Biomedical subjects

F Staud

Publications and source records attributed to F Staud.

12 recordsLinked to original sources

PubMed2002

[Physiologic function of P-glycoprotein].

P-glykoprotein has been proposed to function as a membrane transport protein for a large variety of substrates, ranging from small lipophilic molecules, steroid hormones, lipophilic peptides, some drugs, biologically important molecules and xenobiotics. There is little doubt that P-glycoprotein transports a wide range of substrates out of cells, nevertheless it is difficult to explain its wide substrate specificity and mechanism of the transport. P-glycoprotein has been found to be a major cause of acquired multidrug resistance (MDR) of cancer cells to chemotherapeutic drugs. The identification and localization of P-glycoprotein expression in a variety of normal human tissues raised the question of the physiological functions of P-glykoprotein. Currently, there is considerable evidence that P-glycoprotein can protect the body and sensitive tissues against a range of different xenobiotics. In addition, P-glycoprotein might play a role in regulation of cell differentiation, proliferation, immune response and programmed cell death.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Influence of P-glycoprotein on the transplacental passage of cyclosporine.

The transfer kinetics of cyclosporine across the dually perfused rat placenta in the maternal to fetal direction and a possible involvement of P-glycoprotein were investigated. The transplacental clearance of cyclosporine in the materno-fetal direction was found to be dependent on the maternal inflow concentration of cyclosporine. Coadministration of cyclosporine with an excess of quinidine or chlorpromazine into the maternal compartment revealed 1.7- and 1.9-fold increase in cyclosporine concentration in the fetal compartment. In the experiments where quinidine was present both in the maternal and fetal compartments, cyclosporine appeared in the fetal compartment significantly faster, and its amount was three times higher when compared with controls. Conversely, quinidine or chlorpromazine did not affect the transplacental passage of L-[(3)H]-glucose. The interference of quinidine with the metabolism of cyclosporine in the placenta was excluded because only traces of M-1 and M-17 metabolites were found in the fetal solutions. Sodium azide, a mitochondrial respiratory inhibitor, was found to double the rate of cyclosporine, but not L-[(3)H]-glucose, passage across the placenta. Our findings indicate that P-glycoprotein pumps cyclosporine out of the trophoblast cells of the rat placenta in the ATP-dependent manner and restricts the passage of cyclosporine across the placental barrier.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

Liver uptake and hepato-biliary transfer of galactosylated proteins in rats are determined by the extent of galactosylation.

The effect of molecular mass and surface density of galactose residues on hepatic uptake and subsequent biliary excretion of galactosylated proteins was investigated in rats. Several proteins with different molecular weights (15-70 kDa) and different numbers of galactose units were synthesized and radiolabeled with 111In. Galactosylated proteins were administered i.v. to anaesthetized rats and samples of plasma and bile were collected for 3 h. Liver was harvested at the end of the experiments and the radioactivity of all samples was measured. Galactosylated proteins accumulated primarily in the liver and 2-10% of the administered dose appeared in the bile, mainly in undegraded form. The hepatic uptake clearance (Cl liver) and biliary excretion rate constant (kbile) of galactosylated proteins were calculated. No direct effect of molecular weight was observed, however, on increasing the galactose density, Cl liver increased from about 4 to 400 ml/h whereas kbile gradually decreased from about 0.057 to 0.007 (h-1). In conclusion, both hepatic uptake and biliary excretion of galactosylated proteins were found to be affected by the extent of galactosylation.

Animals↗

PubMed1999

Disposition of radioactivity after injection of liver-targeted proteins labeled with 111In or 125I. Effect of labeling on distribution and excretion of radioactivity in rats.

