Distribution of subcutaneously administered inulin between blood and peripheral lymph in the rabbit.

In experiments on rabbit peripheral lymph, the contribution of the blood and lymphatic system to the whole-body distribution of inulin after subcutaneous administration has been investigated and the effects of hyaluronidase and of thermal stimulus at the administration site examined. Inulin concentrations in lymph exceeded plasma concentrations by more than 100-fold. At the end of the experiment (90 min) the amount of drug in the total lymph collected was about one-seventh the amount found in urine. The blood system, as a result of higher circulation at the administration site distributes inulin from the subcutis more rapidly than does lymph. Hyaluronidase did not influence inulin concentrations in blood and lymph but thermal stimulus significantly decreased both concentration and total distribution. The decrease resulted from a developed oedema and vasoconstriction in the skin and subcutis of the cannulated extremity.

Pharmacokinetics of ortho-I-hippurate in the blood and central lymph of the rat.

The authors studied ortho-I-hippurate kinetics in the blood and central lymph in two groups of intact rats and three groups of animals with induced pathological states (cirrhosis, uraemia, malabsorption). A differentiated lipid concentration in the central lymph was induced in intact animals by depriving them of food (the unfed group) or allowing them food (the fed group) before the experiment. All the hippurate kinetic parameters, including lymphatic bioavailability (FL), in the fed group were very close to those in the unfed group, which was also used as the control for the groups with induced pathological states. Cirrhosis, uraemia and malabsorption altered the blood and lymphatic kinetic parameters in many cases, but the changes mostly followed a parallel course so that FL was maintained (except in the uraemia group, in which it fell).

Effect of plasma binding of ortho- and para-I-benzoates on their distribution in blood and into lymph, biotransformation and excretion in rat urine.

Two positional iodine derivatives of benzoic acid, i.e. ortho- (OIB) and para- (PIB), were used alone and in combination with salicylic acid (SA) to study the effects of plasma binding on their pharmacokinetics. Their lymphatic bioavailability (central lymph), their biotransformation and urinary excretion in rats were also studied. Plasma binding of the two benzoates is different, about 95% of PIB and approximately 50% of OIB are bound. The competitive inhibition effect of SA was shown by an increase in the amount of free drug in plasma in both benzoates. Lymphatic binding is lower compared to plasma binding, an effect of SA of the free faction of drug in lymph was shown only with PIB. Kinetic parameters of benzoates are influenced by plasma binding; significant differences were found mainly in total clearance and areas under concentration curves. Lymphatic bioavailability (FL) differs only slightly with different plasma binding; a significant change in FL was, however, found in PIB after SA premedication. Significantly higher urinary excretion of OIB as compared with PIB corresponds to plasma binding of drugs, SA premedication decreases total excretion of both benzoates. SA also changes the proportion of the individual fractions of metabolites of benzoates in urine.

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.

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.