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A physiologically realistic model is used to provide insight into the design of sampling protocols for accurate determination of AUC(0-infinity) for drugs subject to enterohepatic cycling. Through simulation of plasma concentration-time curves for such drugs it is found that more than one peak is predicted after oral and intravenous administration of a single dose of drug, the relative magnitude of peaks is dependent on the hepatic extraction ratio for both oral and intravenous drug administration, the percent of the AUC(0-infinity) in later time intervals is also a function of the hepatic extraction ratio, and present methods for the design of sampling protocols may not provide accurate estimates of AUC(0-infinity) (especially for highly extracted drugs), because peaks are only evident at later times after intravenous administration when plasma sampling is less frequent, much of the area occurs at later times, and the amount of drug in the sampling compartment after oral administration is much lower than that after intravenous administration of drug and could be incorrectly interpreted as low bioavailability if sampling is not carried out for a long period of time. The types of oral and intravenous profiles predicted for highly extracted drugs are exemplified by data for naltrexone in the monkey.

A study designed to investigate the relationship between the pharmacokinetics of digoxin and a measure of its pharmacological effect has been conducted. Serum digoxin concentrations and systolic time intervals were measured concurrently in 12 normal male volunteers following a 1.0 mg i.v. bolus injection. The averaged serum digoxin concentration--time and response--time data were analyzed pharmacokinetically using a three-compartment open model and nonlinear least-squares fitting. When only the serum level--time data were analyzed, a close relationship was found between calculated digoxin levels in the slowly distributing (deep) peripheral compartment and response of the heart to digoxin, as measured by changes in the QS2 index (delta QS2I). Although it was not possible to distinguish clearly a linear from a nonlinear relationship between digoxin levels in the deep compartment and delta QS2I, the nonlinear relationship gave the best overall fit when both serum digoxin and delta QS2I data were fitted simultaneously. The simultaneous fit yielded a total body clearance of digoxin of 3.6 ml/min/kg and a terminal t1/2 of 42 hr.

The anaerobic bacterium Eubacterium lentum, a common constituent of the intestinal microflora, inactivates digoxin by reducing the unsaturated lactone ring. Reduction of the cardiac glycoside by growing cultures of E. lentum ATCC 25559 proceeded in a stereospecific manner, with the 20R-dihydrodigoxin constituting more than 99% of the product formed. This is in contrast to the 3:1 ratio of 20R and 20S epimers formed in the chemical catalytic hydrogenation. Formation of the reduced glycosides proceeded quantitatively when an overall concentration of 10 micrograms/ml was added to the cultures. E. lentum did not hydrolyze the digitoxose sugars from C-3 of the parent glycoside. However, the synthetically prepared sugar-hydrolyzed metabolites (digoxigenin, digoxigenin monodigitoxoside, and digoxigenin bisdigitoxoside) were reduced to the corresponding dihydro metabolites. Repetition of the experiments with a feces sample from a volunteer who was known to be a converter of digoxin to dihydrodigoxin gave results identical to those obtained with pure E. lentum cultures.