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PubMed1988

Serum zinc binding capacity in pregnant women.

Zinc is an important element during the prenatal period. Since plasma zinc levels are not directly related to the nutritional status of this metal in pregnant women, we designed this study to find out if plasma protein zinc binding capacity is a more reliable parameter than total serum zinc to establish zinc nutritional status during pregnancy. We analyzed total serum zinc and zinc binding capacity in 84 normal pregnant women and in 14 nonpregnant women. Within pregnant women, samples were classified according to the gestational age. Total zinc serum was significantly decreased in pregnant women as compared to control ones. The decrease in zinc occurred slowly during the whole period of pregnancy; a negative correlation was found between serum zinc and gestational time. Protein zinc binding capacity was found to be significantly higher in pregnant women than in the control ones. This parameter was positively correlated to total serum zinc in pregnancy. We conclude that since the protein zinc binding capacity increases with advancing gestation, pregnant women take advantage of this to maintain the levels of serum-free zinc, transferable to the fetus.

Blood Proteins↗
PubMed1989

Protein binding of benzene under ambient exposure conditions.

Based on examination of exposure monitoring studies, we speculate that under ambient conditions benzene binds appreciably to plasma proteins. The binding capacity, n*[beta], is estimated to be on the order of 10(-9) chi M (90.0 ng/L) and the association constant, Kas, on the order of 2 X 10(10) M-1 (.3 L/ng). These values indicate that protein binding of benzene is characterized by a very small capacity with a very large affinity. We predict that steady-state exposure to ambient benzene air concentrations in the range of 10 ppb to 1 ppb will result in 35 to 80 percent of benzene in blood being bound to plasma proteins.

Benzene↗
PubMed1994

Protein binding of brequinar in the plasma of healthy donors and cancer patients and analysis of the relationship between protein binding and pharmacokinetics in cancer patients.

The protein binding of weakly acidic and basic drugs has been shown to be altered in cancer patients. Brequinar is a weakly acidic, low-clearance, and highly protein-bound (> 98% bound) antitumor agent. The pharmacokinetic parameters of brequinar are subject to large interpatient variability. This large interpatient variability may be related to brequinar's plasma protein-binding capacity (assuming no change in the intrinsic clearance of the unbound drug). The objectives of this study, therefore, were (a) to characterize brequinar's protein binding in the plasma of healthy donors and cancer patients and (b) to examine the relationships between brequinar's plasma protein binding and its pharmacokinetics in patients. Brequinar protein binding was determined in human serum albumin (HSA) solution, drug-free donor plasma, and brequinar-free, predose plasma samples obtained from a phase I cancer trial. Pharmacokinetic results from this study were used to examine relationships between plasma protein binding and drug disposition. In HSA solution and healthy donor plasma, brequinar's protein binding as determined using spiked samples was concentration-dependent. The unbound brequinar fraction increased by a factor of 3 (from 0.3% to 0.9% free) in 4% HSA solution and by a factor of 4 (from 0.4% to 1.6% free) in donor plasma as the brequinar concentrations increased from 0.1 to 2.3 mM in the HSA solution and from 0.076 to 1.5 mM in the donor plasma. Analysis of brequinar binding characteristics using the binding ratio and Rosenthal binding plots showed that albumin was the primary protein for brequinar binding in human plasma. The addition of various concentrations of alpha 1-acid glycoprotein to 4% HSA solution did not affect the protein binding of brequinar to HSA. The protein binding determined in the plasma of cancer patients was not quantitatively different, except for variability, from that observed in the plasma of healthy donors. Examination of relationships between the unbound brequinar fraction and pharmacokinetics suggested that plasma protein binding was not a major determinant of brequinar disposition in cancer patients.

Antineoplastic Agents↗
PubMed1993

Cerebrovascular permeability to azo dyes and plasma proteins in rodents of different ages.

