Intestinal absorption and presystemic disposition of sildenafil citrate in the rabbit: evidence for site-dependent absorptive clearance

Sildenafil citrate is the first oral treatment of erectile dysfunction. Its oral bioavailability is about 40%. This research characterized the intestinal transport parameters of sildenafil citrate in rabbit using in situ intestinal perfusion technique. This was studied in flint different anatomical sites, namely duodenum, jejunoileum, ascending-colon and rectum. The results revealed the highest absorptive clearance in the jejunoileum. The value of permeability area product normalized to segment length [ml/min cm] were 0.0101, 0.0063, 0.0059 and 0.0023 and those of percentage absorbed were 67.95, 32.27, 23 and 5.03 in jejunoileum, duodenum, ascending colon, and rectum respectively. The values of the length [cm] required for complete absorption were 87.58, l37.23, 153.27, and 384.09 for each segment in the some order. The absorptive clearance did not correlate with the net water flux in the four anatomical, regions studied, indicating mainly passive diffusion mechanism through transcellular pathway. The plasma sildenafil concentrations achieved dosing intestinal perfusion experiments and sildenafil total body clearance in rabbit were used to calculate the fraction of sildenafil that reached the systemic circulation relative to the amount disappeared from the intestinal segment. Only.34% of sildenafil disappeared from the intestinal segment appeared in the systemic circulation indicating that the presystemic elimination of slidenafil is 66%. These results confirm that the incomplete bioavailability of sildenafil is mainly due presystemic elimination

Predictors of anticonvulsants-induced osteopathy in epileptic children

Anticonvulsants are known to have many side effects specially is growing epileptic children. Among these side effects are that bad effects on calcium metabolism and bone mineral density. This study was designed to find sensitive predictors of calcium homeostasis and bone mineral status with possible osteopathy in epileptic children. 60 epileptic children aged 4-14 years, admitted at neurology ward of pediatric department of Tanta university were enrolled in the study. They were subdivided into 4 subgroups according to monotherapy given: 15 cases phenytion-treated, 15 cases phenobarbital-treated, 15 cases carbamazepine-treated and 15 cases valproate-treated. 15 healthy children matched for age and sex plotted as control. After establishment of diagnosis and control and after one year of initiation of anticonvalsant therapy they were subjected to full serological surgery of calcium metabolism: serum calcium, serum phosphorus, serum alkaline phosphatase. As indicators of bone resorption, fasting urinary calcium and total urinary hydroxyproline were measured. Bone mineralization was estimated with plain X-ray films of spine and extremities and dual-energy X-ray absroptiometry for estimation of bone mineral density [BMD] at the trabecular and cortical bone of distal third of radius. We found normal calcium and phosphorous levels in the 4 patient groups denoting possibly the successful homeostasis by parathormone. But we found significant increase of urinary fasting excretion of calcium and hydroxyproline in patients receiving phenytion and phenobarbtione denoting bone resorption which is supported by the significant increase of alkaline phosphatase in these patient groups confirming osteoclastic activity found. Serum basal calcitonin was found to be significantly reduced in all patients groups except carbarnazepine treated group [mean 46.00 +/- 0.9 picogram/ml] denoting presented complete homeostasis of calcium in CBZ-treated children in contrast to the other three groups who are prone to osteopenia specially if the tendency to increased osteoclastic activity is aggravated by secondary' hyperparathyroidism. Bone mineral density [BMD] is decreased in the four patients groups, the worst was phenytoin - treated group [Mean 0.284 +/- 0.049 gm/cm[2]] as compared to controls [mean 0.436 +/- 0.047 gm/cm[2]]. The best BMD was in carbamazepine-treated group [mean 0.39 +/- 0.045 gm/cm[2]], denoting nearly no deleterious effect of the drug on both calcium homeostasis and bone mineral density. From this study, we recommend the full radiologic survey of epileptic children before and during anticonvulsant therapy specially if prolonged. We also recommend both high dietary calcium and vitamin D intake in patients treated with phenytion, phenobarbitone and valproate with special emphasis of 1,25 dihydroxy D3 supplement. Also we recommend radiological survey of these patients with attention to measurement of bone mineral density using sensitive non-invasive techniques as dual -energy x-ray absorptiometry

Effect of s-adenosyl-l-methionine on acetaminophen pharmacokinetics in the rabbit

The effect of SAMe on acetaminophen pharmacokinetics has been studied in rabbits. SAMe administration [IM] resulted in a decrease in acetaminophen half-life from 0.85 +/- 0.12 [control group] to 0.68 +/- 0.10 h in the treated group. Acetaminophen total body clearance increased from 1.98 +/- 0.08 L/h, [control group] to 2.38 +/- 0.46 L/h in the treated group. It was not possible to determine which of the acetaminophen metabolic pathways is affected by SAMe administration because acetaminophen metabolities were not determined. To investigate the mechanism of SAMe protective effect against acetaminophen intoxication, acetaminophen was administered in the form of suspension either alone or after pretreatment with SAMe administered intramuscularly. The activity of the serum transaminase enzymes, liver glutathione level as well as histopathological examination were measured to assess liver function. SAMe administration resulted in reduction of the serum activity of alanine aminotransferase [ALT] and aspartate aminotransferase [AST] enzymes. The pathological changes in the liver produced by acetaminophen also decreased SAMe pretreatment prevented liver glutathione [GSH] depletion in acetaminophen intoxicated animals