Effect of oral administration of glycyrrhizin on the pharmacokinetics of prednisolone.

The pharmacokinetics of total and free prednisolone (PSL) in six healthy men, with or without pretreatment with oral glycyrrhizin (GL), was investigated to confirm whether oral administration of GL influences the metabolism of PSL in man. Each subject received an intravenous administration of 0.096 mg/kg of prednisolone hemisuccinate (PSL-HS) with or without pretreatment with 50 mg of oral GL four times. Blood samples were taken from a peripheral vein at 5, 10, 15, 30, 45 min and 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 h after the start of PSL-HS infusion. The concentrations of total PSL in plasma were analyzed by high-performance liquid chromatography, and the free PSL was measured by an isocolloidosmolar equilibrium dialysis method. The pharmacokinetic parameters of PSL were determined by non-compartment analysis. Oral administration of GL was found to significantly increase the concentrations of total PSL at 6, 8 h, and of free PSL at 4, 6 and 8 h after PSL-HS infusion. Moreover, oral administration of GL was also found to modify the pharmacokinetics of both total and free PSL. After oral administration of GL, the area under the curve (AUC) was significantly increased, the total plasma clearance (CL) was significantly decreased, and the mean residence time (MRT) was significantly prolonged. However, the volume of distribution (Vdss) showed no evident change. This suggests that oral administration of GL increases the plasma PSL concentrations and influences its pharmacokinetics by inhibiting its metabolism, but not by affecting its distribution.     

A model for the study of the oral administration of peptide hormones.

The intragastric administration of lysine vasopressin (LVP) to rats is used as a model to study the biological activity of orally administered peptide hormones. Using a modification of the antidiuretic assay of Sawyer, LVP given by stomach tube caused a significant antidiuresis that was dose dependent in doses of 300 to 2000 mU. The simultaneous administration of the protease inhibitor, Trasylol, increased the antidiuretic effect of LVP. The synthetic peptide (1-deamino, 4 valine)-8-D-arginine-vasopressin also caused a dose-dependent prolonged and significant antidiuresis. No pressor effect was observed after intragastric administration of LVP in doses up to 40 U/rat. We are now using this model to test other procedures for enhancing the activity of lysine vasopressin administered in the gastrointestinal tract such as encapsulation into liposomes. The information gained with vasopressin will then be applied to insulin with the ultimate goal of making oral administration practical.     

Is interferon effective after oral administration? The state of the art.

At present the evidence that interferon can be effective when administered by oral route is tenous and the purpose of this minireview is to focus attention on this problem. Interferon may act on the oral-associated lymphoid tissue and trigger a cascade of events leading to activation of the immune system with little or no presence of interferons in body fluids and lack of toxicity. If this is true, the oral administration could be the ideal route for the treatment of some viral diseases and immunodeficiencies.     

Liposome-encapsulated midazolam for oral administration

The oral administration of midazolam has often been used for sedation in pediatric patients. However, oral administration of an intravenous formulation of midazolam is difficult for younger pediatric patients because of its bitter taste. Liposomes have been developed as vesicles encapsulating various kinds of drugs to serve as a medical drug-delivery system. Thus, the aim of the present study was to produce pH-sensitive liposomes encapsulating midazolam and to evaluate its pharmacokinetics on rabbits. Liposome-encapsulated midazolam was produced from hydrogenated L-α-phosphatidylcholine, cholesterol, dipalmitoylphosphatidic acid, and midazolam. The capacity of liposomes to encapsulate midazolam (encapsulation efficiency), stability of encapsulation, and release efficiency were evaluated in vitro. Further, the produced liposome-encapsulated midazolam solution was orally administered to rabbits in vivo. As a result, midazolam was encapsulated by liposomes with a high encapsulation efficiency and was stably encapsulated in a physiological medium. Further, the produced liposomes rapidly and effectively released midazolam in an acidic medium in vitro. When the liposome-encapsulated midazolam solution was orally administered to rabbits, the time to achieve the maximum plasma concentration of midazolam after administration was slightly longer, but both the maximum plasma concentration and area under the concentration-time curve were higher than those receiving midazolam solution. In conclusion, we produced pH-sensitive liposome-encapsulated midazolam, which remained stable in a physiological medium and showed efficient release in an acidic environment. The results suggest that it is possible to clinically use liposome-encapsulated midazolam for oral administration as a useful drug-delivery vehicle.     

