Abetraet. The effect of acute uraemia on glucose and urea formation by isolated perfused liven of fasting rats was investigated.The basal gluconeogenesis following nephrectomy was significantly increased as compared to normal and sham operated controls. Enhanced glucose formation was associated with an increase in both urea synthesis and output of the p r l y metabolizable amino acids valine, leucine, and isoleucine. In the presence of a mixture of amino acids (serine, threonine, lysine, glutamic acid, ornithine, and citrnlline) all added at near physiological concentrations, the stimulating effect of uraemia on gluconeogenesis was further enhanced. This was paralleled by an increased formation of urea and an increased uptake of the amino acids. It is concluded that acute uraemia may stimulate glucose synthesis by increased substrate supply. This seems to be achieved by a t least two different mechanisms, namely increased protein degradation and accelerated amino acid utilization.

Plasma levels and diuretic response were determined in seven healthy subjects and six patients with severe nephrotic syndrome (NS) after 40 mg furosemide (Fu). Mean apparent volume of distribution and distribution volume at steady state of the groups did not differ. Total Fu clearance was higher in NS (251 +/- 54 ml/min) that in healthy subjects (174 +/- 32 ml/min) (P less than 0.01), a difference that correlated with the nonrenal clearance of 56 +/- 28 ml/min in healthy subjects and 154 +/- 45 ml/min in patients with NS (P less than 0.001). Normal beta-elimination half-life of 51 +/- 7.7 min was 37 +/- 6.2 min (P less than 0.001) in NS. Mean normal Fu protein binding pf 98.6 fell to 97.2%, with decreasing plasma albumin levels. After 40 mg IV Fu, sodium and volume excretion decreased in NS (P less than 0.001 and P less than 0.005). In patients Na+/Fu excretion rate ratios showed "tubular resistance" to Fu over the time when large amounts of Fu were excreted. The reduced diuretic response to Fu in NS is taken to be mainly a consequence of its impaired renal excretion.

After rapid intravenous injection of furosemide 40 mg (Fu), plasma levels were determined in 7 healthy volunteers, 8 patients with liver cirrhosis with ascites and 7 patients with end-stage renal disease (ESRD). The diuretic response was evaluated by measuring the urinary excretion of sodium and potassium and the urine volume. The mean elimination half life (t 1/2 beta) of Fu averaged 51 +/- 7.7 (+/- SD) min in healthy subjects, 52 +/- 7.7 min in cirrhosis and 200 +/- 57 min in ESRD. The non-renal clearance (Clnr) in healthy subjects (56 +/- 28 ml/min) corresponds to the total plasma clearance in functionally anephric patients (54 +/- 18 ml/min). In cirrhosis there was no significant change in the disposition parameters of Fu in comparison to the healthy volunteers, but there was a significant reduction in urine sodium and volume, whereas potassium excretion remained unchanged. Fu "excretion rate--response" curves showed diminished tubular sensitivity to Fu in cirrhosis.

The disposition profile of ceftriaxone was studied in 12 functionally anephric patients (creatinine clearance less than 10 ml/min) who received bolus injections of 150, 500, and 1500 mg IV in a noncrossover fashion. As in healthy subjects, the kinetics in uremic patients were nonlinear for total (bound plus unbound) and linear for free (unbound) drug. The plasma protein binding was reduced due to a decreased association constant, resulting in a doubling of the free fraction in plasma. Ten of 12 patients showed nonrenal clearance values of unbound drug (ClFNR) identical to those in healthy adults and only minor increases in their biologic t1/2(beta) compared to normal (12 and 8 hr). These patients would require no dose adjustments in their dosing regimen. Two of the patients exhibited decreased ClFNR values and increased t1/2(alpha) of 20 and 34 hr. Anephric patients with impaired nonrenal elimination would require minor dose adjustments.