The effect of radiolabeling liver-specific proteins on the in vivo disposition of radioactivity was investigated. The suitability of 111In and 125I as radiolabels for protein disposition studies in vivo was examined. Galactosylated and cationized bovine serum albumin were labeled with either 125I by the chloramine-T method or 111In, using 1-(4-isothiocyanatobenzyl)ethylenediaminetetraacetic acid (SCN-BZ-EDTA) or diethylenetriaminepentaacetic acid (DTPA) as bifunctional chelating agents (BCAs) and administered intravenously to rats. 125I radioactivity disappeared rapidly from the liver with subsequent excretion in the urine and bile, mainly in the TCA soluble fraction. 111In-associated radioactivity, on the other hand, remained in the hepatic tissue in considerably higher amounts during the experiment and was excreted in the bile and urine to a lower extent when compared with 125I. When the effect of BCA on excretion of 111In radioactivity was compared, no significant differences were observed in the urinary clearances. However, biliary excretion was significantly higher for 111In-SCN-BZ-EDTA-bound radioactivity. In conclusion, when compared with 125I, 111In labeling seems to more accurately characterize the in vivo distribution of liver-targeted proteins after their iv administration in rats and allows a more accurate pharmacokinetic evaluation to be performed.

Albumins↗

PubMed1999

Pharmacokinetic evaluation of biodistribution data obtained with radiolabeled proteins in mice.

Radiolabeling of proteins is a widely used approach to study their in vivo disposition patterns. However, the obtained results may largely depend on the radiolabeling method used. The purpose of the present study was to investigate the effect of the radiolabeling method on the pharmacokinetic analysis of liver targeted protein in mice. Galactosylated bovine serum albumin (Gal-BSA) was labeled with 125I or 111In, using diethylenetriamine-pentaacetic dianhydride (cDTPA) or 1-(4-isothiocyanobenzyl)ethylenediaminetetraacetic acid (SCN-Bz-EDTA) as bifunctional chelating agents. The Gal-BSA was then injected in mice by a bolus intravenous injection. Samples of plasma, urine, liver, kidney, intestine and feces were collected at various time intervals and their radioactivity was measured. In none of the samples examined was there any significant difference in radioactivity distribution originating from the radiolabeling methods within 5 min after administration. After this period, 125I radioactivity in the liver started to decrease significantly faster than that of 111In, which would indicate the intracellular degradation of the protein. Consequently, the reappearance of trichloracetic acid (TCA) soluble 125I radioactivity in the plasma occurred. But whereas the hepatic uptake clearance (CLliver) of [111In]DTPA-Gal-BSA remained constant during 8 h postinjection, the CLliver of [125I]Gal-BSA at 30 min represented only one eighth of its initial values. The CLliver of [111In]SCN-Bz-EDTA-Gal-BSA resembled that of [111In]DTPA-Gal-BSA within 1 h of the experiment but it started to decline after this interval. The observed discrepancies most probably resulted from the formation of different radiolabeled metabolites in the hepatocytes and their different capability of crossing biological membranes. Our findings indicate that among the three methods employed, [111In]DTPA radiolabeling of Gal-BSA is the most appropriate method to study its tissue disposition.

Animals↗

PubMed1998

Unidirectional transfer of D-xylose across the rat placenta.

1. The transplacental transfer of D-xylose was investigated in the present study. 2. Umbilical perfusion of the rat term placenta was used to study materno-foetal (M-F) and foetomaternal (F-M) transfer of this compound. 3. D-Xylose was found to cross the rat term placenta very quickly in the M-F direction, with subsequent accumulation in the foetal compartment (the F-M ratio being 2.23 at the end of the experiments). In contrast, no transfer in the F-M direction was observed. 4. A possible facilitation of the transplacental transfer of D-xylose from the mother to foetus in rats is suggested.

Animals↗

PubMed1998

Different transfers of N-acetyl-p-aminobenzoic acid and p-aminobenzoic acid across the placenta and the small intestine in rats.

