Respective Plasma Concentrations Research Articles

Bioequivalence.

The bioequivalence of two formulations of the same drug may be determined by evaluating the similarity of their respective plasma concentration curves. The similarity of two plasma concentration functions can be measured by an index called the bioequivalence index. This paper shows how such an index may be defined and calculated.

Spatially Resolved Adsorption Kinetics of Immunoglobulin G onto the Wettability Gradient Surface

Total internal reflection fluorescence (TIRF) was combined with charge-coupled-device (CCD) photon detection in measuring spatially resolved protein adsorption kinetics along one of the linear dimensions of a flat surface. The experimental method was designed to study the kinetics of binding of fluorescein-labeled immunoglobulin G (FITC-IgG) onto the surfaces with the wettability gradient. Protein was adsorbed from a flowing buffer solution. The buffer solution contained either only fluorescein-labeled immunoglobulin G or FITC-IgG and two other unlabeled proteins: albumin and fibrinogen. The concentrations of proteins were 1/1000 of the respective protein concentrations in plasma. Adsorption of FITC-IgG was dependent on the wettability of the surface as well as on the presence of other proteins in the adsorbing solution. The exchange of surface-bound FITC-IgG with other proteins was observed along the wettability transition region of the gradient surface but not at either the hydrophobic or the hydrophilic sides. The amphiphilic interface between the microscopic hydrophobic and hydrophilic domains in the wettability transition region of the gradient surface was proposed to explain the adsorption behavior of FITC-IgG. The spatially resolved TIRF-CCD method has the potential of detecting the fast protein adsorption, desorption, and exchange processes from complex protein mixtures, such as serum and plasma.

Hemophilia as a defect of the tissue factor pathway of blood coagulation: effect of factors VIII and IX on factor X activation in a continuous-flow reactor.

The effect of factors VIII and IX on the ability of the tissue factor-factor VIIa complex to activate factor X was studied in a continuous-flow tubular enzyme reactor. Tissue factor immobilized in a phospholipid bilayer on the inner surface of the tube was exposed to a perfusate containing factors VIIa, VIII, IX, and X flowing at a shear rate of 57, 300, or 1130 sec-1. Factor Xa in the effluent was determined by chromogenic assay. The flux of factor Xa (moles formed per unit surface area per unit time) was strongly dependent on wall shear rate, increasing about 3-fold as wall shear rate increased from 57 to 1130 sec-1. The addition of factors VIII and IX at their respective plasma concentrations resulted in a further 2- to 3-fold increase. The direct activation of factor X by tissue factor-factor VIIa could be virtually eliminated by the lipoprotein-associated coagulation inhibitor; however, when factors VIII and IX were present at their approximate plasma concentrations, factor Xa production rates were enhanced 15- to 20-fold. These results suggest that the tissue factor pathway, mediated through factors VIII and IX, produces significant levels of factor Xa even in the presence of an inhibitor of the tissue factor-factor VIIa complex; moreover, the activation is dependent on local shear conditions. These findings are consistent both with a model of blood coagulation in which initiation of the system results from tissue factor and with the bleeding observed in hemophilia.

Absolute Bioavailability of Carbamazepine After Oral Administration of a 2% Syrup

Two healthy male volunteers received 10 mg carbamazepine (CBZ) as a 2-h constant-rate intravenous (i.v.) infusion and 100 mg 15N-labeled CBZ as a 2% oral suspension, concomitantly. The two compounds have identical pharmacokinetics. Their respective concentrations in plasma were determined by gas chromatography-mass spectrometry (GC-MS) for 168 h. The comparison of the areas under the plasma curves (AUC) obtained by the two routes of administration, showed the systemic availability of CBZ given as an oral suspension to be equal to its availability when given intravenously. A two-compartment model was estimated: The apparent volume of distribution of CBZ at the steady-state (Vss) was approximately 1 L/kg.