The often quoted investigation by Behnsen [4] provides some evidence for an increased permeability of the neonatal mouse blood-brain barrier (BBB) to trypan blue compared to the adult. Trypan blue, which circulates in plasma mainly bound to albumin, is commonly used as a macromolecular tracer, although Behnsen probably injected dyes in amounts exceeding the dye-binding capacity of plasma proteins. The cerebrovascular permeability in neonatal and adult mice and rats was investigated using the visual tracers trypan blue and Evans blue and immunocytochemical staining for endogenous plasma proteins. By administering different concentrations of the dyes, the permeability of the BBB was assessed. The presence of the dyes in plasma as either dye-protein complexes or as free dye was measured by a plasma protein binding assay. When dyes occurred in plasma as macromolecular dye-protein complexes, dyes and plasma proteins were restricted to CNS regions normally devoid of a BBB in both neonates and adults. When unbound (free) dyes occurred in plasma, dyes were observed intraneuronally in regions without projections beyond the BBB in both neonates and adults corresponding to that observed by Behnsen; intraneuronal accumulation of plasma proteins also occurred in regions with projections confined to the BBB but only in neonates. It is concluded that the BBB to macromolecular tracers is fully developed at birth in mouse and rats. However, when free dye is present in plasma, there is a differential permeability to plasma proteins between neonates and adults.

Aging↗
PubMed2006

Analysis of plasma proteins that bind to glycosaminoglycans.

Glycosaminoglycan-binding proteins, with specific emphasis on dermatan sulfate, have been investigated in human plasma by affinity chromatography, mass spectrometry and Western blotting. Diluted plasma was applied to affinity columns and bound protein was eluted with 500 mM NaCl. Dermatan sulfate and heparan sulfate bound 7% of the total protein. Heparin bound 22% of the total protein, but chondroitin sulfate A bound only 0.23%. Mass spectrometric analysis identified 20 proteins as dermatan-sulfate-binding proteins, most of which were confirmed by Western blotting. Some of these binding proteins, such as fibrinogen, fibronectin, apolipoprotein B, LMW kininogen, inter-alpha-trypsin inhibitor, and factor H, were degraded to various extents during the chromatography step, but this degradation could be prevented by the inclusion of a serine protease inhibitor. The protein fraction binding to the dermatan sulfate column showed amidase activity, whereas that binding to the heparan sulfate and heparin columns showed 1/2 and 1/20, respectively, of the activity of the dermatan sulfate binding fraction. Dermatan sulfate was similar to heparan sulfate with respect to its capacity to bind plasma proteins and its activation of protease, but differed from chondroitin sulfate and heparin in these properties.

Amidohydrolases↗
PubMed1992

Pharmacokinetics of levonorgestrel and ethinylestradiol in 9 women who received a low-dose oral contraceptive over a treatment period of 3 months and, after a wash-out phase, a single oral administration of the same contraceptive formulation.

The pharmacokinetics of levonorgestrel (LNG) and ethinylestradiol (EE2) were determined in 9 healthy women (age 23 to 42 years), during a treatment period of three months with a low-dose oral contraceptive, containing 0.15 mg LNG together with 0.03 mg EE2 (Microgynon). After a wash-out period of 3 months, 8 of these women received a single administration of the same formulation. The results showed that there was an increase in serum trough levels of LNG, reaching steady-state in the second half of each treatment cycle. The LNG levels achieved were about 3 to 4 times higher than anticipated on the basis of single dose administration. At the end of treatment cycles one and three, the terminal half-life of LNG was in the range of 24-26 h, while a mean value of 20 h was observed following single dose administration. An EE2-induced increase in the SHBG concentration of about 50% as compared to pretreatment values was observed during a treatment cycle. Pretreatment values were reached following the drug-free interval of 7 days between two cycles. After single dose administration, the free fraction of LNG was 1.3 +/- 0.2% and the fractions bound to SHBG and albumin were 64.1 +/- 4.2% and 34.6 +/- 4.0%, respectively. Serum protein binding of LNG did not change during chronic treatment. An about 50% reduction in total and unbound clearance of LNG was observed during chronic treatment, as compared to single dose administration. Increased SHBG binding capacity and a reduced hepatic metabolic capacity were discussed as possible causes of accumulating LNG concentrations in the serum. On the last day of treatment cycles one and three, the AUC(0-24h) values of EE2 were 728 +/- 314 and 778 +/- 318 pg x ml-1 x h, respectively, and were in keeping with data reported from others.

