Increased gastrointestinal absorption of large molecules in patients after 5-fluorouracil therapy for metastatic colon carcinoma.

Chemotherapeutic agents may damage gastrointestinal epithelium and thereby impair the mucosal barrier to bacteria and their products. In order to obtain an objective measurement of gastrointestinal permeability to large molecules, we measured urinary excretion of [14C]polyvinylpyrrolidone administered p.o. (mean molecular weight 11,000) and tobramycin (molecular weight 467) in ten patients receiving 5-fluorouracil therapy for metastatic cancer of the colon. Base-line absorption of [14C]polyvinylpyrrolidone was 0.013 to 0.048% of the administered dose. Dose-related increases in absorption (range, two to 20 fold) occurred after 5-fluorouracil administration, but the dose response differed markedly between individuals. Absorption was maximal 8 to 15 days after the start of therapy, was correlated in time but not necessarily in severity with the presence of gastrointestinal symptoms, and was unaffected by oral nonabsorbable antibiotics. Tobramycin excretion was 8.5 times greater than [14C]polyvinylpyrrolidone excretion, but the two were highly correlated in simultaneous determinations (r, 0.93; p, < 0.001). With the exception of an episode of Escherichia coli bacteremia, infections coincided not with maximal [14C]polyvinylpyrrolidone absorption but with maximal granulocytopenia 17 to 24 days after the start of therapy. The gastrointestinal absorption of polyvinylpyrrolidone provides an objective measurement of mucosal integrity which may have applications in assessing the gastrointestinal toxicity of other cytotoxic agents.

Changes in fluid-phase endocytosis in the rat with age and their relation to total albumin elimination.

Rates of fluid-phase endocytosis were determined in several organs and tissues of female WAG/Rij rats of several ages by using 125I-labelled polyvinylpyrrolidone ([125I]-PVP) as a marker. Liver, muscle and skin accounted for a high level of [125I]PVP uptake 28 h after injection. When PVP uptake was expressed per gram of organ/tissue, the liver and spleen were found to be the most active. An age-related increase in [125I]PVP uptake was seen at between 12 and 36 months of age in liver, kidneys and heart. Except for the kidneys this increase is caused by an increase in wet weight of these organs and not by an increase in the specific endocytic rate. These data, together with reported findings on the major sites of albumin catabolism, in liver, kidney, spleen and intestine, indicate that fluid-phase endocytosis is a main mechanism for the observed age-related increase in albumin elimination in these rats.

Pharmacokinetics and tissue disposition of the biological response modifier BAY i 7433 (copovithane) in patients with cancer.

Copovithane is an uncharged, water-soluble, synthetic polymer with an average molecular weight of 5800 daltons. It demonstrates antitumor activity in vivo against a variety of tumors in animal models but is inactive in vitro. This agent has been found to have immunorestorative activity in man. In concert with its phase I clinical trial, copovithane concentrations were analyzed by HPLC in plasma, urine, and autopsy and in tumor biopsy specimens obtained from patients. Copovithane was cleared from plasma biphasically with a mean t1/2 alpha of 11.1 +/- 4 min and a t1/2 beta of 246 +/- 78 min at the dose of 1 g/m2, while the plasma half-lives increased to 57.7 +/- 12 and 718 +/- 149 for the alpha and beta phases, respectively, at the 10 g/m2 dose, demonstrating clear, dose-dependent pharmacokinetics. There were no significant differences between dose 1 and dose 4 pharmacokinetics. The apparent volume of distribution (Vd) was 14.5 +/- 1. at the 1 g/m2 dose and increased to 73 1. at the 33 g/m2 dose. The calculated mean clearance rate for copovithane in plasma was between 2.4 and 5.4 mg/kg X min and did not appear to be dose-dependent. The urinary excretion of copovithane was approximately 5% of the administered dose over 120 h at the 1 g/m2 dose and decreased to 1% at the 33 g/m2 dose. In seven tumor biopsy samples, concentrations of drug in tumor varied from 1- to 1000-fold higher than that found in concurrent plasma samples. In three autopsy samples, the highest concentrations were found in kidney, intestine, and liver, in decreasing order. These studies show that copovithane exhibits dose-dependent changes in pharmacokinetics at doses between 1 and 33 g/m2. However, copovithane does penetrate well to tumor tissues, achieving high tumor/plasma ratios. In addition, copovithane concentrations were highest in kidney tissue, which may be a site for potential organ toxicity.

