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The equation log(concentration) = a + bl V'TTTO + c + d -(T -4) was used to calculate serum level curves from individual data sets of drug serum concentrations, obtained from experiments with orally administered drugs. These curves were subsequently used to calculate peak values, times for onset of peak, area, and other pharmacokinetic parameters that ought to be independent of any preconceived theory about the behavior of the drug in the system. A program is described by which parameters for individual data sets can be calculated and a mean curve with a peak value, time for onset of peak, and area equal to the arithmetic mean of the corresponding values for the participating subjects, is produced. The results of this method are compared to those of the ''one-compartment model with lag time" and shown to be superior in all the test cases. In particular, the proposed method performs well with data from a highly protein-bound drug, for which the one-compartment model fails completely. Data sets of six to eight samples taken over the entire period of detectable serum levels, with 10% analytical error in the results, gave estimates of peak value and area with a coefficient of variation of 6 to 9%, whereas the variation in the estimates for different subjects in a treatment group amounted to 20 to 60%. This shows that the proposed method, although able to cope with a short series of imprecise measurements available in practical work, is still sufficiently sensitive to detect real differences between the individual subjects. This model implies that the following conditions are true. (i) At the moment of application, (T = 0), the whole dose is instantaneously transferred to the sites of absorption. (ii) The absorption then takes place at a rate proportional to the remaining, unabsorbed part of the drug, all of which is gradually absorbed into the blood stream. Diffusion processes through membranes do not influence the absorption process, and drug loss by destruction in the stomach or excretion through the intestines can be ignored. (iii) Either no reversible exchange of drug takes place between serum and the various body organs or the equilibrium concentrations for such exchanges are established at a rate much greater than the absorption and elimination proper. Drug loss from these organs in ways other than through the blood stream is negligible. (iv) If alternative routes of elimination compete, e.g., metabolization and renal excretion, each of these processes must be of the first order, i.e., proceed at a rate proportional to the drug concentration in the serum. (v) If part of the drug is eliminated via the enterohepatic system, reabsorption in the intestines can be ignored.Equation 1 should not be used for a drug that is suspected of violating one or more of the above-mentioned conditions. Many drugs may belong to this category, and many modifications of the basic model have been proposed to counteract the effects of such deviations. The simplest modification is the introduction of a lag time, 4, to account for the ...

A mathematical model, involving three consecutive first order reactions, has been applied to already existing experimental material in order to explain the hourly variation in serum levels obtained after administration of varying repeated doses of different preparations of p-aminosalicylic acid to human volunteers. The model closely agrees with the experimental data for all the orally administered preparations concerned, and the differences in blood levels for different preparations can be explained in terms of the values attributed to the parameters involved in the model.The same model adequately describes the elimination of aminosalicylic acid from the blood after a single intravenous infusion provided that the initial blood level attained does not exceed about 11 mg/100 ml., but fails at higher values. In the latter instance a second order model gives a good fit to the experimental curves. The increase in serum levels found experimentally for the same subjects during the first weeks of prolonged treatment with phenyl-p-aminosalicylate corresponds to a change in the values of the parameters for the elimination from the blood only.First order reactions have previously been proposed to explain the elimination of various drugs from the blood stream, and a combination of two consecutive first order processes has been used to account for the absorption into and subsequent elimination from the blood of orally administered preparations. Wiegand & Taylor (1960) have developed formulae for the combination of three consecutive first order reactions in order to explain the effects of sustained-release tablets.Various methods for estimating the rate constants in the first order reactions involved have been described in the literature. Dominguez & Pomerene (1945), using a model not specifying the absorption process, determined the rate constant for elimination from that part of the experimental curve where absorption has become negligible, and calculated the absorption rate from the fitted curves for blood level and excretion rate as found by urine determinations. Nelson (1960), using a similar model calculated the absorption rate from urine values only, while Wiegand & Taylor (1960) determined the rate constant for the sustained-release process from in vitro experiments. METHODSIn the present study none of these methods were applicable because the already existing experimental material did not include urinary determinations or in vitro experiments for the sustained-release process; moreover the scheme involving three doses per day prevented the elimination process from becoming dominant for a sufficiently long time to obtain a reasonably good estimate of the elimination rate constant. Therefore, it was decided to obtain direct estimates of the three rate constants and the apparent distribution volume by non-

Summary1. By combining the agar plate diffusion technique for determination of antibiotic activity and zone microelectrophoresis in agar gel, the activity of fusidic acid in individual serum proteins of blood and pus obtained from patients given sodium fusidate revealed albumin to be responsible for the protein binding of this antibiotic. 2. Based on the assumption that only free fusidic acid is microbiologically active, the relationship between the concentration of albumin and the ratio of free to total fusidic acid was determined at four concentrations of free fusidic acid, using as test organisms four differently sensitive variants of a Staphylococcus aureus strain. At each concentration an increasing amount of albumin (0-40 mg/ml culture medium) decreased the activity of fusidic acid as determined in serial dilutions (IC50 4. The mean blood concentration was 20-8 jg/ml and the mean pus concentration 17-2 ,ug/ml in nineteen sets of blood and pus samples. The ratio of pus to blood corresponds to the ratio of published values for the protein concentrations in serum and in inflammatory oedema. 5. It is concluded that for albumin bound drugs the 'storage depot' of the organism also includes the fluid of the tissue spaces including the inflammatory oedema. As recent studies have revealed an extravascular albumin pool similar in size to the plasma pool, this 'storage depot' should not be neglected.

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