Gastric and biliary excretion of meperidine in man

The role and importance of enterogastric secretion in the disposition and elimination of the weak base, meperidine (pKa 8.63), was studied after intravenous administration (50 mg) of the drug to 6 normal volunteers. Continuous collection of the gastric fluid over a 4-hr period demonstrated the establishment of high gastric fluid/plasma concentration ratios for meperidine (mean about 50, range, 10 to 200). However, the total amount of drug recovered, even after correction for incomplete collection, was only a small percentage of the administered dose. Under basal conditions a mean +/- SE of 1.9 +/- 0.3 mg, equivalent to 3.7% of the administered dose, was found in the total gastric aspirate. Stimulation of gastric secretion by subcutaneous injection of betazole (1.5 mg/kg) increased this recovery to 3.6 +/- 0.3 mg (7.2%) primarily due to the increase in gastric volumen output. Aspiration of the gastric fluid in either the basal or stimulated situation had no observable effect upon the plasma concentration/time profile of meperidine whether assessed by the terminal half-life, t 1/2 beta, or the plasma clearance; control values were 3.8 +/- hr and 1,190 +/- 130 ml/min, respectively. In 2 subjects "bile fluid" was also collected for 2.5 hr and found to contain less than 0.2% of the administered dose. Enterosystemic recycling is therefore of minor importance in the disposition and elimination of meperidine in man.     

Effects of anti-emetics on water excretion in humans

To evaluate the effectiveness of CT and MRI at 0.5 T in the diagnosis and staging of retinoblastoma, we studied 11 patients in whom retinoblastoma was clinically suspected. Nine of the eleven had surgically proven retinoblastoma; in the other two a diagnosis of Coats' disease was made. MRI was not as specific as CT for diagnosing retinoblastoma, due to its lack of sensitivity in detecting calcification; it did, however, have superior contrast resolution. On MRI, Coats' disease was reliably diagnosed and easily differentiated from retinoblastoma. Moreover, the greater ability of MRI to differentiate subretinal fluid from tumour also confers high accuracy in measuring tumour size. CT is still the study of choice in the diagnosis of retinoblastoma, but when MRI is available, it should be performed for better differentiation from lesions such as Coats' disease.     

Stereoselectivity of biliary excretion of 2-arylpropionates in rats

To examine the stereoselectivity of biliary excretion, the optically pure enanatiomers of ketoprofen (KT), ibuprofen (IBU), and flurbiprofen (FLU) were intravenously administered to normal and bile duct-cannulated rats at 10 mg/kg. The recovery of total KT in bile was significantly higher after administration of (S)-KT than after (R)-KT [90.1 +/- 3.5% vs 68.8 +/- 8.2%, n = 3, P < 0.05]. In normal rats the terminal half-life of (R)-KT was significantly shorter than that of (S)-KT after administration of (R)-KT (2.2 +/- 0.6 h vs 14.3 +/- 4.9 h, n = 3, P < 0.05). The terminal half-life of both enantiomers was significantly shorter in rats with continuous bile drainage as compared to normal rats. No significant differences in pharmacokinetic parameters could be found between both enantiomers in bile duct-cannulated animals. The total amount of IBU in bile was slightly higher after administration of (S)-IBU than after (R)-IBU administration. The percentage of (R)-IBU after (R)-IBU administration, however, was very low [(R)-IBU: 1.5 +/- 0.9%, (S)-IBU: 23.4 +/- 5.8%]. In normal rats the clearance of (R)-IBU was significantly higher as compared to (S)-IBU. Differences in pharmacokinetic parameters between normal and bile duct-cannulated rats were not statistically significant due to high interindividual variability. The total recovery of FLU, which was excreted in bile to a lower extent than either KT or IBU, also tended to be greater after S-enantiomer administration. Only small amounts of (S)-FLU could be recovered in bile after (R)-FLU administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Iodipamide kinetics: capacity-limited biliary excretion with simultaneous pseudo-first-order renal excretion

Iodipamide was infused into three dogs with bile fistulas to achieve various steady-state blood levels. When using ultracentrifugation techniques, iodipamide was found to be highly bound to plasma protein. The total blood clearance was low relative to hepatic blood flow. For either the whole blood concentration or the unbound concentration of iodipamide, the biliary excretion was shown to be capacity limited with a transport maximum, Tm, of approximately 1.0mumole/kg/min. The steady-state renal excretion rate, plotted against the whole blood concentration of iodipamide, resulted in a concave ascending curve, which could lead to the false conclusion that iodipamide was undergoing active renal tubular reabsorption. However, when corrected for plasma protein binding, a linear relationship was obtained, suggesting that the renal excretion of iodipamide is a pseudo-first-order process. The Michaelis-Menten parameters for the extrarenal elimination, when calculated using the whole blood concentration of iodipamide, led to a similar discrepancy compared to the parameter estimates obtained from biliary excretion rate data. This discrepancy can be eliminated when one uses the unbound concentration of iodipamide in the parameter estimates.     