Adult↗
PubMed1996

Effects of pravastatin sodium and simvastatin on plasma fibrinogen level and blood rheology in type II hyperlipoproteinemia.

Elevated plasma fibrinogen level is known to progress atherosclerosis and to be one of the risk factors for the occurrence of cardiovascular diseases. The objective of this study is to evaluate the changes in plasma fibrinogen level and blood rheology in patients with type II hyperlipoproteinemia before and after random administrations of HMG-CoA (3-hydroxy-e-methylglutaryl-cocarboxylase-A) reductase inhibitors, pravastatin sodium and simvastatin, and compare with results in normal subjects. Of a total of 28 patients with type II primary hyperlipoproteinemia with > 230 mg/dl fasting total plasma cholesterol, 16 patients (mean, 59.7 years old) were administered 10-15 mg/day of pravastatin sodium for an average of 10.2 weeks, and 12 patients (mean, 62.0 years old) were administered 5-10 mg/day of simvastatin for an average of 13.9 weeks. Patients were evaluated before and after drug administration and results were compared with those of 16 normal subjects of similar age (mean, 56.9 years old). Blood viscosities were measured using a cone-plate viscometer (Biorheolizer, BRL-1000, Japan). The following were measured before and after drug administration: whole blood viscosity at shear rates of 75-375 s-1, corrected blood viscosity at low (112.5 s-1) and high (225.0 s-1) shear rates for the standard hematocrit of 45%, plasma viscosity, hematocrit, total protein, serum albumin, and plasma fibrinogen. Total cholesterol level was significantly decreased (from 270 to 225, mg/dl, mean values; P < 0.0007) an average of 10.2 weeks after start of pravastatin sodium administration. In addition to the reductions of whole blood viscosity, at every shear rate examined, corrected blood viscosity, and plasma viscosity, plasma fibrinogen levels were significantly decreased (from 354 to 309 mg/dl, mean values; P < 0.0007) after start of pravastatin sodium administration. Fibrinogen level and blood rheology were not significantly changed after start of simvastatin administration despite similar significant reductions in total cholesterol level (from 260 to 207 mg/dl, mean values; P < 0.0001) to those in the case of pravastatin sodium. From the results, we conclude that administration of pravastatin sodium, but not simvastatin, reduced the plasma fibrinogen level and blood viscosities to normal levels in type II hyperlipoproteinemic patients while both drugs reduced total cholesterol level. The hydrophilicity and a small binding capacity with plasma protein of pravastatin sodium may be responsible in part for the beneficial hemorheologic effects observed in the patients with type II hyperlipoproteinemia. Further investigations should be conducted to confirm the findings observed.

Acyl Coenzyme A↗
PubMed1985

Fluorescein distribution in retinas of normal and diabetic rats.

