Biomedical subjects
Publications and source records attributed to M Láznícek.
An analytical method for analysis of 3-(o-bromo)-phenyl-2-(2',3'-dihydroxypropylthio)-4(3H)-quinazolinone from rat plasma using HPLC with reversed phase C18 and liquid-liquid extraction was developed. This method was used for a pharmacokinetic study in rat.
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.
Inflammation is a complex reaction of the organism which develops as a response to invasion of an infectious subject or as a response to injury to cells or tissues. Correct and early localization of infection or an inflammatory lesion allows removing the inflammatory cause quickly. Over the recent thirty years, a wide range of radiopharmaceuticals, more or less applicable in scintigraphic imaging of inflammatory and infectious diseases, have been developed. The aim has been to develop new substances that are non-toxic, do not provoke immune reactions, and produce a minimal absorbed radioactive dose. Furthermore, these substances should accumulate significantly in the target tissue (i.e. in inflammation), while the accumulation in non-target tissues should be minimal or the elimination of radiopharmaceuticals from non-target tissues must be quick. The goal is that these substances may also be easily available and inexpensive. Another purpose is to develop such substances that could possess not only sufficient sensitivity but also specificity in relation to certain types of inflammation and infection. The main indications for radionuclide imaging are as follows: inflammatory bowel disease, soft tissue sepsis, predominantly abdominal sepsis, musculoskeletal infection, and fever of unknown origin.
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.
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.
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.
The distribution and elimination of 99Tcm-complexes with methylene-diphosphonate (MDP) and with the calcium salt of diethylene-triamine-penta(methylene phosphonate) (DTPMP) were compared in rats. Both compounds exhibited high bone uptake and long-term retention of radioactivity in the skeleton. No significant accumulation of the complexes in non-osseous tissues was found. The pharmacokinetics of both chelates were similar, small differences in their distribution and elimination probably being due to different binding to plasma proteins. Two processes, namely bone uptake and kidney elimination, contributed to the disappearance of the complexes from the blood. The higher protein binding of 99Tcm-MDP probably caused its slower rate of urine elimination and insignificantly higher bone uptake compared with 99Tcm-DTPMP. On the other hand, the more rapid reduction in blood and muscle radioactivity with 99Tcm-DTPMP resulted in accelerated non-osseous tissue clearance compared with 99Tcm-MDP. This suggests that the time between administration and imaging may be shorter for 99Tcm-DTPMP than for 99Tcm-MDP. Furthermore, the much greater stability of 99Tcm-DTPMP may also reduce degradation of the complex and 99Tcm liberation in the body. For a general evaluation of both compounds, it will be necessary to determine lesion-to-bone ratios.
Quantitative relationships between lipophilicity (characterized by the octanol-water partition coefficient) and binding to both human plasma proteins and blood cells have been studied in a group of model anionic drugs (benzoic and phenylacetic acid derivatives). Protein binding in plasma and accumulation in blood cells in suspension increases with increasing lipophilicity. For quantitative evaluation, the equation log R = a + b log D has been employed, where R is the bound-to-free drug ratio, D is lipophilicity, and a and b are constants. Whereas the protein bound-to-free drug ratio is proportional to drug lipophilicity, the cell bound-to-free drug ratio correlates with lipophilicity to the power 0.685. Distribution in whole blood is affected by protein binding and also by cell accumulation. In blood, the free drug fraction and the fraction in blood cells decrease with increasing lipophilicity, whereas the protein-bound fraction correspondingly increases.
The pharmacokinetics and elimination of EDTMP chelates with different radionuclides (99mTc, 111In and 153Sm) has been investigated in rats. The biodistribution of the complexes under study was similar and two main processes, namely bone uptake and the elimination of glomerular filtration, take part in their rapid blood clearance. A substantially slower blood clearance of 111In-EDTMP in comparison with the other complexes suggests partial indium exchange between the chelate and transferrin. All the complexes exhibited high affinity for bone and the radionuclide uptake into the skeleton was in the order 153Sm > 111In > 99mTc. No specific extra-skeletal uptake was found.
The changes of pharmacokinetics and distribution of 3H radio-labelled ribonuclease (RNase) and RNase adduct with monomethoxypoly(ethylene glycol) (MPEG) were studied after intravenous administration in the dose of 25 mg kg-1 to rats. Whereas the value of total plasma clearance of RNase is close to the value of glomerular filtration rate, the value of that for MPEG-RNase is about three hundred times lower. The half-life of elimination is 79 min, 181 min and 65 h for RNase, MPEG and MPEG-RNase, respectively. The main elimination pathway of compounds under study was elimination into urine and no evident specific distribution in the examined organs (liver, kidney, muscle, lung, brain, spleen and heart) was found. The study indicates that conjugation of RNase with MPEG can improve its pharmacokinetic properties.
The effect of lipophilicity on the renal clearance for a group of weak organic acids (benzoic, phenylacetic and hippuric acid derivatives) was studied in rabbits, rats and mice. These compounds are eliminated in the kidney by glomerular filtration and undergo both tubular secretion and tubular reabsorption. For quantification of the effect of lipophilicity, an equation [formula: see text] was employed, where CLR represents renal clearance of the parent drug, ERPF is effective renal plasma flow, D is the partition coefficient of the acids between octanol and water, and a and b are constants. In interspecies comparison, the values of parameters a and b are similar indicating no significant interspecies differences in this route of elimination.
We have investigated the possibility of interspecies scaling of relationships between the structure and total plasma clearance in a group of nine organic acids (iododerivatives of benzoic, phenylacetic and hippuric acids) in rabbits, rats and mice. The intercompound comparison established the dependence of total plasma clearance predominantly on the molecular structure in all the animals under study, but the dependence on drug lipophilicity was also meaningful. For interspecies scaling of total plasma clearance, the use of a biological clock with an effective renal plasma flow as the unit seemed most suitable and is probably connected with the principal role of the kidney in the elimination of the compounds under study.
