentiating toxic from non-toxic patients. Lancet ii, 727-729 (1971). 

The maximum possible amount of digoxin present in the body at 12 hours, if it were completely absorbed and not lost at all, would be (0.5 -I- 0.5) = 1 mg. The plasma half-life (the length of time it takes for the plasma concentration to fall by 50%) of digoxin in normal individuals is around 36 hours, so at 12 hours after the first dose we would anticipate rather less than 1 mg to be retained - probably about 0.6 mg if digoxin in this case is 70% absorbed. So a very crude estimate of Vd would be... 

UnUke quinidine, disopyramide does not increase the plasma concentration of digoxin in patients receiving a maintenance dose of the cardiac glycoside. Hypoglycemia has been reported with the use of disopyramide, particularly in conjunction with moderate or excessive alcohol intake. 

FIGURE 28.3 Effect of Pluronic P85 on the digoxin brain/plasma ratio in the wild-type mice when compared to the mdr la/b (—/—) knockout mouse at 5 h postdose. A tracer dose of [3H]-digoxin (4 p,Ci 7.8 gg/kg) in PBS control or 1% Pluronic P85 solution (100 xL) was administered intravenously into wild-type control group or Pgp knockout mice. Four hours following injection animals were sacrificed and the amount of digoxin in the blood in the brain was assayed. (From Batrakova, E., et al. J. Pharmacol. Exp. Ther., 296, 551, 2001. With permission.)... 

Drug interactions include rise in plasma concentration when concomittant administration with cimetidine and lowering of the concentration with barbiturates, phenytoin, rifampin. Digoxin levels may be variably affected, can rise. 

ACE INHIBITORS DIGOXIN t plasma concentrations of digoxin when captopril is co-administered in the presence of heart failure (class II or more severe) or renal insufficiency. No other ACE inhibitors seem to interact in the same way Uncertain postulated to be due to 1 renal excretion of digoxin Monitor digoxin levels watch for digoxin toxicity... 

DIGOXIN RIFAMPICIN Plasma concentrations of digoxin may be 1 by rifampicin Rifampicin seems to induce P-gp-mediated excretion of digoxin in the kidneys Watch for a 1 response to digoxin, check plasma levels and t the dose as necessary... 

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