The aim of the present study was to evaluate the transfer of N-acetyl-p-aminobenzoic acid (AcPABA) across the rat term placenta and the rat small intestine and to compare it with that of its parent drug p-aminobenzoic acid (PABA). Umbilical perfusion of the rat term placenta was used to determine the materno-fetal transfer. AcPABA appeared in the fetal compartment significantly more slowly than PABA (k transfer = 0.023 and 0.064 min(-1), respectively). The rate of equilibration between the maternal and fetal compartments was slightly lower for AcPABA than for the parent drug (k eqilibration = 0.0082 and 0.011 min(-1), respectively). Similarly, AcPABA was shown to be absorbed from the small intestine significantly more slowly than PABA (ka = 0.052 and 0.82 min(-); tmax = 37 and 3.1 min, respectively). Our results showed that both investigated compounds which are structurally related and very similar in their physical-chemical characteristics crossed both the placental and small intestinal barrier with a different kinetics. AcPABA was transported across both barriers significantly more slowly than its parent compound, which might indicate a possible equipment of the placenta with a carrier for PABA, a similar one to that previously found in the rat small intestine.

4-Aminobenzoic Acid↗

PubMed1997

Pharmacokinetic examination of p-aminobenzoic acid passage through the placenta and the small intestine in rats.

In the present study the permeability of the rat small intestine and the placenta to p-aminobenzoic acid (PABA) and antipyrine (AP) was investigated. Perfusion of the rat term placenta was used to determine the materno-fetal transfer of both compounds. PABA appeared in the fetal compartment faster than AP (ktransfer = 0.064 and 0.046 min-1, respectively). The rate of equilibration between the maternal and fetal compartments and placental clearance were lower for PABA than for AP (kequilibration = 0.011 and 0.020 min-1; Clp = 0.22 and 0.33 ml/min, respectively); the feto-maternal concentration ratios at equilibrium (FMCReq) were, however, mutually comparable. Similarly, PABA proved to be absorbed from the small intestine significantly faster than AP (ka = 0.824 min-1 and 0.479 min-1; tmax = 3.1 min and 8.9 min, respectively). The apparent volume of distribution (Vd) of AP in non-pregnant animals showed that the drug is distributed into the whole body water as expected (Vd = 0.66 l/kg); however, Vd of AP in pregnant animals was estimated to be 1.81 l/kg. Vd of PABA in non-pregnant animals showed its partially limited distribution, which was only slightly increased in the pregnant animals. Our results confirmed a faster penetration of hydrophilic PABA across the placenta and the small intestine than that of lipophilic AP. The mechanism of transplacental passage of PABA, however, remains to be determined.

4-Aminobenzoic Acid↗

PubMed1997

Phenytoin transfer across the in situ perfused rat term placenta.

Transfer of phenytoin (PHT) across the rat term placenta perfused in situ was investigated and compared with that of antipyrine (AP) as a marker of passive diffusion. PHT was shown to cross the placenta with similar kinetics as AP did. Both the first order transfer constant (ktr = 0.070 min-1) and the first order equilibration constant (keq = 0.027 min-1) of PHT were comparable to those of AP (ktr = 0.046 min-1, keq = 0.022 min-1). Similarly, there were significant differences between PHT and AP in the foeto-maternal concentration ratio at equilibrium (FMCReq = 1.01 and 1.09, respectively). The present data indicate that the transfer of PHT through the rat placenta is governed by the same principles as that of AP, i.e. by the mechanism of passive diffusion. Surprisingly, maternal plasma protein binding of PHT (60.5%) did not seem to influence either its rate of transfer or its eventual foeto-maternal concentration ratio.

Analgesics↗

PubMed1996

[Effectiveness of oral administration of ivermectin on warble fly larvae (Hypoderma diana B.) in roe deer].