The contribution of the kidney and liver to the total metabolism of (125I)ortho-iodobenzoate (OIB) was studied in rats with the aim considering the suitability of the use of this radiopharmaceutical as a diagnostic agent of the conjugation function of the liver. For the analysis of OIB metabolism (formation of conjugates with glycine and glucuronic acid) in rats, the techniques of the perfused rat kidney "in situ" and the isolated perfused rat livers were used. A comparison of the relative representation of OIB metabolites in the urine of intact rats with the results obtained in the urine from the perfused kidney and the perfusion fluid from the isolated perfused liver gives evidence of preferential biotransformation of OIB in the kidney. As shown in a biodistributional study of OIB in rats, OIB concentration in the renal tissue and thus the supply for the metabolic processes in the kidney is higher by orders than it is in the liver tissue, which could explain the above-mentioned finding. Assuming that the biotransformational organ capacity for this drug in man is similar to that in the experimental rat, the use of OIB for quantification of the detoxicating function of the liver in man is debatable.
An analysis of the mechanisms of elimination of o-125I-benzoate in the rabbit kidney on the basis of the inhibition of the secretionary transport by probenecid has shown that o-125I-benzoate is eliminated in the kidneys not only by glomerular filtration but by tubular secretion as well. An effect on the total amount of the drug excreted in the urine is exerted by tubular resorption (apparently by the process of passive diffusion), which exceeds tubular secretion. A comparison of the chromatograms of the plasma and urine before and after the competitive inhibition of the tubular active transport by probenecid revealed a higher share of o-125I-benzylglucuronide in the urine in the case of inhibition. The results suggested a partial share of the kidneys in total biotransformation of o-125I-benzoate. Excretion of the original drug and metabolites in the bile forms a negligible share (less than 1%) of total clearance in rabbits.
The biological behaviour of complexes of 99mTc with aminopolycarboxylic and aminocarbohydroxamic ligands EDTA (ethylenediaminetetraacetic acid), DTPA (diethylenetriaminepentaacetic acid), EDTAH (ethylenediaminetetraacetohydroxamic acid) and HIDAmH (N-2-hydroxyethyl-N-carboxymethyl-aminoacetohydroxamic acid) was studied in rabbits. The pharmacokinetic parameters determined in intact rabbits were compared with the results obtained in the study of renal and hepatic clearance of the complexes under study. Hepatobiliary excretion, which in [99mTc]EDTA forms 20-30% of the total excreted amount, is of negligible magnitude in the other 99mTc-complexes studied (less than 2%). Their renal clearance is not influenced by the inhibition of tubular secretion with probenecid. Binding to plasma proteins increases in the order [99mTc]DTPA less than [99mTc]EDTA less than [99mTc]HIDAmH less than [99mTc]EDTAH and the elimination half-life increases in the same order. The value of renal clearance of the complexes studied related to inulin clearance correlates well with the fraction of the free drug in the plasma. In rabbits the complexes under study are excreted mainly by the mechanism of glomerular filtration in the kidney.
Changes in the pharmacokinetics and metabolism of sodium salicylate were studied in rabbits with acute renal damage induced by intravenous administration of uranyl nitrate in the dose of 0.2 mg/kg. In the pathological group there occurs a marked decrease in elimination characteristics, the total plasma clearance of salicylate linearly decreasing with a decrease in the value of glomerular filtration rate. The plasma levels of creatinine and urea are suitable indices for the estimation of the changes in the plasma binding of salicylate. An increase in the fraction of free salicylate in the plasma of rabbits with acute impairment of the kidney results in a not very conclusive increase in the size of distributional volumes. In the control group mainly the unchanged drug is excreted into urine, whereas in rabbits with acute renal damage salicylate metabolites represent the majority of the eliminated amount.
Binding of 14C-pethidine to erythrocytes of some species, particularly human, rat and rabbit, was examined in two different concentrations. This binding was investigated by direct measurement of the relative representation in erythrocytes, plasma proteins and the free fraction in blood. In the case of human erythrocytes the relative representation was 33%, in the rat ones 44%, and in the rabbit ones 54%. The fraction bound to plasma proteins was 45% in man, 29% in rats, and 27% in rabbits. The portion of the free fraction was 22% in man, 27% in rats, and 19% in rabbits. The ratio of the concentrations of the fraction bound to erythrocytes and the fraction free in the blood was 1.72 in man, 2.09 in rats, and 3.92 in rabbits. On the basis of these results it can be concluded that binding of pethidine to erythrocytes does not play an insignificant part in total pharmacokinetics of pethidine.
Changes in renal function in rats after single-dose intravenous administration of CBDCA (cis-diammine-1,1-cyclobutane dicarboxylate platinum(II) and oxoplatinum [cis-dichlorodiammine-trans-dihydroxo-platinum(IV)] at a dose of 20 mg/kg were determined and compared. Renal function was monitored by several determinations of effective renal plasma flow (ERPF), glomerular filtration rate (GRF), plasma creatinine and urea and urine beta 2-microglobulin. A significant reduction of ERPF and GRF and a significant increase of plasma creatinine and urea concentration after oxoplatinum treatment were found. On the other hand, no significant changes in renal function parameters were determined after CBDCA. The increase in beta 2-microglobulin amount in rat urine and polyuria persisted until the 14th day after oxoplatinum administration. Histological examination of the kidneys in the experimental animals revealed marked nephrotoxicity changes in the distal tubules after the single-dose administration of oxoplatinum. Administration of CBDCA did not produce pathological renal changes.