Antigen Levels of Plasminogen Activator Inhibitor Type 1 in Citrated Plasma: Determination of the Contribution of Platelets

To estimate the extent of the release of plasminogen activator inhibitor type 1 (PAI-1) from platelets following their accidental activation in vitro during blood collection, we studied the antigen levels of PAI-1 and beta-thromboglobulin (beta TG) in plasma and sera from 38 healthy volunteers. For each volunteer, we calculated the ratio of platelet-derived PAI-1/platelet-derived beta TG from the difference in their respective concentrations in serum and plasma. The mean +/- SD (0.012 +/- 0.003) and median (0.012) ratios were identical before and after 10 or 20 min of venous occlusion. The platelet contribution of PAI-1 in plasma was estimated by multiplying the plasma concentration of beta TG (as a marker of platelet activation) with the above-mentioned individual ratio. Under our conditions of blood collection (1/10 vol of 0.1 M citrate, pH 4.5, as anticoagulant, and handling of blood at 4 degrees C and within 30 min), the platelet contribution to the PAI-1 concentration in plasma was on average 12% and always negligible in plasma with high levels of PAI-1.

Quantitative analysis of polyols in human plasma and cerebrospinal fluid

We used gas chromatography in conjunction with flame ionization detection to quantitative nine polyls and aldo and keto sugars (as silyl derivatives) in human plasma and cerebrospinal fluid (CSF). Rhamnose, not found in CSF or plasman, was used as an internal standard with a lower limit of quantitation of 0.4 mg/l. CSF polyol and sugar concentrations (mean ± S.D.) in fourteen healthy subjects (age range 27.1-85.9 years) were: anhydroglucitol, 19.9 ±5.3 mg/l;arabitol, 4.8±0.9 mg/l; erythritol, 2.4±0.5 mg/l; myoinositol, 29.6±8.3 mg/l; ribitol, 1.6±0.1 mg/l; fructose, 25.5±11.1 mg/l;glucose, 587±70 mg/l;glucitol, 7.7±1.5 mg/l;and mannose, 10.6±2.4 mg/l. The respective plasma concentrations were 30.6±11.5, <0.4, 0.4±0.2, 6.3±2.6, <0.4, 23.4±21.4, 897±214, <0.4 and 13.7±6.3 mg/l. Polyol CSF-to-plasma concentration ratios greater than 2 were observed for myoinositol, erythritol, arabitol, glucitol and ribitol, indicative of active accumulation or synthesis of these polyols within the central nervous system.

Subfractionation of 1.006-1.063 g/ml components of badger plasma lipoproteins by using heparin-Sepharose affinity chromatography: relevance to the endocrine regulation of lipoprotein metabolism

Badger plasma lipoproteins with density 1.006-1.063 g/ml have been subfractionated by means of affinity chromatography on a heparin-Sepharose column, using a modification of the method reported by Weisgraber and Mahley (1980. J. Lipid Res. 21: 316-325). These experiments have provided evidence for the presence of three lipoprotein subfractions hereinafter termed fractions I, II, and III. Fraction I was cholesteryl ester- and phospholipid-rich (ca. 35% and 30% of lipoprotein mass, respectively), and contained apoA-I as its prominent apolipoprotein constituent. In contrast, triglyceride-rich fractions II and III both exhibited a complex apolipoprotein pattern, including apoB-100, apoA-I, and apoE whose amino acid composition and NH2-terminal sequence in the badger are reported. However, fraction III appeared markedly enriched in apoE when compared to fraction II. On polyacrylamide gel electrophoresis, fraction I presented as a spectrum of particles with diameters in the 140-190 A range. In contrast, fraction II migrated as a single band with a diameter of approximately 200 A, and fraction III presented as a single band or a doublet with a diameter of 195-200 A. The respective plasma concentrations and chemical compositions of the three chromatographic fractions were determined at four different dates of the year (i.e., April, August, November, and January), each of which corresponded to a different endocrine status in the badger. Thus hypothyroidism appeared to be associated with an increase in the concentration of fraction I, while the lowering in summer of the plasma level of testosterone correlated well with an increase in the concentration of fraction II. At the same time, the respective proportions of hydrophobic lipids in this latter material modified with an increase of triglycerides. Finally, both the apolipoprotein pattern of fraction III, and the chronologic profile of the successive variations of its concentration, suggest that it could represent a metabolic precursor of fraction II. These results suggest that the respective metabolism of the lipoproteins constituting the three chromatographic fractions could be under control by thyroid and testis secretions, operating via a complex combined regulation of the activities of the enzymes and receptors involved in these metabolic processes.

Red blood cell catecholamine levels in normotensive and DOCA-salt hypertensive rats.