Hypodermosis and cephenemyiosis are largely widespread diseases in roe deer in the conditions of the Czech Republic. Both kinds of parasitosis cause great losses of game. The aim of this study was to test peroral administration of ivermectin with respect to the control of larval stages of hypodermosis (Hypoderma diana B.) in roe deer. Studies were performed on three localities within one three-year study and two 18-month studies. Ivermectin was administered for two days at a daily dose of 0.30 mg/kg body weight during winter game feeding. The shot deer were checked for the presence of larvae throughout the year. Prevalence and intensity of infection were determined. A total of 147 animals were checked in 1992-1994 (Tab.I); prevalence and intensity of infection were very low in comparison with the situation before treatment and with the control group (1994). Similar results were obtained in both shorter studies (Tab. II) performed on 27 animals in total. The results suggest (on the base of detail discussion) that the low values of prevalence and intensity of infection should be taken as partly distorted due to the methodical conditions of checks. The efficacy of ivermectin treatment was complemented by observation of several cases and their results employing direct checks of shot deer (Tab. III), including a six-year observation of a group of 6 to 10 individuals of tame deer treated year by. These results explicitly document the high efficacy of mass peroral ivermectin administration in the control of warble fly larvae. Ivermectin is the first drug suitable for the treatment of roe deer hypodermosis.

Administration, Oral↗

PubMedDate not supplied

Pharmacokinetic examination of antipyrine passage through the placenta and the small intestine in rats.

The placental and small intestinal barriers, though obviously different, show many functional as well as morphological similarities. When the surface area of both barriers in man was recalculated to a unit of body weight, nearly identical values (2.71 and 2.86 m2/kg of body mass, respectively) were obtained. The aims of the present study were (1) to compare mutual permeability of these two barriers to antipyrine (AP), and (2) to describe pharmacokinetics of AP in pregnant and non-pregnant rats. In placental studies AP showed that its rapid transfer through the placenta (k(tr) = 0.046 min(-1)) was governed by the mechanism of passive diffusion. In the closed circuit, FMCR(eq) was 1.085, t(eq) was 112.10 min and k(eq) was 0.020 min(-1). Absorptive studies performed on the rat small intestine indicated an identical mechanism of drug transport. The apparent first-order absorption rate constant of AP was 0.479 min(-1), and Tmax was 8.95 minutes. Differences in AP pharmacokinetics between pregnant and non-pregnant rats were significant during the distribution phase (t(1/2) = 3.78 and 5.87 min, respectively), whereas the elimination phase was unaffected. AP has been demonstrated, as expected, to be an excellent marker for drug transport studies through different body barriers.

Animals↗

PubMedDate not supplied

Corticosterone transfer and metabolism in the dually perfused rat placenta: effect of 11beta-hydroxysteroid dehydrogenase type 2.

Although rat is the most widely used model of glucocorticoid programming of the fetus, the role of rat placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in the transplacental pharmacokinetics of the naturally occurring glucocorticoid, corticosterone, has not yet been fully elucidated. In this study, expression of 11beta-HSD2 in the rat placenta on two different gestation days (16 and 22) was examined using quantitative RT-PCR and Western blotting, and dually perfused rat term placenta was employed to evaluate its functional capacity to transfer and metabolize corticosterone. Marked decrease in placental expression of 11beta-HSD2 toward term was observed on both mRNA and protein levels. In perfusion studies, increasing maternal corticosterone concentration from 3 to 200 nM resulted in the fall of 11beta-HSD2 conversion capacity from 64.3 to 16.3%, respectively. Enzyme saturation occurred at about 50 nM substrate concentration. When delivering corticosterone (3 or 100 nM) from the fetal side, a similar decline of 11beta-HSD2 conversion capacity was observed (66.5% and 48.5%, respectively). Addition of carbenoxolone (10 or 100 microM), a non-specific 11beta-HSD inhibitor, to maternal perfusate decreased conversion capacity from 66.7 to 12.6 or 8.1%, respectively. Similarly potent inhibitory effect was observed in feto-maternal studies. Neither saturation nor inhibition of 11beta-HSD2 was associated with transformation of corticosterone in metabolites other than 11-dehydrocorticosterone. These data suggest that 11beta-HSD2 is the principal enzyme controlling transplacental passage of corticosterone in rats and is able to eliminate corticosterone in both maternal and fetal circulations.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