The elimination of albumin, ployvinylpyrrollidone and dextran from the circulation in sheep.

The rates of elimination of iodinated human serum albumin (ALBUMIN-125I), polyvinylpyrrolidone (PVP-125I); and tritiated dextran (DEXTRAN - METHOXY-3H) (mol masses of 69 000 - 72 000, 30 000 - 40 000 and 60 000 - 90 000 respectively) from the circulation of sheep were studied; albumin and PVP initially disappeared from the circulation rapidly having half-life times (t 1/2) of 10,5 +/- 3,7 and 43 +/- 45 hours respectively. This phase is regarded as being due to equilibration within the initial volume of distribution, the rate being determined primarily by the relative mol. mass of the molecule. Hereafter PVP-125I was eliminated considerably faster (t 1/2 = 176 +/- 39 h) principally via the kidneys. The limited data available for dextran-3 H suggests that this particular substance is rapidly excreted via the kidneys (t 1/2 = 9 h).

Permeability studies with exogenous macromolecules: problems arising from the use of iodinated PVP and dextrans.

The permeability of the glomerular filtration barrier with respect to molecular size could best be studied by substances which are neither secreted nor reabsorbed and have a mean molecular weight of about 40,000--80,000 daltons. Uncharged molecules are preferred because the charge definitely influences the glomerular filtration. Several such substances are available; however, in most permeability studies labelled PVP, mainly 125I- or 131I-PVP, and dextrans have been applied. Gel filtration and binding studies with 125I-PVP have demonstrated that this substance should not be used because of unspecific binding of radioactive material. The application of dextran gives more reliable results. Disadvantages, however, include the large amounts which must be administered and some cases of intolerance, particularly in rats. Therefore, experiments with dextran seem feasible in some species but not in others. Ficoll, a synthetic polysucrose, is better tolerated than dextran but still causes allergic reactions in susceptible animals.

Determination of glomerular intracapillary and transcapillary pressure gradients from sieving data. II. A physiological study in the normal dog.

The two theoretical models proposed previously to calculate the intracapillary and transcapillary glomerular pressure gradients from the sieving of macromolecules such as PVP have been used to analyse in 22 normotensive dogs the sieving curve relating the sieving coefficients, phi, to molecular size (phi: glomerular clearance of PVP fractions/GFR). Neither the "local c2" model-filtrate unmixed at the outer face of the capillaries walls--nor the constant c2 model-filtrate well mixed--allowed to obtain realistic values for the hemodynamical parameters. Indeed with the local c2 model, the best fit between calculated and experimental sieving curves could be obtained only by reversing the intracapillary pressure gradient; conversely the constant c2 model obliged to decrease the intracapillary pressure so abruptly along the capillaries, that retrofiltration took place in the distal parts of the vessels. This difficulty has been overcome by combining the two models; the so-called "hybrid model" considers that the filtrate is well mixed in the vicinity of the urinary pole only. The following results were obtained: 1. PGCa and PGCe (intracapillary pressures at the afferent and efferent extremities of the capillaries) equal to 49.7 +/- 1.03 and 41.8 +/- 1.00 mm Hg respectively. 2. Pressure equilibrium is generally reached at the efferent extremity of the vessels. 3. The slope of PGC (see article) varies inversely to FF. (filtration fraction). 4. The model, however, does not allow to rule out the possibility of retrofiltration.

Selectivity of proteinuria during pregnancy assessed by different methods.

Relative protein clearance measurements have gone a long way toward characterizing the nature of pregnancy proteinuria but have failed to distinguish between preeclampsia and primary renal disease. The prognostic significance of different degrees of selectivity has been a source of disagreement in past studies. The polymer clearance studies reported here, using tracer doses of labeled PVP, have demonstrated two forms of proteinuria: a benign form due to a vasoconstrictor effect where fetal outlook is good ("vasoactive"), and a form associated with intravascular coagulation which indicates worse fetal prognosis ("membranous"). Underlying chronic renal damage of minor degree is identifiable with PVP clearance. Concurrent measurements of protein clearance, using smaller-sized proteins than is customary, gave hope for future development of meaningful clinical tests.