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The linear trapezoidal rule method is commonly used for the estimation of the area under the plasma level-time curve. Error analyses are performed when the method is used in first-order absorption and first-order elimination kinetics in the one-compartment system. It is found that significant underestimations and overestimations in area during the absorption phase and postabsorption phase, respectively, can occur when the method is improperly used. During the exponential postabsorption phase the relative error is only a function of the ratio (n) of the time interval over the half-life of the two plasma data points in the interval. The error from the linear trapezoidal rule method at n = 0.5 is about 1%. The error increases to 15.5% and 57.1% when n is increased to 2 and 4, respectively. It is recommended that for most absorption studies the linear trapezoidal method be used for prepeak and plateau plasma data and the logarithmic trapezoidal method for postpeak plasma data.

Potential causes for reported incomplete (usually 40-60%) and often highly variable (e.g., 11-79%) bioavailability of furosemide in humans were investigated. The drug was found to be fairly stable in gastric fluids and its hepatic first-pass elimination (HFPE) was estimated to be much less than 6% based on published i.v. data. The rat was used as the main model for extensive evaluation. About 4% (n = 4) of dose was recovered unchanged in the GI tract after i.v. injection while about 40% (n = 12) was recovered after a 120-fold (0.05-6 mg) dose range of oral administration. In another study 70% of the oral dose eventually disappearing (presumably due to absorption and first-pass elimination) from the GI tract was estimated to occur in just 20 min. These data indicate an unsaturable, incomplete, site-specific absorption as well as a lack of dissolution-rate-limited absorption at the doses studied. Based on plasma data, oral bioavailability in four rats was only 30%, and the HFPE much less than 10%. After oral administration, 61% of the dose was absorbed and/or metabolized in the GI recovery study. Thus, 20-30% of oral dose in rats must be metabolized in the GI wall during absorption. The metabolic activity of stomach (homogenate) from 5 rats was found to be much (e.g., 5-10.5-fold) greater than those of liver and small intestine. This was also confirmed in preliminary studies with 3 rabbits and 1 dog. Large intersubject variability in enzyme activity was found in rats and rabbits. The phenomenon of a presystemic first-pass effect was also substantiated by urinary excretion data of a metabolite. It is postulated that variable gastric and intestinal first-pass metabolism may be a major factor causing incomplete and irregular absorption of furosemide in humans.

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A single-compartment model is proposed to describe the pharmacokinetics of creatinine in man. Based on the information from the literature, it was estimated that the average biological half-life of creatinine in normal male adults between 20 to 39 years old is 3.85 hours. This half-life is prolonged in renal patients and becomes 77 hours when renal function decreases to 5 per cent of normal. Based on pharmacokinetic analysis, it was also shown that the time required to reach a new steady-state serum creatinine level after onset of renal failure is highly dependent upon the degree of renal insufficiency. For example, for the subjects analyzed in this paper, it was estimated that it will take 1.1, 2.5, 6.7, and 13.4 days to reach 95 per cent of the steady-state levels when the renal function drops to 50, 25, 10, and 5 per cent of the normal capacity. The model analysis also predicts that from a practical point of view the daily fluctuation in serum level in patients with better than 25 per cent of normal renal function is not very significant. On the other hand, the fluctuation in the early stage of severe renal failure is predicted to be very dramatic. The analysis also predicts that the serum level will decrease to a normal or near normal value within two days after improvement of renal function from moderately to severely impaired state. The data obtained from an anuric patient seems to support the validity of the pharmacokinetic approach used in this study. The implications of the above pharmacokinetic analyses for the monitoring of renal function and dosage regimen modifications in patients with renal insufficiency were discussed.