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.

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.

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.

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.

Lymphatic bioavailability of diazepam and desmethyldiazepam in the rat.

The lymphatic bioavailability (FL) of diazepam (DZ) and its major metabolite desmethyldiazepam (DDZ) was studied. DZ was administered in intravenous and intraduodenal boluses, and in intravenous infusion in three groups of rats with different total lipid (TL) content in the central lymph. The effect of a) different lipophilicity of DZ and DDZ, b) lymphatic TL content, and c) route of DZ administration on FL was determined. It was found that a) FL values of DZ exceeded the FL values of DDZ and b) FL values of DZ increased with increasing TL content in the lymph (an opposite relation was found in DDZ), and c) the highest FL value of DZ + DDZ sum after intravenous bolus administration was attained contrary to the lowest one after intraduodenal bolus administration.

N-demethylation activity of renal and hepatic subcellular fractions: an interspecies comparison.

The enzymatic activity of the mixed-function oxidase system in the kidney and liver was evaluated by means of an in vitro N-demethylation activity assay with aminopyrine as the substrate. Renal and hepatic demethylation activity of 9000 x g supernatant fraction was determined in the rat, rabbit, and guinea-pig. In terms of interspecies comparison, the renal tissue demethylation activities were on a similar level with a slight increase in the order guinea-pig, rabbit and rat. In relation to hepatic activity, these relative demethylation activities of renal tissue had the same values in the rat and rabbit, whereas that in the guinea pig was significantly lower. The distribution of demethylation activity in the kidney was determined by comparing the cortex and medullary activity in relation to the total kidney tissue activity in the rabbit and guinea-pig. Although the higher demethylation activities were obtained in rabbit renal preparations and low demethylation activity was detected in the guinea-pig renal medulla only, no significant interspecies differences were found by the statistical evaluation. It may be concluded that the mixed-function oxidase system responsible for renal demethylation activity seems to be concentrated in the renal cortex and its distribution coincides in the rabbit and guinea-pig kidney.

Influence of the composition of rat central lymph on the pharmacokinetics (the steady state during infusion, bioavailability, absorption) of diazepam, studied in the blood and lymph.

Diazepam was administered by infusion to three groups of rats with an induced differentiated total lipid content in their lymph (unfed, fed, oil-fed) and its lymph/blood concentration ratios in the steady state were determined. Ratio values were highest in the group with the highest lymph lipid content (the oil-fed group, 2.20 +/- 0.08) and fell significantly in the other groups (fed group 1.46 +/- 0.09, unfed group 1.15 +/- 0.05). The areas under the blood and lymph concentration curves after the intravenous (i.v.) and intraduodenal (i.d.) administration of diazepam were used to determine absolute (F) and lymphatic (FL) bioavailability. The F value in the blood can be raised by increasing the amount of lipids, whereas in the lymph, under the same conditions, it falls. During the i.v. and i.d. administration of diazepam, FL always rises with an increase in the amount of lipids in the lymph. The role played by the lymphatic system in total diazepam absorption was determined from the experimental results of its i.d. administration. The absolute values are very low (0.043-0.316%), but are significantly influenced by the presence of lipids.

The pharmacokinetics of intravenously administered diazepam in the rat influenced by composition of the lymph.

Diazepam, a drug with hydrophobic properties, was used as a model drug for the study of its distribution after i.v. administration into the central lymph of the rat. The intestinal lymph, which prevails in the central lymph, was modified for the presence of total lipids chylomicrons by fasting and a normal or an artificial diet (olive oil). Lymphatic levels of diazepam in all three experimental conditions exceeded the corresponding blood levels, being lowest in the fasted group, higher in the normally fed animals and highest in the oil-fed group. Experimental blood and lymphatic data were subjected to pharmacokinetic analysis. The changes in the parameters were found to depend quantitatively upon the presence of chylomicrons in the lymph. Lymphatic availability of diazepam in the central lymph is stimulated by an increased content of the chylomicrons fraction of the lymph.

The pharmacokinetics of intraduodenally administered diazepam in rats as influenced by composition of the central lymph.

Diazepam, a drug with hydrophobic properties, was used as a model for studying its distribution (after intraduodenal administration) into the central lymph of rats. The intestinal lymph, which prevails in the central lymph, was modified for the presence of total lipids (chylomicrons) by means of fasting, a normal or an artificial diet (olive oil). The lymphatic levels of diazepam exceeded the corresponding blood levels in the fed and oil-fed group; the levels were steady in the fasted group with the exception of the absorption phase of the curves. The kinetic parameters assessed in the blood and lymph of the individual groups obtained by mathematical evaluation of the concentration curves differed because of quantitative differences in the presence of chylomicrons in the lymph. Lymphatic bioavailability in comparison with i.v. administration was found to be substantially lower.

Plasma imipramine levels and demethylase activity in the liver of stressed animals.

The steady-state values in rats after a second 14-day period of daily subcutaneous administration of imipramine were the same as during the first period; liver demethylation activity rose for up to 3 days and then returned to normal. The imipramine-binding capacity of the serum, brain myelin, synaptosomes and mitochondria did not alter after repeated administration, but a decrease was found in the red blood cells. Stress (an electric current or immobilization) led to marked reduction of the plasma imipramine level, with a simultaneous increase in liver demethylase activity. Adrenalectomy caused a drop in demethylase activity; stress had no effect either on these values or on imipramine levels.