Steady state pharmacokinetics of trimethoprim 300 mg once daily in healthy volunteers assessed by two independent methods.

The steady state pharmacokinetics of trimethoprim was determined after 300 mg orally once daily to 6 healthy volunteers for 9 days. The microbiological assay of plasma level was unreliable at trimethoprim concentrations greater than 4 micrograms/ml, so results from an HPLC-assay are given. Steady state was present after 3 days. The plasma concentration peaked 1 to 4 h (mean 2.0 h) after the dose at a mean of 6.0 micrograms/ml (range 3.1-9.5 micrograms/ml); the minimum value was 1.5 micrograms/ml (range 0.6-2.9 micrograms/ml). The mean AUCss was 77 micrograms/ml X h and the mean plasma clearances was 67 and 74 ml/min on Days 8 and 9. Renal clearance was about 60% of the plasma clearance. The average plasma half life was 10.6 h (range 8.7-15.3 h). Thus, there was considerable interindividual variation in all pharmacokinetic parameters. 72 h after the last dose trimethoprim was detectable in plasma in only 1 of the 6 subjects. The minimum urinary concentration of trimethoprim during treatment was always well above (range 22 to 220 micrograms/ml) the MIC values for most urinary tract pathogens. Therefore, a daily dose of 300 mg trimethoprim results in a therapeutic concentration in urine at steady state that lasts throughout the dosing interval and in most subjects probably lasts also for a further 24 h. Trimethoprim administration raised mean serum creatinine from 67 to 97 mumol/l, probably due to competitive inhibition of the tubular secretion of creatinine.

Total serum IgE in uremia and after renal transplantation.

Uremic patients on maintenance hemodialysis, but without clinical evidence of atopy or diabetes mellitus, had serum levels of total IgE significantly lower than in healthy controls matched for age and sex. Patients with uremia due to diabetic nephropathy had higher IgE levels than the reference group. No correlation was found between total IgE levels and length of dialysis treatment. After renal transplantation, the IgE levels decreased on average to 31% of the pretransplant values over a 60-day observation period. Bacterial or viral infections or episodes of kidney rejection had no apparent influence on the IgE synthesis in the patients with transplant. No correlation was detectable between pretransplant IgE levels and six-month survival of the kidney graft. The low IgE concentrations in uremia are suggested to reflect altered T-cell regulation of the IgE production. The raised IgE levels in diabetic patients could not be explained by specific reagins against insulin, but may have reflected an influence of abnormal carbohydrate metabolism on IgE synthesis. The fall in IgE levels following transplantation is proposed to be attributable to the combined corticosteroid-azathioprine treatment.

Abnormal pancreatic polypeptide response to intravenous glucose in uraemics. A possible mechanism behind impaired glucose tolerance in uraemia.

Glucose handling and insulin secretion were studied in chronic haemodialysis patients and correlated with circulating levels of immunoreactive pancreatic polypeptide (PP). No correlation was found between the elevated basal levels of PP and K-rate or the maximum insulin response after a single intravenous injection of glucose. Fifty-three per cent of the patients had a normal glucose tolerance defined as a K-rate more than 1. This group of uraemics had a tendency to an exaggerated insulin response compared with the controls but no significant changes of serum-PP levels after a glucose stimulus were observed. In contrast, uraemic patients with a K-rate less than 1 and normal insulin response, showed significant increases of serum-PP at 4 and 6 min after glucose administration. Among all uraemic patients we found a significant inverse correlation between the K-rate and the early PP response (P less than 0.05) and a significant positive correlation between the K-rate and early insulin response (P less than 0.05). PP release in response to acute hyperglycaemia may be one mechanism behind impaired glucose handling in uraemics, either by reducing peripheral insulin activity or by preventing insulin secretion sufficient to overcome the decreased tissue sensitivity to insulin.

Gastric acid secretion in uraemia and circulating levels of gastrin, somatostatin, and pancreatic polypeptide.

Basal circulating levels of gastrin, somatostatin, and pancreatic polypeptide were measured in 30 chronic haemodialysis patients. Five patients had considerably raised serum gastrin (greater than 400 pmol/1) and also gastric achlorhydria while 75% of the patients who had normal (less than 55 pmol/1) or moderately increased (less than 400 pmol/1) serum gastrin had raised maximal acid outputs. Patients with serum gastrin greater than 400 pmol/1 had significantly lower plasma concentrations of somatostatin compared with both healthy individuals and uaremic patients with normal gastrin levels. Raised serum concentrations of pancreatic polypeptide were observed in the majority of the patients but no correlation was found between this peptide and gastric acid secretion or circulating levels of gastrin and somatostatin, respectively. Prolonged circulation time for gastrin and pancreatic polypeptide was demonstrated after food stimulation. Prolonged gastrin stimulation of the parietal cell mass may lead to work hypertrophy and gastric acid hypersecretion. Whether long-standing over-stimulation by gastrin also may induce atrophy of the cells remains to be studied.