Under basal conditions in anesthetized rats, significant concentrations of free norepinephrine (NE), epinephrine (E), and dopamine (DA) were detected in red blood cell (RBC) lysate. These concentrations were not proportional to their respective plasma concentrations and thus RBC-to-plasma concentration ratios were different for each catecholamine (CA). DA was by far the most concentrated amine inside the RBC. An acute increase in plasma NE and E levels, induced by hemorrhagic hypotension in normotensive (NT) rats, did not result in any modification of the RBC CA content. However, chronic elevation of the NE plasma levels in bilaterally adrenalectomized rats and in deoxycorticosterone acetate (DOCA)-salt hypertensive rats (DOCA-salt HT) were associated with increased NE levels in the RBC. In addition, the large elevation in plasma E concentrations following hemorrhagic hypotension in DOCA-salt HT rats, as well as the greater plasma NE response to hypotension in adrenalectomized animals, were accompanied by increases in the respective RBC amine concentrations. During a steady-state intravenous infusion of tritiated NE, we observed a slow accumulation of radioactivity inside the RBC, indicating that CA can enter the RBC from the plasma. Moreover, catechol methyltransferase activity was measured in the cytosolic fraction of the RBC of both NT and DOCA-salt HT rats suggesting that, once inside the RBC, the catecholamines can be metabolized.

Enamel fluoride in nursing rats with mothers drinking water with high fluoride concentrations.

The purpose of this study was to determine the F levels in plasma and molar enamel from rat pups whose mothers had received various levels of F during pregnancy and/or lactation. Rats were started on water containing 0 (Group I), 50 (Group II), or 100 (Group III) ppm F at the beginning of pregnancy or on the day of delivery. The mothers and pups were killed 13 days after delivery, and plasma F levels, milk F levels, and pup molar enamel F levels were determined. The mean maternal plasma F concentrations were 0.02 +/- 0.005 ppm in Group I, 0.10 +/- 0.031 ppm in Group II, and 0.21 +/- 0.057 ppm in Group III. The milk F values were about twice as high as the respective plasma concentrations. The plasma F concentration in control pups was 0.003 +/- 0.0002 ppm, and there was a rise to 0.006 +/- 0.0002 ppm in Group III. Enamel F concentrations were 0.62 +/- 0.13 ppm, 4.72 +/- 0.79 ppm, and 8.80 +/- 1.74 ppm, respectively. The plasma and enamel F values obtained from pups were not significantly different between the pre-natal/post-natal, and the post-natal-only groups. It was concluded that: fluoride levels in the plasma and enamel of control rat pups were much lower than those found in adult rats, such values could be increased only slightly when high doses of F were given to the mother, and unlike values reported for other species, rat milk fluoride concentrations were higher than the respective plasma values.

Indices of Protein Metabolism in Term Infants Fed Human Milk, Whey-Predominant Formula, or Cow's Milk Formula

Relationships between intakes of amino acids and total nitrogen, and blood indices of protein utilization were studied in 37 term infants fed either human milk, whey-predominant formula, or cow's milk formula as the sole nutritional source for 8 weeks. Biochemical analyses of two-hour fasting blood samples, and intakes calculated using three-day dietary records and direct analyses of milk samples were used to evaluate these relationships. Intakes of total nitrogen were positively correlated with plasma valine, leucine, isoleucine, phenylalanine, and serum urea nitrogen concentrations (r = .46 to .62, P less than .01 to .001). Intakes of the four amino acids whose plasma concentrations were positively correlated with total nitrogen intakes plus four additional amino acids (threonine, tyrosine, histidine, and methionine) were correlated with their respective plasma concentrations (r = .41 to .74, P less than .01 to .001). These relationships have not been previously described in term infants. Compared with values in infants fed human milk, plasma concentrations of valine, phenylalanine, methionine, and serum urea nitrogen were elevated with whey-predominant formula and cow's milk formula feeding. Values for four additional amino acids (threonine, lysine, leucine, and isoleucine) were elevated with whey-predominant formula feeding. Data indicate that altering the whey-to-casein ratio and, thus, the amino acid pattern of formulas will not achieve the desired blood indices characteristic of human milk feeding without a reduction in the total nitrogen content of formulas.

Pharmacokinetics of acetohydroxamic acid in patients with staghorn renal calculi.