Quantitative fluorescence microscopy was used to study fluorescein distribution across the blood-retinal barrier in control and streptozotocin diabetic rats at 2 min, 1 and 2 hr after dye injection (12.5 and 125 mg kg-1 i.v.). Fluorescence intensities of choriocapillaris and retina were compared with plasma fluorescein levels. Diabetic rats had only one-half the total plasma fluorescein concentration of controls by 1 hr after injection, but the proportion of free fluorescein was greater in diabetic animals than in controls, providing the total plasma dye levels did not exceed the binding capacity of plasma proteins. Diabetic rats also had more unbound fluorescein glucuronide in plasma. With fluorescence microscopy no focal fluorescein leakage from retinal capillaries or pigment epithelium was seen in any diabetic or control eye. However, the dye was detected in retinas of diabetic and control animals at all intervals except 2 hr after injection of the lower dose when its fluorescence was too low to measure. Initial fluorescein entry occurred from the choroid by diffusion through pigment epithelial cells creating a steep intensity gradient decreasing from outer to inner retinal layers. With time this gradient flattened and then completely reversed, suggesting removal of dye from outer retinal layers and concomitant equilibration of inner layers with a pool of fluorescein in vitreous humor. Although the pattern of transretinal fluorescence distribution was similar in all rats, in specific instances, retinal fluorescence intensity differed significantly between control and diabetic animals. Fluorescence intensity was higher in diabetic than in control rats at 2 min after the 12.5 mg kg-1 dose and lower at 1 hr after the 125 mg kg-1 dose (P less than 0.05). These differences were directly related to transient differences in plasma free fluorescein concentrations, and in both cases, retinal fluorescence in diabetic rats returned to control values in conjunction with return to control levels of their plasma free fluorescein concentrations. The amount of dye detected in diabetic retinas was not in excess of normal levels at any interval after injection when related to concurrent plasma free fluorescein concentrations. These data do not indicate blood-retinal barrier dysfunction in the diabetic rat, but interpretation of the results is limited by the experimental conditions. With the high dose there was probably initial saturation of active transport mechanisms for dye removal, and with the low dose, dye distribution could not be followed to 2 hr when evidence of abnormal accumulation in retina may be more apparent.

Animals↗
PubMed1978

[Metabolic studies under administration of oral contraceptives. A review].

The use of oral contraceptives can produce changes in the metabolism of carbohydrates, lipids, proteins, vitamins, and minerals. Responsible for the alterations seems to be the used oestrogen- and gestagen derivative and not so much the type of the contraceptive. The most frequent findings are raised serum-glucose-, insulin-, and triglyceride levels; disturbances in protein-metabolism increase the risk of developing thrombosis and hypertonia. Little is known about the significance of oral contraceptives on the vitamin- and mineral metabolism--yet extreme deficiencies have not been observed so far. Oral contraceptives can become an extra risk factor when given to women with metabolic disturbances.

Amino Acids↗
PubMed1993

Pharmacokinetics of gestodene and ethinylestradiol in 14 women during three months of treatment with a new tri-step combination oral contraceptive: serum protein binding of gestodene and influence of treatment on free and total testosterone levels in the serum.

The pharmacokinetics of gestodene (GEST) and ethinylestradiol (EE2) were determined in 14 healthy women (age 18 to 32 years) during a treatment period of three months with a new tri-step combination oral contraceptive (Milvane). Prior to this treatment period, the same women received a single administration of a coated tablet containing 0.1 mg GEST together with 0.03 mg EE2. There was a wash-out phase of one week between both treatments. Following single dose administration, a mean terminal half-life of 18 h was observed for GEST. The total clearance was 0.9 ml x min-1 x kg-1 and the volume of distribution was 84 l. During a treatment cycle, GEST levels in the serum accumulated by a factor of 8 as compared to single dose administration. Steady-state drug levels were reached during the second half of each cycle. As compared to single dose administration, the following changes were observed for GEST at the end of treatment cycles one and three: prolonged terminal half-life (20 to 22 h), reduced total (0.16 ml x min-1 x kg-1) and free clearance (ca. 27 ml x min-1 x kg-1), reduced volume of distribution (ca. 18 l). A concomitant EE2-induced increase in the SHBG concentrations by a factor of three as compared to pretreatment values was observed during a treatment cycle and appeared to be mainly responsible for the changes in the pharmacokinetics of GEST. Marked changes were also seen for the serum protein binding of GEST. After single dose administration, the free fraction of GEST was 1.3% and the fractions bound to SHBG and albumin were 69.4% and 29.3%, respectively. At the end of cycle one, the free fraction was only 0.6% and the fractions bound to SHBG and albumin were 81.4% and 18.0%, respectively. There was no difference in corresponding pharmacokinetic parameters and in the serum protein binding of GEST at the end of cycles one and three. On the last day of treatment cycles one and three, the AUC(0-4h) values of EE2 were 299.2 and 278.1 pg x ml-1 x h, respectively, which corresponds to an about 30% increase as compared to single dose administration, where an AUC(0-4h) value of 216.1 pg x ml-1 x h was found. Total and free testosterone concentrations decreased during treatment cycles one and three by about 36% and 60%, respectively, compared with the corresponding values measured prior to treatment. The fraction of unbound testosterone thus decreased from 0.5% to 0.3% during treatment.