Role of metabolism in the biliary excretion of methadone metabolites

1. The effects of six local anaesthetics have been studied on the activities of soluble phospholipases A2 (EC 3.1.1.4) and lysophospholipase (EC 3.1.1.5). 2. Phospholipase A2 activity in human seminal plasma towards sonicated radioactively-labelled phosphatidylethanolamine was slightly stimulated a low and inhibited at high concentrations of all anaesthetic compounds employed. The order of decreasing potency was chlorpromazine, dibucaine, tetracaine, lidocaine, cocaine and procaine. In line with previous findings, the mode of inhibition was seen to be competitive with respect to Ca2+. 3. Phospholipase A2 activity in crude venom of Crotalus adamanteus was not affected or slightly stimulated by local anaesthetics up to 10(-2) M concentrations, when egg yolk was used as substrate. However, with sonicated radioactively-labelled phosphatidylcholine or phosphatidylethanolamine as substrate, stimulation of phospholipase activity was seen with all local anaesthetics up to 10(-2) M, the order of decreasing potency again being chlorpromazine, dibucaine, tetracaine, lidocaine, cocaine and procaine. The mode of stimulation was seen to be un-competitive with respect to substrate and probably independent of any involvement of Ca2+. 4. As in seminal plasma phospholipase A2, the activity in crude Naja naja venom towards sonicated radioactively labelled phosphatidylcholine was stimulated at low and inhibited at high concentrations of dibucaine and chloropromazine, for example. The mode of inhibition was seen to be competitive with respect to Ca2+, whereas stimulation by the anaesthetic drugs was independent of Ca2+. Binding between drug and enzyme was demonstrated by equilibration filtration of purified phospholipase A2 of Naja naja venom through a Sephadex G 25-fine column, previously equilibrated with 0.5 mM radioactively labelled chlorpromazine. 5. Lysophospholipase activity in rat liver cytosol towards radioactively labelled lysophosphatidylcholine was inhibited by all local anaesthetics used; the order of decreasing potency was chlorpromazine, dibucaine, tetracaine, cocaine, lidocaine and procaine. The inhibition was un-competitive with respect to substrate. 6. The inhibitory and stimulatory potencies of the local anaesthetics employed closely parallel their lipid solubilities and anaesthetic potencies.     

Intestinal uptake and biliary excretion of the isoflavone genistein in rats

The intestinal absorption, biliary excretion and metabolism of genistein, a potent and specific protein tyrosine kinase inhibitor that occurs naturally in soy foods, was examined in anesthetized, adult female rats fitted with indwelling biliary cannulas. 4-14C-Genistein, when infused into the duodenum, was rapidly absorbed from the intestine, taken up by the liver and excreted into the bile as its 7-O-beta-glucuronide conjugate. Cumulative recovery of 14C-radioactivity in the bile over a 4-h period was 70-75% of the dose. When genistein was infused into the portal vein, it was also taken up efficiently by the liver, conjugated with glucuronic acid and transported into bile. However, portal blood collected after duodenal infusions of genistein contained mostly genistein 7-O-beta-glucuronide, suggesting that in vivo glucuronidation occurred in the intestinal wall rather than the liver. This was confirmed using everted intestinal sac preparations. Reinfusion of genistein 7-O-beta-glucuronide into the duodenum or into the mid small intestine resulted in its reappearance in the bile, albeit more slowly than when genistein was infused. Over a 4-h collection period, the cumulative recovery of 14C-radioactivity in bile was 27 and 70-75% of the administered dose for duodenal and ileal infusions, respectively. These data indicate that genistein is highly bioavailable in rats and because of its enterohepatic circulation may accumulate within the gastrointestinal tract.     

Improvement of biliary excretion of ioglycamide by pretreatment with phenobarbital

The influence of a phenobarbital pretreatment on the distribution and biliary excretion of Ioglycamide was studied in 6 experiments in the anaesthetized minipig. The phenobarbital pretreatment led to a significant increase of the biliary transportmaximum and the biliary concentration of Ioglycamide. A detailed analysis suggests a phenobarbital induced stimulation of the hepatocellular excretion. The applicability of a pretreatment with phenobarbital in order to improve the opacification of the biliary system during x-ray-examinations with Ioglycamide is discussed.     