Acetohydroxamic acid (AHA), a bacterial urease inhibitor, has been recently approved by the United States Food and Drug Administration as a potential drug for the successful treatment of patients with infection induced staghorn renal calculi. The present study was designed to evaluate the disposition of 14C-AHA following oral administration to patients. The results of the study, while in a limited number of patients, indicate that upon oral administration, AHA is very rapidly absorbed from the gastrointestinal tract. Evaluation of urinary excretion data suggests that patients with compromised renal function have low recoveries of AHA in the urine. These data are supported by a strong linear correlation between creatinine clearance and AHA elimination. Acetamide and CO2 are identified as the two major metabolites of AHA in man. CO2 is eliminated in the breath and accounts for 20-45% of the administered dose, while acetamide is eliminated in the urine and accounts for only 9-14% of the administered dose. The remaining dose is eliminated as intact AHA in the urine (19-48%). Saliva concentrations of total radioactivity depict a strong positive correlation with their respective plasma concentrations. Parameter estimates from 14CO2 concentrations in breath as a function of time data closely correspond to the pharmacokinetic parameters of AHA in patients indicating that CO2 may be a primary metabolite derived directly from AHA rather than a secondary metabolite formed by the metabolism of an intermediate product. Upon multiple dose administration of AHA, there is the potential for significant accumulation of acetamide due to its relatively long half-life.

Distribution of zinc and copper in maternal and cord blood at delivery.

For 17 normal births, the concentrations of trace metals (zinc and copper) and related metalloenzymes, i.e., carbonic anhydrase isoenzymes (CA-I and CA-II) and Cu2Zn2 superoxide dismutase (SOD1) were simultaneously determined in maternal and cord blood at delivery. Eleven healthy nonpregnant women served as controls. CA-I concentration in maternal erythrocytes was higher than in controls (p less than 0.05), whereas the concentrations of both CA isoenzymes in cord erythrocytes were in the range of one seventh to one ninth of those in controls. On the other hand, the erythrocyte SOD1 concentration was constant. A very low total zinc concentration was noted in cord erythrocytes, and this was due to the low concentrations of both CA isoenzymes. Total copper concentration in maternal erythrocytes was significantly lower than in controls (p less than 0.05); in contrast, that in cord erythrocytes was significantly higher than in controls (p less than 0.05). Thus, variations in erythrocyte copper concentrations are due to changes in other forms of copper (not SOD1-derived). Copper concentration in maternal plasma was about three times higher than in controls, while copper concentration in cord plasma was less half of that in control plasma. Conversely, zinc concentration in cord plasma was significantly higher than in controls (p less than 0.05). The concentrations of these metals in maternal erythrocytes and plasma were significantly different from the respective concentrations in cord erythrocytes and plasma. Likewise, the concentrations of these metals in maternal and cord erythrocytes contrasted with the corresponding concentrations in their plasma.

INDICES OF PROTEIN METABOLISM IN TERM INFANTS FED HUMAN MILK, WHEY PREDOMINANT FORMULA, OR COW MILK FORMULA

Infants (n=37) received either human milk (HM), whey predominant formula (WF), or cow milk formula (CF) as the sole nutritional source for 2 mos. At age 2, 4, and 8 wks, 2 hr fasting blood was analyzed for plasma amino acids (AA) and serum urea nitrogen (SUN). From 3-day dietary records and direct analyses of milks, intakes of AA and total nitrogen (TN) were calculated. Compared to HM feeding, elevated plasma valine (VAL), phenylalanine (PHE), methionine (MET), and SUN concentrations were observed with WF and CF feeding. Feeding WF resulted in elevations of 4 additional AA [threonine (THR), lysine, leucine (LEU), and isoleucine (ILE)]. Intakes of TN were positively correlated with plasma concentrations of VAL, LEU, ILE, tyrosine (TYR), histidine (HIS), and SUN (r=0.38-0.64, p<0.05-0.001), and negatively correlated with plasma arginine concentrations (r=-0.41, p<0.05). Intakes of the essential amino acids THR, VAL, LEU, ILE, PHE, HIS, TYR, and MET were correlated with their respective plasma concentrations (r=0.38-0.74, p<0.05-0.001). Data indicate that feeding WF does not result in indices of protein metabolism more similar to those obtained with HM feeding than does feeding CF, and that such indices will not be achieved unless TN content of formula is reduced, regardless of relative whey to casein ratios. (Supported in part by the Illinois Agricultural Experiment Station and Ross Laboratories.)