Adolescent↗
PubMed1994

Pharmacokinetics of levonorgestrel and ethinylestradiol in 14 women during three months of treatment with a tri-step combination oral contraceptive: serum protein binding of levonorgestrel and influence of treatment on free and total testosterone levels in the serum.

The pharmacokinetics of levonorgestrel (LNG) and ethinylestradiol (EE2) were determined in 14 healthy women (age 18 to 27 years) during a treatment period of three months with a tri-step combination oral contraceptive (Triquilar). Prior to this treatment period, the same women received a single administration of a coated tablet containing 0.125 mg LNG together with 0.03 mg EE2. There was a washout phase of one week between both treatments. Following single dose administration, a mean terminal half-life of 22 h was observed for LNG. The total clearance was 1.0 ml x min-1 x kg-1 and the volume of distribution was 128 l. During a treatment cycle, LNG levels in the serum accumulated by a factor of about four as compared to single dose administration. Steady-state drug levels were reached during the second half of each cycle. As compared to single dose administration, the following changes were observed for LNG at the end of treatment cycles one and three: reduced total (0.5 ml x min-1 x kg-1) and free clearance (50 ml x min-1 x kg-1) and a reduced volume of distribution (52 l). A concomitant increase in the SHBG concentrations by a factor of two as compared to pretreatment values was observed during treatment and appeared to be mainly responsible for the changes in the pharmacokinetics of LNG. Marked changes were also seen for the serum protein binding of LNG. After single dose administration, the free fraction of LNG was 1.4% and the fractions bound to SHBG and albumin were 55.0% and 43.6%, respectively. At the end of cycle one, the free fraction was only 1.0% and the fractions bound to SHBG and albumin were 69.4% and 30.0%, respectively. There was no difference in corresponding pharmacokinetic parameters and in the serum protein binding of LNG at the end of cycles one and three. On the last day of treatment cycles one and three, the AUC(0-4h) values of EE2 were 331.2 and 369.6 pg x ml-1 x h, respectively, which corresponds to an about 11-24% increase as compared to single dose administration, where an AUC(0-4h) value of 298.3 pg x ml-1 x h was found. Total and free testosterone concentrations decreased during treatment cycles one and three by about 41% and 55%, respectively, compared with the corresponding values measured prior to treatment.

Administration, Oral↗
PubMed1980

Interaction between diflunisal and warfarin.

The effect of diflunisal on steady-state warfarin dynamics and kinetics was studied in five healthy men taking daily subtherapeutic doses of warfarin. Diflunisal 500 mg twice daily for 2 wk increased the percentage unbound warfarin from 1.02% to 1.24% and lowered total warfarin from 741 to 533 ng/ml, but did not alter the anticoagulant response (prothrombin complex activity, PCA). When diflunisal was discontinued but warfarin continued, there was a loss of anticoagulant effect and a difference in the rates at which percentage unbound warfarin and total warfarin concentration returned to prediflunisal levels. There was a correlation between plasma diflunisal and percentage unbound warfarin. Diflunisal reduced both the maximum plasma protein-binding capacity for warfarin and the apparent association constant.

Absorption↗