A physiological model of renal drug clearance is presented with the aim of establishing a basis for adjusting drug dosing regimens in renal insufficiency. In agreement with the morphology of blood supply to the nephron, the model assumes serial arrangement of the processes involved in drug excretion. Fractional extraction by filtration in the glomeruli is defined in terms of the product of the unbound fraction of the drug, the filtration fraction being responsible for the limited extraction efficiency of this process. For a description of the limitations of the tubular secretory process by plasma flow through peritubular capillaries, the parallel tube model is utilized. The assumption of direct proportionality between the transport maximum of the secretory process and filtrate flow in the tubules permits a quantitative comparison of the intrinsic tubular secretion clearance and the effectiveness of the filtration process. Provided that the secretory mechanism is highly effective, renal clearance becomes dependent only on kidney plasma flow and the fraction of drug not reabsorbed in the tubules. Tubular reabsorption results only in a proportional decrease in renal clearance. The model predicts proportionality of renal drug clearance to GFR, which as a rule is used for dosage adjustment of drugs in renal insufficiency, only for compounds exclusively excreted by filtration. Compounds also excreted by tubular secretion in general exhibit a curvilinear relationship. The curvature is less pronounced as an increasing fraction of the drug is protein bound in blood. Therefore, for dosage adjustment of drugs secreted in the tubules and highly bound in blood, proportionality between renal clearance and GFR can serve as a reasonable approximation.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship of L-DOPA plasma level, parameters of ERG and severity of extrapyramidal symptoms after a single dose of L-DOPA was investigated in 11 patients suffering from parkinsonism of idiopathic or arteriosclerotic origin. After a drug-free night, each patient received his/her usual morning dose of L-DOPA. In the subsequent 3 h, the ERG recordings, blood levels and clinical ratings of extrapyramidal symptoms significantly dropped after a delay of 60 min in relation to the occurrence of the peak plasma L DOPA level. The initial "b" wave amplitudes as well as initial serum potassium values were abnormally high. There was a statistically significant correlation between the decrease of "b" wave amplitude (delta "b") and the potassium "normalization index" (i.e. the ratio between the observed decrease of serum potassium and the pretreatment difference from the middle normal potassium value). A definite interpretation of the data cannot be provided until more knowledge about the origin of "b" wave of ERG is available. It can be concluded tentatively that dopaminergic processes influence electrophysiological reactivity of the retina.

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Both transport and biotransformation processes for a series of pyrimidine nucleobases, ribonucleosides, 2'-deoxyribonucleosides, and acetyl and 5'-substituted derivatives of the cancerostatic agent araC were studied in the isolated everted rat jejunum with a continuous perfusion technique. Metabolic alterations during penetration were assessed by HPLC. 5'-Halogeno and 5'-deoxy derivatives of cytosine nucleosides exhibited higher transport rates and higher stability towards the deamination reaction than did unsubstituted derivatives. Octanol-buffer partition coefficients were estimated for the study compounds, and fragmental constants for the sugar moieties of nucleosides were assessed. With the present study compounds there was no correlation between lipophilicity and transport rate, as previously reported, but there was a correlation between lipophilicity and metabolic alteration of araC derivatives (r = 0.99, n = 5).