High Renal Clearance Research Articles

Piperacillin kinetics

Piperacillin was administered to normal, healthy volunteers by an intravenous infusion over 30 min at dosage regimens of 12 gm daily (4 gm every 8 hr) and 24 gm daily (6 gm every 6 hr) for 5 consecutive days. Mean peak serum level after 12 gm daily was 244 +/- 24 (SE) microgram/ml and after 24 gm daily, 353 +/- 7 microgram/ml. After infusion the serum level declined monoexponentially in most subjects. On the 12-gm daily dosage mean values were 60 min for half-life (t1/2), 16 1 for volume of distribution, 188 ml/min for body clearance, and 139 ml/min for renal clearance. The same values on day 4 were 47 min, 12 1, 181 ml/min, and 125 ml/min; the volume of distribution was lower than on day 1. On the 24-gm daily dosage regimen, t1/2 was 60 min; volume of distribution, 16 1; body clearance, 183 ml/min; and renal clearance, 101 ml/min on day 1 compared to 68 min, 15 1, 148 ml/min, and 71 ml/min on day 4, the last 2 being significantly lower than on day 1. High renal clearance values were observed at low serum concentrations and vice versa, suggesting saturation of the tubular secretion process at high piperacillin concentrations in serum.

Evidence for renal control of urinary excretion of bile acids and bile acid sulphates in the cholestatic syndrome.

1. The bile acids and bile acid sulphates in the urine, serum and bile of eight cholestatic patients were studied quantitatively by gasliquid chromatography and gas-liquid chromoatography/mass spectrometry. 2. The primary bile acids (cholic acid and chenodeoxycholic acid) comprised on average 94% of the total bile acids in bile, 70% in the serum and 64% in urine. 3. The percentage composition of bile acids in bile was relatively constant and was not influenced by the degree of cholestasis. In contrast, in the serum only the primary bile acids were increased, the concentrations of the secondary bile acids (deoxycholic acid and lithocholic acid) and the minor bile acids remaining constant. 4. The data do not support the hypothesis that monohydroxy bile acids accumulate in cholestasis and are related to the pathogenesis of this syndrome. 5. The pattern of bile acid urinary excretion was similar to that in the serum. But in one patient, 3alpha, 7beta, 12alpha-trihydroxy-5beta-cholan-24-oic acid was a principal urinary bile acid, although very low concentrations of the compound were found in that patient's serum, suggesting that some of the minor bile acids in urine may originate by epimerization in the kidney. 6. In bile only a small proportion of the bile acids was sulphated (range 2.1-4.6%) and in serum the degree of sulphation was very variable (9-50%). However, in urine, sulphate esters accounted for a large proportion of the total bile acids (33-72%). 7. The output of bile acid sulphate in the urine was related to the urine total bile acid output but the serum concentration of bile acid sulphate remained relatively constant. Consequently, in contrast to the non-sulphated bile acids, whose renal clearance was relatively constant, the renal clearance of sulphated bile acids was directly related to the urine total bile acid output. This finding is inconsistent with the earlier hypothesis that their predominance in urine was due to a high renal clearance. It may indicate renal synthesis of some of the bile acid sulphates in the urine and/or inhibition of active renal tubular reabsorption of sulphated bile acids by non-sulphated bile acids.

Hyperdibasicaminoaciduria, hyperammonemia, and growth retardation: Treatment with arginine, lysine, and citrulline

A 9-year-old girl with hereditary dibasicaminoaciduria has been studied for three years. Initially, clinical features were: growth failure; anorexia and aversion to protein, spontaneous daily protein intake averaging only 10 gm; fasting and postprandial venous hyperammonemia; subnormal plasma concentrations of lysine, arginine, ornithine, and citrulline, with generalized hypermonobasicaminoacidemia; abnormally high renal clearances of lysine, arginine, and ornithine; and intestinal malabsorption of lysine and arginine. Intestinal absorption of citrulline, a precursor of arginine and ornithine, was normal. The patient was observed during four sequential 6-month periods as follows: no treatment (Period I); dietary supplement of arginine and lysine (Period II); dietary supplement of citrulline and lysine (Period III); no treatment (Period IV). During Periods II and III growth rate increased 3- to 4-fold, spontaneous protein intake increased 2- to 3-fold, and abnormalities in blood NH3 and the plasma aminogram were partially corrected. In most respects the citrulline plus lysine supplement was more beneficial than that of arginine plus lysine.

PHARMACOKINETICS OF DICLOXACILLIN IN PATIENTS WITH CYSTIC FIBROSIS

The frequent episodes of peribronchial pneumonia seen in patients with cystic fibrosis require antibiotic administration often with anti-staphylococcal agents. Until now the data upon which to base dosage regimens have not been available. Serum dicloxacillin concentrations and urinary excretion rates were measured in 10 patients ranging in age from 9 to 22 years and in 5 normal adult subjects at various times after oral administration of a single dose (6.25 mg/kg) of antibiotic suspension in order to investigate absorption and disposition kinetics. The disease did not appear to cause impaired absorption of the antibiotic since the total urinary recovery of the drug in the patients usually exceeded that of normal subjects. However, the peak plasma levels and areas under the concentration versus time curves of dicloxacillin were much lower and more variable in the patients than in the normal subjects. Less antibiotic is therefore available for therapeutic effect. This was the result of unusually high renal clearances of dicloxacillin (3x normal). It was significant that the dicloxacillin:creatinine clearance ratios (1.55 versus 0.87, respectively) were larger in the patients than in normal subjects. Because of this rapid renal excretion, treatment of cystic fibrosis patients with dicloxacillin warrants use of increased doses. Measurements of the serum concentration of the antibiotic may be needed to assure adequacy of therapy.