Methylmalonic acidemia controlled with oral administration of vitamin B12.

A 3-month-old male infant had two episodes of fever, projectile vomiting, dehydration, generalized fine tremors and gross metabloic ketoacidosis. Methylmalonic acid was found in high concentration in both serum and urine, although the concentration of serum vitamin B12 was normal. A therapeutic trial of vitamin B12, administered parenterally, reduced greatly the methylmalonic aciduria. The patient has since been given vitamin B12 supplements continuously, initially 1 mg intramuscularly every other day, then 15 mg/d orally, and the protein in his diet was subsequently restricted. The most effected control of the methylmalonic aciduria was achieved with the combined regimen of oral vitamin therapy and dietary protein restriction. His physical and intellectual development have progressed normally and he has survived several acute respiratory tract infections without recurrence of metabolic acidosis.     

Urinary marker of oral pregnenolone administration

Pregnenolone (PREG) can potentially be abused by athletes to maintain an equilibration of the steroidal environment after sex steroids administrations. Five men volunteers orally ingested 50 mg PREG to determine optimal urinary markers for detection of this steroid. Our findings show that ingestion of PREG has no significant effects on the testosterone/epitestosterone (T/E) and testosterone/luteinizing hormone (T/LH) ratios, whereas variable changes on the carbon isotopic values of three T metabolites: androsterone, etiocholanolone, 5beta-androstane-3alpha,17beta-diol (5beta-androstanediol) together with 16(5alpha)-androsten-3alpha-ol (androstenol) and 5beta-pregnane-3alpha,20alpha-diol (pregnanediol) have been observed. The difference between the carbon isotopic values (delta13C-values) of androstenol and pregnanediol is potentially the most reliable marker of exogenous PREG administration in males. For all subjects, the differences differ by 3.0 per thousand or more over a period of about 10 h and for both of them the detection window for positivity is extended over 40 h.     

Immunologic suppression after oral administration of antigen. I. Specific suppressor cells formed in rat Peyer's patches after oral administration of sheep erythrocytes and their systemic migration.

Rats given 10(10) sheep erythrocytes (SRBC) orally were found to contain specific suppressor cells to SRBC in their Peyer's patches (PP) and mesenteric lymph nodes (MLN) after 2 days of feeding. After 4 days of feeding, similar suppressor cells were found in the thymus and spleen, but they were missing in the PP or MLN. These suppressor cells effectively blocked IgM and IgG plaque-forming cell responses to SRBC in Mishell-Dutton cultures and delayed-type-hypersensitivity responses to SRBC when transferred to syngeneic recipients, but they did not affect responses to horse erythrocytes. The orally induced specific suppressor cells appeared to be T2 cells since their activity was eliminated by in vivo treatment of SRBC-fed rats with anti-rat lymphocyte serum but not by adult thymectomy. Because carrageenan partially relieved the suppression observed in culture, the actual suppressive mechanism may also involve a macrophage.     

Rat liver amino acid balances after the administration of an oral protein load.

The hepatic balances of amino acids, ammonia and urea have been measured in rats for three hours after receiving a protein load. The liver took up practically all of the portal ammonium. Alanine was retained to a large extent during all three hours. Other portal amino acids, mainly essential amino acids, were largely retained in about one hour after the gavage, to be released in a similar proportion thereafter. The other amino acids were also retained and then released, but to a lower extent. These amino acids were used in part by the liver for the synthesis and release of urea, which appearance in hepatic vein peaked at two hours after the protein administration.     

Rat intestinal amino acid balances after the administration of an oral protein load.

The intestinal amino acid balances in rats given an oral load of protein were measured three hours after the gavage. During that period, about one half of the nitrogen from the protein given appeared as net balance in the portal blood. The release of amino acids was not a continuous process, since two peaks of maximal intestinal efflux were found at 1 and 2.5 hours after gavage. This pattern followed that of portal blood flow with a 30 minute delay. Under prandial conditions, the intestine showed a net uptake of glutamine, aspartate, serine, threonine, phenylalanine, tyrosine, leucine, isoleucine and valine. It also showed a net production of alanine, glutamate, ornithine skeleton (arginine + citrulline + ornithine) and ammonia. There was also a surge of taurine, attributed to reabsorption of secreted taurine conjugates. There was a net unchanged absorption of glycine, proline, lysine and histidine, with respect to their proportions in the protein administered. The results suggest that the amino acid metabolism in the intestine under prandial conditions is much less passive than is generally assumed. The intestinal action upon the luminal amino acids is not limited to absorption, but is directly implied in their transformation to complement the ensuing homeostatic action of the liver upon them.     