High-Performance Liquid Chromatographic Assay for Etomidate in Human Plasma: Results of Preliminary Clinical Studies Using Etomidate for Hypnosis in Total Intravenous Anesthesia

□ A sensitive and specific high-performance liquid chromatographic assay was developed for the measurement of etomidate in human plasma following extraction of the drug and the internal standard. Using 0.5-ml aliquots of plasma, the assay was linear in the concentration range of 20–2000ng of etomidate/ml of plasma. This method was used to evaluate a preliminary clinical study of an etomidate infusion regimen for hypnosis in a total intravenous anesthesia protocol in 23 patients. The average duration of the infusion was 30min, and awakening and alertness occurred 20 and 36min after the termination of the infusion, respectively, at the respective plasma concentrations of 297 and 214ng/ml. These results and this assay will be used to design and evaluate an improved etomidate infusion regimen.

Glutamine: a new metabolic substrate.

Glutamine serves important metabolic functions in a variety of tissues, but it has only recently been recognized as a new component of the metabolism of bone-Glutamine and glutamate are present as free amino acids in bone water at concentrations 2.5 and 40 times greater than their respective concentrations in plasma. The mediated transport of glutamine into calvaria occurs almost exclusively by Na+-dependent system(s). Glutamine uptake is not inhibited by N-methyl-D-L-alanine or 2-(methylamino)-isobutyric acid which are inhibitors of the A system of transport. Calvaria, when incubated in vitro degrade significant amounts of glutamine to ammonia, glutamate, other amino acids (alanine, aspartate, proline, ornithine) and CO2. The purpose of this report is to further delineate several of these processes with a view to their possible physiological significances.

Red blood cells: [formula omitted][formula omitted] site for transport and inactivation of biogenic amines in man and rats

Red blood cell lysate contains catecholamines, octopamine and normetanephrine in various concentrations usually equal to or higher than respective plasma concentrations. During sympatho-adrenal activation an increase in plasma norepinephrine is associated with a simultaneous but smaller increase in lysate norepinephrine. The ratio of normetanephrine to norepinephrine is consistently higher in red cell lysate than in plasma. suggesting norepinephrine may be catabolized inside red cells. These data indicate a physiologically significant role for red blood cells in the disposition of peripheral amines and their metabolites.

Salivary concentrations and plasma protein binding of carbamazepine and carbamazepine 10,11-epoxide in epileptic patients.

1. The relationships between saliva, free and total plasma concentrations of carbamazepine (CBZ) and carbamazepine 10,11-epoxide (CBZ-EP) were studied in 24 chronically medicated epileptic patients. Four patients were taking CBZ alone, while 20 were taking one or more additional anticonvulsant drugs. 2. The free fraction of CBZ in plasma ranged from 0.19 to 0.33 (mean 0.24) while the saliva:plasma (S:P) concentration ratios ranged from 0.20 to 0.35 (mean 0.27). The free fraction of CBZ-EP in plasma ranged from 0.16 to 0.50 (mean 0.32), while the S:P ratios ranged from 0.14 to 0.70 (mean, 0.43). The plasma protein binding and S:P ratios of these compounds appeared to be independent of age, sampling time and concurrently administered anticonvulsant drugs. 3. Significant linear relationships between saliva and total plasma concentrations and between saliva and free plasma concentrations were observed for both compounds (P less than 0.001). However, salivary concentrations of CBZ and CBZ-EP were significantly more reliable as predictors of their respective free plasma concentrations than of their respective total plasma concentrations (P less than 0.01). 4. It is concluded that measurement of CBZ and CBZ-EP in the saliva of chronically medicated epileptic patients provides a more reliable estimate of the pharmacodynamically active, free concentrations of these compounds in plasma.

