Estimation of area under the curve for drugs subject to enterohepatic cycling

Abstract

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.

Pharmacokinetic Profile of Fosfomycin Trometamol (Monuril)

“…From the values of Clu = 7, since V3 is equal to 10.4 liters, one obtains for the urinary elimination constant a value of 0.67, in close agreement with the value of k3s = 0.69 of table X. thy first-pass effect, which however, because of the intes tinal reabsorption of the drug excreted by the biliary route, does not decrease its bioavailability [Shepard et al, 1985]. The appearance of secondary peaks has not been pointed out in previous papers on fosfomycin phar macokinetics [Foltz et al, 1970a, b;Kwan et al, 1971;Cadorniga et al, 1977;Shimizu, 1977;Kirby, 1977;Goto et al, 1981;Baron and Drugeon, 1985].…”

Combining Naltrexone and Prazosin in a Single Oral Medication Decreases Alcohol Drinking More Effectively Than Does Either Drug Alone

“…NTX has an oral bioavailability of only 1% in rats (Hussain et al, 1987) which is much lower than the level of bioavailability in humans (5-40%) (Goodman and Gilman, 2006). The low oral potency of NTX in rats is due to rapid first pass metabolism, rather than to poor absorption (Shepard et al, 1985). For instance, 20 mg NTX/kg, when delivered via gavage in rats, produces a peak plasma level of only 15 ng NTX/ml during the first hour and plasma levels fall by half in the second hour (Hussain, et al 1987).…”

Absorption and disposition including enterohepatic circulation of (14C) roquinimex after oral administration to healthy volunteers

“…A multi-compartmental model with discontinuous gallbladder emptying was first suggested by Veng Pedersen et al [16]. This model has been further developed to include multiple gallbladder emptying at equal time intervals [17] and at unequal time intervals [18 -20]. In the present work, urinary excretion of an intact drug has been added to the two-compartment model with EHC.…”