Biochemical and genetic studies in cystinuria: observations on double heterozygotes of genotype I-II.

10 families with cystinuria were investigated by measuring: (a) quantitative 24 hr urinary excretion of amino acids by column chromatography; (b) endogenous renal clearances of amino acids and creatinine; (c) intestinal uptake of (34)C-labeled L-cystine, L-lysine, and L-arginine using jejunal mucosal biopsies; (d) oral cystine loading tests. All four of these were studied in the probands and the first two in a large number of the family members.49 members of 8 families were found to have a regular genetic pattern as described previously by Harris, Rosenberg, and their coworkers. Clinical or biochemical differences between the homozygotes type I (recessive cystinuria) and homozygotes type II (incompletely recessive cystinuria) have not been found. Both types excreted similarly excessive amounts of cystine, lysine, arginine, and ornithine, and had high endogenous renal clearances for these four amino acids. Some homozygotes of both types had a cystine clearance higher than the glomerular filtration rate. Jejunal mucosa from both types of homozygotes exhibited near complete inability to concentrate cystine and lysine in vitro. This was also documented in vivo with oral cystine loads. The heterozygotes type I were phenotypically normal with respect to the above four measurements. The heterozygotes type II showed moderate but definite abnormalities in their urinary excretion and their renal clearances of dibasic amino acids. Of the four amino acids concerned, cystine was the most reliable marker to differentiate between the heterozygotes type II and the homozygous normals. In this study, type III cystinuria, as described by Rosenberg, was not encountered. In two additional families, double heterozygotes of genotype I/II were found. The disease affecting these is clinically and biochemically less severe than that affecting homozygotes of either type I or type II. With respect to the four parameters used in this study, the double heterozygotes type I/II have results which are intermediate between those of the homozygotes type I and II and those of the heterozygotes type II.

Hypophosphataemic osteomalacia presenting in adults.

Nine patients were studied with primary hypophosphataemic osteomalacia presenting in adult life. The clinical features of this relatively homogeneous syndrome include bone pains, muscle weakness, and often marked height loss due to vertebral collapse. There is no history of rickets or other disease in childhood, and the incidence is entirely sporadic. Radiological and biochemical findings are otherwise typical of the sex-linked form of ‘vitamin D resistant’ osteomalacia, with normal plasma and urinary calcium, variably raised alkaline phosphatase, and persistent hypophosphataemia due to high renal phosphate clearance. In addition many patients exhibit increased urinary glycine excretion readily detectable on routine paper chromatography. Treatment of this condition requires oral phosphate supplements, probably for life, in addition to high doses of vitamin D. Calcium supplements are also valuable during the healing phase (approximately one year). Gastrointestinal upset, especially diarrhoea, may complicate necessary phosphate treatment. Our initial regime now includes vitamin D2 5 mg daily, dibasic sodium phosphate (Na2HPO4.10H2O) 10 g daily (or equivalent, e.g. ‘Phosphate Sandoz’), and a calcium supplement providing approximately 1000 mg daily. The maintenance dose of vitamin D is under 2 mg a day and calcium supplements may be withdrawn after approximately 1–2 years.

The fate of guanethidine in two hypertensive patients.

Metabolites of [3H]‐guanethidine were identified in human urine. It was found that 90 per cent of the radioactivity in urine could be accounted for as guanethidine and two metabolites which had much less antihypertensive activity. After intramuscular injection, 50 per cent of the radioactive dose was eliminated in the urine in the first 2 to 3 days and 2 to 3% in the feces. Thereafter the dose left in the body declined exponentially with a half‐life of 9 to 10 days. Plasma level measurements indicated high renal clearance for guanethidine (300 ml. per minute). The hepatic clearance of the drug was also estimated to be high. The long half‐life of the drug is therefore not due to inefficient metabolism or renal clearance and must be due to a high degree of tissue localization. After an oral dose, plasma levels of the drug stayed approximately constant from 1 to 10 hours, indicating slow but continuous absorption of the drug, while radioactivity in the urine showed that absorption was incomplete. The ratio of metabolites to unchanged guanethidine in the urine was much larger after oral than after intramuscular administration of guanethidine to the same patient, suggesting that a significant amount of the drug was metabolized while passing through the liver. The results indicate that absorption, renal clearance, metabolism, and tissue uptake of guanethidine all play important parts in determining the amount of drug in the body of patients receiving regular treatment.

C AUTOSOMAL TRISOMY WITH MOSAICISM: A NEW SYNDROME?

The presence of a C trisomy with euploid mosaicism was observed in the blood and marrow cells of a 2-month-old boy. The autosomal nature of the supernumerary chromosome was inferred from the absence of sex chromatin bodies, the lack of "drumstick" appendages on polymorphs, and a failure to identify a late-replicating member among the submedian chromosomes of aneuploid cells which were studied by autoradiography. Malformations included an asymmetrical head, corneal opacity, abnormal ears, tapered fingers with joint limitations, anomalies of the right kidney, and a probable congenital heart defect. Analysis of amino acid excretion revealed a high renal clearance for proline, hydroxyproline, and glycine. The patient's condition has been compared to seven other patients with a C trisomy, five of which had euploid mosaicism. Certain recurrent findings, such as normal stature, advanced bone age, skeletal anomalies, particularly of the ribs and vertebrae, narrow pelvis, joint limitations, finger retractions, and hypertonicity, were noted. Therefore, it is possible that a rare trisomy for a C autosome exists which may be responsible for a definite syndrome.