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Theoretical analysis of the stability of finite difference deconvolution (FDD) indicates that if the cumulative amount function is used to characterize the drug input the method is stable for any sampling schedule for an intravenous unit impulse response function. The analysis also indicates that the method is stable for an oral unit impulse response only for well designed sampling schedules. This article confirms these results through numerical simulation experiments. It is shown that the assumption that the unit impulse response is error-free has an influence on the performance of FDD which is generally of no practical significance, except possibly for the first few points estimated. It is also shown that there is no significant interaction between the statistical error due to data noise and the deterministic algorithm error. The major source of error in practice is likely to be the data noise in the input response function. The simulations confirm that, with the estimated cumulative amount function as the quantity estimated and, with a well designed sampling schedule for the case of an oral unit impulse response, FDD is in practice an accurate and stable method with acceptable precision under a typical error disturbance.

Analysis of the stability of finite difference deconvolution (FDD) shows that it is dependent on the characteristics of the unit impulse response function and the sampling schedule of the input response function, and that stability properties are improved when the cumulative amount function is directly estimated rather than the rate function. The estimated input rate for an intravenous (iv) unit impulse response function and the release rate for an oral solution unit impulse response function are unstable for any sampling schedule of the input response function. However, for an iv unit impulse response function, the estimated cumulative amount absorbed is stable for any sampling schedule of the response function. For an oral unit impulse response function, the estimated cumulative amount released is unstable for all the sampling points of the input response function located before the time of the maximum of the oral unit impulse response function, but it can be made stable if an appropriately designed sampling schedule of the input response function is used. In addition, the theoretical basis for choosing a sampling schedule to overcome the instability of FDD has been established.

The disposition of hydroxychloroquine enantiomers has been investigated in nine patients with rheumatoid arthritis following administration of a single dose of the racemate. Blood concentrations of (-)-(R)-hydroxychloroquine exceed those of (+)-(S)-hydroxychloroquine following both an oral and intravenous dose of the racemate. Maximum blood concentrations of (-)-(R)-hydroxychloroquine were higher than (+)-(S)-hydroxychloroquine after oral dosing (121 +/- 56 and 99 +/- 42 ng/ml, respectively, P = 0.009). The time to maximum concentration and the absorption half-life, calculated using deconvolution techniques, were similar for both enantiomers. The fractions of the dose of each enantiomer absorbed were similar, 0.74 and 0.77 for (-)-(R)- and (+)-(S)-hydroxychloroquine, respectively (P = 0.77). The data suggest that absorption of hydroxychloroquine is not enantioselective. The stereoselective disposition of hydroxychloroquine appears to be due to enantioselective metabolism and renal clearance, rather than stereoselectivity in absorption and distribution.

Hydroxychloroquine, a slow acting antirheumatic drug, is administered as the racemic mixture. Blood concentrations of the two enantiomers of hydroxychloroquine were measured in two studies, one study of eight patients, in whom blood and urine concentrations were measured during the first 6 months of therapy with rac-hydroxychloroquine, and one of 43 patients who had received rac-hydroxychloroquine therapy for at least 6 months. In the latter study rheumatoid disease activity was also measured. The pharmacokinetics of hydroxychloroquine were found to be enantioselective. The concentrations of (-)-(R)-hydroxychloroquine were higher than those of the (+)-(S)-antipode in all patients at all time points, although the ratios of the two enantiomers did display a two to three fold variability between patients. Both total and renal clearance were greater for the (+)-(S)-enantiomer. From the observational, cross-sectional study design used, it was not possible to differentiate concentration-effect relationships of the two enantiomers. The 11-fold range of drug concentrations swamped any effect of variability between patients in enantiomer proportions. Blood concentrations of both enantiomers were significantly higher in groups of patients with less active disease.

A new definition of the mean residence time is proposed which includes the commonly used definition as a special case. The advantage of the new definition is that it applies for both linear and non-linear systems. Some practical advantages which follow from the new definition are discussed. Procedures for using urinary excretion data in mean residence time estimation are discussed.

The potential importance of lysosomes as a site of accumulation of weak bases in tissues is discussed. A simple mathematical treatment predicts the quantitative significance of lysosomal trapping for monoacidic and diacidic weak bases. The features which are characteristics of lysosomal trapping are discussed, particularly in comparison with active transport and intracellular binding mechanisms. These features include: linear accumulation at low concentrations; nonlinearity at higher concentrations; dependence on structural integrity of tissue; energy dependence and competition with other weak bases. Subcellular distribution studies have previously shown that weak bases accumulate extensively in membranes; however, the dependence of accumulation on the structural integrity of tissue suggests that this is not the only significant mechanism of accumulation. The results of a range of studies of tissue distribution of weak bases are discussed to illustrate that these findings are consistent with accumulation in lung and liver being attributable to a combination of lysosomal trapping and accumulation in membranes whereas, in muscle, accumulation in membranes is the predominant mechanism of accumulation. The possible pharmacokinetic significance of lysosomal trapping of weak bases is also discussed.