Prostacyclin, thromboxane and prostaglandin F 2αin suction blister fluid of human skin: Effect of systemic aspirin and local glucocorticosteroid treatment

Changes in prostaglandin (PG) metabolism are known to be involved in various skin diseases. To elucidate the behavior of hree vasoactive PGs in human skin, namely prostacyclin (PG1 2), thromboxane A 2 (TxA 2) and PGF 2α, their stable metabolites, 6-keto-PGF 1α. TxB 2, and 13, 14 dihydro-15-keto PGF 2α (MPGF 2α), respectively, were measured by radioimmunoassays in suction blister fluids of 29 healthy male subjects. Nine of them were treated with acetylsalicylic acid (0.5 g × 4/day for one day beforehand), eight with local glucocorticoid (clobetasol-17-propionate, Dermovat R Cream, twice a day for seven days) and 12 served as controls. All three PGs were detected in blister fluid. In controls the mean (± SD) concentration of 6-keto-PGF 1α was 1160 ± 470 pg/ml (n=12) that of TxB 2 1590 ± 610 pg/ml (n=12) and that of MPGF 2α 1800 ± 710 pg/ml (n=12), levels which are higher than the respective concentrations in human plasma. The preceding aspirin treatment decreased the 6-keto-PGF 1α levels by 40 % (P<0.005), the TxB 2 levels by 80 % (P<0.001) and MPGF 2α levels by 35 % (P<0.05), whereas the preceding local glucocorticoid caused no changes in these PG levels. The results show that 1) PG1 2, TxA 2, and PGF 2α are locally released in the suction blister fluid of healthy human skin, 2) systemic treatment with a PG synthesis inhibiting drug, acetysalicylic acid, reduces this release, and 3) locally applied clobetasol-17-propionate does not affect the levels of prostaglandins and thromboxane as measured by our methods.

Multiple intravenous dose pharmacokinetics of ceftriaxone in man.

Multiple-dose pharmacokinetics of ceftriaxone were investigated following 1 g every 12 h (1GMQ12H) and 2 g every 12 h (2GMQ12H) intravenous dosage regimens. In each dosage regimen, seven successive doses were infused at a constant rate over 30 min to 12 normal subjects. Plasma and urine samples were collected after the first and last dose and assayed for ceftriaxone by HPLC. After the first and last dose, the respective mean values of maximum plasma concentrations were 145 and 168 <i>μ</i>g/ml for the 1GMQ12H and 255 and 280 <i>μ</i>g/ml for the 2GMQ12H dosage regimen. Pharmacokinetic analyses of the data indicated the following: (i) the elimination half-life (6.6 h) and fraction of dose excreted unchanged in the urine (0.37) remained constant with dose and were not affected by the subchronic administration; (ii) steady-state ceftriaxone concentrations in plasma after the last dose indicated a 20% accumulation for both dosage regimens; (iii) the plasma clearance (Cl_p) and apparent volume of distribution (V_d) increased with dose; and (iv) V_d and Cl_p also increased within a dosage regimen (first dose vs. last dose comparison) by a factor of 14% at the 1GMQ12H and 19% at the 2GMQ12H dosage regimen. Utilizing the first dose data of each dosage regimen and assuming linear pharmacokinetics, respective steady-state plasma concentrations were predicted. The predicted concentrations were higher than the observed concentrations by 10% at the 1GMQ12H and by 15% at the 2GMQ12H dosage regimen. The observed increases in V_d and Cl_p as well as the prediction errors may be explained by the concentration-dependent plasma protein binding of ceftriaxone in man. The clinical significance of the increases observed in V_d and Cl_p is probably negligible since the increase in either V_d or Cl_p was not more than 20% even after a two-fold change in the dose. Therefore, linear pharmacokinetics can be reasonably assumed for ceftriaxone under clinical situations.

Tubular extrusion of D-glucose in the isolated rabbit kidney perfused in vitro.

The extrusion mechanism of d-glucose by tubular cells was investigated in isolated rabbit kidneys perfused with normal or hyperglicemic blood, added with 14C-inulin, by relating the values of the ratio between the intracellular and extracellular glucose concentration (Gi/Ge) in the cortical tissue to the respective plasma concentration Gp (= Ge). The apparent extracellular space was calculated in each experiment from the kinetics of the 14C-inulin efflux from cortical slices excised at the end of the perfusion period (mean value = 20.7 +/- 1.7 of the total vol.). The total intra and extracellular amount of glucose was measured in two contiguous slices excised from the cortex. The total water was expressed by the difference between the fresh and dry weight of the slice, the intracellular water by the difference between the total and extracellular water. From these volumes the respective apparent glucose concentrations could be found. The Gi/Ge values tend to 1, that is to a uniform intra and extracellular distribution of glucose, only at high plasma glucose levels. These results do not seem to be in agreement with a D-glucose transfer from the cell to the subepithelial spaces down a concentration gradient.