Effects of short-term oral salbutamol administration on exercise endurance and metabolism.

The present study examined whether oral short-term administration of salbutamol (Sal) modifies performance and selected hormonal and metabolic variables during submaximal exercise. Eight recreational male athletes completed two cycling trials at 80-85% peak O(2) consumption until exhaustion after either gelatin placebo (Pla) or oral Sal (12 mg/day for 3 wk) treatment, according to a double-blind and randomized protocol. Blood samples were collected at rest, after 5, 10, and 15 min, and at exhaustion to determine growth hormone (GH), cortisol, testosterone, triiodothyronine (T(3)), C peptide, free fatty acid (FFA), blood glucose, lactate, and blood urea values. Time of cycling was significantly increased after chronic Sal intake (Sal: 30.5 +/- 3.1 vs. Pla: 23.7 +/- 1.6 min, P < 0.05). No change in any variable was found before cycling except a decrease in blood urea concentration and an increase in T(3) after Sal that remained significant throughout the exercise test (P < 0.05). Compared with rest, exercise resulted in a significant increase in GH, cortisol, testosterone, T(3), FFAs, and lactate and a decrease in C peptide after both treatments with higher exercise FFA levels and exhaustion GH concentrations after Sal (P < 0.05). Sal but not Pla significantly decreased exercise blood glucose levels. From these data, short-term Sal intake did appear to improve performance during intense submaximal exercise with concomitant increase in substrate availability and utilization, but the exact mechanisms involved need further investigation.     

Urinary excretion of hydroxycinnamates and flavonoids after oral and intravenous administration.

The urinary recoveries of the hydroxycinnamates, ferulic acid (3-methoxy, 4-hydroxy cinnamic acid), and chlorogenic acid (the quinic acid ester of 3,4-dihydroxycinnamic acid), and three structurally related flavonoids were studied in the rat. For the latter, the aglycone quercetin was compared with its 3-glucoside (isoquercitrin) and 3-rhamnoglucoside (rutin). Doses of 50 mg/kg were administered via the oral and intravenous routes and urine collected over the subsequent 24-h period. Reverse phase HPLC with photo-diode array detection was used to analyze the unchanged compound and their metabolites excreted in the urine. Ferulic acid and isoquercitrin were orally absorbed (5.4 and 0.48% of administered dose, respectively) and are therefore bioavailable. In contrast, neither unchanged chlorogenic acid, rutin, quercetin, nor the conjugated metabolites in the form of glucuronide or sulphate were detected in the urine after oral dosing. All the flavonoids studied produced low total urinary recoveries after intravenous administration, 9.2% for quercetin-3-rhamnoglucoside, 6.7% for the 3-glucoside, and 2.4% for the aglycone, indicating that extensive metabolism to low molecular weight compounds or excretion via other routes may be occurring. Overall it can be stated that renal excretion is not a major pathway of elimination for intact flavonoids and hydroxycinnamates in the rat.     

Cardiovascular and pulmonary response to oral administration of ATP in rabbits.

Extracellular purines such as ATP and adenosine participate in the regulation of cardiovascular and respiratory functions through specific P1 and P2 purine receptors. These properties have mainly been described after intravenous infusion. Experiments reported herein were designed to explore the possible effect of oral ATP administration (3 or 20 mg. kg(-1). day(-1)) on vascular, cardiac, and pulmonary functions in rabbits. Whereas a unique oral dose of ATP has no effect, chronic supplementation during 14 days reduces peripheral vascular resistance, pulmonary resistance, and respiratory frequency and increases arterial PO(2). No effect on central blood pressure and heart rate is observed, but an increase of the left ventricular work index is noticed subsequent to the diminution of vascular resistance. Rather similar cardiovascular modifications are observed in rabbits given 20 mg. kg(-1). day(-1) adenosine for 14 days but without variation of respiratory parameters. These original effects of repeated oral treatment with ATP may result from an adaptive metabolic response to nucleoside supplementation that might affect the turnover of extracellular purines leading to P1- and/or P2-receptor activation.