A comparison has been made of the urinary metabolites of volunteers who had taken therapeutic doses of paracetamol with those of persons who had taken an overdose in an attempt to highlight the metabolic changes associated with massive doses. The main technique for examining urine samples was two-dimensional thin layer chromatography. Other chromatographic techniques were used for the isolation and purification of metabolites. The urinary metabolites after a therapeutic dose of paracetamol were identified as free paracetamol, paracetamol sulphate, 3-hydroxy-paracetamol-3-sulphate, 3-methoxy-paracetamol sulphate, paracetamol glucuronide, 3-methoxy-paracetamol glucuronide, paracetamol 3-cysteine conjugate and paracetamol 3-mercapturate. The same metabolites were also present in urine following overdosage but the proportions were quite different. There was particularly a big increase in the relative amounts of cysteine and mercapturic acid conjugates excreted. No new metabolites were found. The significance of these findings is briefly discussed in relation to the metabolism and toxicology of paracetamol.
We studied four patients with cystinuria to assess the effects of glutamine and dietary sodium on the urinary excretion of dibasic amino acids. In Patient 1, at an ad libitum dietary sodium intake of about 300 mmol per day, oral administration of glutamine led to reproducible and marked anticystinuria and antiornithinuria, whereas the excretion of lysine and arginine was not significantly affected. In Patient 2, at an ad libitum dietary sodium intake of about 150 mmol per day, no effect of glutamine could be demonstrated in studies lasting up to three weeks. Since the principal difference between Patients 1 and 2 was their dietary intake of sodium, Patient 3 was studied during dietary sodium intakes of 150 and 300 mmol per day. His cystine excretion was found to be higher at 300 than at 150 mmol per day. Glutamine suppressed his cystine excretion at a sodium intake of 300 mmol per day but had no effect at 150 mmol per day. When the effect of a further reduction in sodium intake alone was studied in a fourth patient, a decrease of 150 to 50 mmol per day was found to reduce cystine excretion markedly within 17 days. The low-sodium diet alone also reduced the excretion of lysine, arginine, and ornithine. We conclude that glutamine may reduce the excretion of dibasic amino acids at a high sodium intake but not at an intake of about 150 mmol per day. However, since a sodium-dependent excretion of the dibasic amino acids occurs at an intake down to about 50 mmol of sodium per day, dietary restriction of sodium can provide a safe approach to the treatment of cystinuria.
The renal transport of 125I-diatrizoate was examined in three species, dog, rabbit, and rat. In the rabbit this organic acid behaved like many such compounds, i.e. it was secreted by the proximal tubular organic anion process as judged by stop-flow analysis. The proximal tubular peak was abolished by probenecid. In vitro experiments with renal cortex slices gave results entirely consistent with the in vivo studies. Diatrizoate uptake by the slices was an energy-dependent, saturable process that was blocked by several organic acids known to be accumulated by the organic acid transport system. Rat renal cortex slices showed significant diatrizoate uptake, although of a lesser magnitude than noted with rabbit tissue (rat S/M = 1–2; rabbit S/M = 3–5). Except for the failure of acetate to stimulate diatrizoate uptake, accumulation by the rat slices appeared to be by the organic acid transport process. On the other hand, dog slices failed to accumulate diatrizoate. The process was not stimulated by acetate or any other metabolic substrate nor was it blocked by metabolic inhibitors or various organic acid competitors. No evidence of proximal tubular secretion was noted in the dog using stop-flow analysis; diatrizoate-inulin U/P ratios were approximately 0.9. Furthermore in p-amino-hippurate (PAH) clearance experiments in the dog, administration of diatrizoate failed to alter PAH clearance. These data indicate active renal transport of diatrizoate in certain species, but not in others.
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