Ehanced biliary thyroxine excretion in rats treated with pregnenolone-16alpha-carbonitrile

Normal rats were treated with pregnenolone- 16alpha - carbonitrile (PCN) 10 mg/100 g by stomach tube twice daily for 3 days. In these animals the biliary excretion of intravenously injected 125I-thyroxine (T4) was enhanced and the bile: plasma 125I ratio (B/P ratio) and the biliary clearance rate of plasma 125I-T4 was increased. Normal rats were treated with PCN for 3 days and homozygous Gunn rats for 13 days. In both groups PCN enhanced the bile flow and elevated the B/P ratios and the biliary clearance rate of plasma T4 following ip injection of 125I-T4 17 h previously. PCN-treatment had no effect on the fractions of biliary 125I present as T4-glucuronide, T4 and I- in either the normal or Gunn rats. Treatment with PCN for 10 days produced goitres in normal and Gunn rats and in normal rats elevated the serum TSH (bioassay) levels and the 17 h thyroid 131I uptake as well as the serum PB125I concentrations, without affecting stable PBI concentrations. These data indicated increased pituitary TSH release in response to increased peripheral metabolism of thyroid hormone; enhanced hormonal release from the thyroid kept pace with the accelerated peripheral loss.     

Urinary excretion half-life of 11-nor-9-carboxy-delta9-tetrahydrocannabinol in humans

The excretion of marijuana metabolites occurs over an extended period of time, yet few studies have been designed for accurate estimation of excretion half-lives. The authors monitored excretion of the primary urinary metabolite of marijuana, 11-nor-9-carboxy-delta9-tetrahydrocannabinol (THCCOOH), by gas chromatography-mass spectrometry in a controlled clinical study of marijuana smoking that included measurement of the drug in each urine void collected during the 3-week study. Terminal excretion half-lives of THCCOOH were determined in six healthy male subjects with histories of marijuana smoking; the study was conducted on the clinical research unit of a major medical institution. Subjects smoked a single marijuana cigarette (placebo, 1.75% or 3.55% THC) each week. Urine specimens (N=953) were analyzed under blind conditions for THCCOOH by gas chromatography-mass spectrometry. Mean+/-SEM half-lives calculated by the amount remaining to be excreted method after the low and high doses were 31.5+/-1.0 hours (range, 28.4 to 35.3 hours) and 28.6+/-1.5 hours (range, 24.9 to 34.5 hours), respectively, when a 7-day monitoring period was used. The amounts of THCCOOH excreted over a 7-day period were 93.9 +/-24.5 microg (range, 34.6 to 171.6 microg) and 197.4+/-33.6 microg after the low- and high-dose sessions. Longer half-lives, 44.3 to 59.9 hours, were obtained with a 14-day sample collection. This study documents the prolonged excretion of THCCOOH in urine and emphasizes the importance of study design in the precise estimation of terminal excretion half-lives. A sensitive analytical method and a prolonged specimen collection period are important study considerations in the monitoring of marijuana excretion.     

Bile flow in a mutant Sprague-Dawley rat with defective biliary excretion of glutathione

The Eisai hyperbilirubinemic rat is a mutant strain of Sprague-Dawley origin with hereditary defects in the biliary excretion of bilirubin glucuronide, glutathione, and several other organic anions. The correlation between bile flow and bile acid excretion rates during taurocholate infusion revealed that bile acid-independent flow was smaller in the mutant than in intact Sprague-Dawley rats (19.3 vs 56.0 microliters/kg per min), while bile acid-dependent flow was similar. The correlation between bile flow and glutathione excretion rates in Sprague-Dawley rats with modified hepatic glutathione levels revealed that a certain portion of bile flow was proportional to the biliary excretion of glutathione, with a coefficient of 551 bile per 1 mol glutathione. One-third of bile acid-independent bile flow in intact Sprague-Dawley rats was accounted for by glutathione osmosis, which feature was absent in the mutant rats.     

The effects of oral diazepam pretreatment on the biliary excretion of sulfobromophthalein in rats

Studies were performed with rats to examine the effects of single, as well as repetitive oral diazepam (DZP) pretreatment on biliary sulfobromophthalein (BSP) excretion rates and on bile flow parameters. One-hour pretreatment of male rats with 150 mg/kg of DZP resulted in about a one-third reduction in the peak biliary excretion rate of BSP (60 mg/kg, iv) and this was associated with a decrease in relative proportions of conjugated BSP in bile. The biliary excretion of preconjugated BSP was unaffected. BSP hepatic uptake and storage were apparently unaffected. In vitro DZP markedly inhibited BSP conjugating activity. In contrast to the above results, when BSP excretion was examined 1 h after the last of five daily oral doses of DZP (150 mg kg-1 day-1), no change in the peak elimination rate of this dye was evident. However, bile flow rates were higher in DZP-treated rats than in controls. When rats were examined 24 h after the last of five daily oral doses of DZP (150 mg/kg), the choleretic response persisted. Further studies showed that the repetitive DZP pretreatment enhanced the bile salt-independent mechanisms of bile formation.     

Effect of microcrystalline cellulose on the excretion of total biliary acids in feces]

Dipolar restoration at the magic angle (DRAMA) has been used to measure the 31P-31P internuclear distance between phosphine-sulfide substituted sidechanins on the fourth and eighth residues of a 12-residue helical peptide. The 7.4 A distance is the same for the peptide lyophilized in bulk or isolated in a cryo- and lyoprotected matrix of poly(ethylene glycol) and sucrose. However, the 31P linewidth for the undiluted peptide is an order of magnitude greater than for the matrix-isolated peptide indicating charge and hydration heterogeneity in the bulk state.     

Postprandial biliary and pancreatic secretion during profound inhibition of gastric secretion in humans

This study assessed the effect of profound inhibition of gastric secretion by an H2 antagonist on postprandial gastric emptying of acid and chyme, and on bile acid and pancreatic enzyme secretion under physiological conditions in humans. Six subjects were studied before and while they were given famotidine (40 mg). This study combined a continuous intestinal perfusion technique using 14C-polyethylene glycol (14C-PEG) as duodenal recovery marker, with intermittent sampling of gastric content using PEG 4000 as meal marker. During the three hour study, the area under the curve for gastric acid output decreased from mean (SEM) 88.9 (7.6) mmol for those not receiving treatment, to 21.2 (2.7) mmol for subjects receiving famotidine (p < 0.01). The corresponding values for the rate of acid delivery into the duodenum decreased from 65.2 (11.9) to 16.6 (2.9) mmol (p < 0.05), and those for the rate of gastric emptying of chyme remained unchanged for the group receiving no treatment and during famotidine (1040 (200) v 985 (160) ml respectively, NS). Duodenal bile acid and trypsin output remained unchanged (area under the curve, 457 (128) v 373 (86) umol/kg and 5022 (565) v 5058 (400) IU/kg respectively, NS) receiving no treatment and during famotidine. It is concluded that profound inhibition of postprandial gastric acid secretion by anti-secretory drugs is not accompanied by changes in biliary and pancreatic secretion, mainly because the gastric emptying of chyme is unaffected.     

Granulocyte colony-stimulating factor enhances endotoxin-induced decrease in biliary excretion of the antibiotic cefoperazone in rats

We have recently reported that endotoxin (lipopolysaccharide [LPS]) derived from Klebsiella pneumoniae dramatically decreased the biliary excretion of the beta-lactam antibiotic cefoperazone (CPZ), which is primarily excreted into the bile via the anion transport system, in rats. The present study was designed to investigate the effect of human recombinant granulocyte colony-stimulating factor (G-CSF), which is reported to be beneficial in experimental models of inflammation, on the pharmacokinetics and biliary excretion of CPZ in rats. CPZ (20 mg/kg of body weight) was administered intravenously 2 h after the intravenous injection of LPS (250 microgram/kg). G-CSF was injected subcutaneously at 12 microgram/kg for 3 days and was administered intravenously at a final dose of 50 microgram/kg 1 h before LPS injection. Peripheral blood cell numbers were also measured. LPS dramatically decreased the systemic and biliary clearances of CPZ and the bile flow rate. Pretreatment with G-CSF enhanced these decreases induced by LPS. The total leukocyte numbers were increased in rats pretreated with G-CSF compared to the numbers in the controls, while the total leukocyte numbers were decreased (about 3,000 cells/microliter) by treatment with LPS. Pretreatment with G-CSF produces a deleterious effect against the LPS-induced decrease in biliary secretion of CPZ, and leukocytes play an important role in that mechanism.     

Effect of sodium restriction on urinary excretion of cortisol and its metabolites in humans

The adrenal gland is involved in the control of urinary sodium excretion mainly via the secretion of the mineralocorticoid aldosterone. Although under certain conditions glucocorticoid seem to be also involved in the regulation of sodium homeostasis, there are contradictory reports on the relationship between cortisol secretion and sodium intake. Given recent findings linking regulation of physiological activity of steroids to the activity of specific enzymatic pathways, we have examined changes in urinary excretion of cortisol and its metabolites in eight healthy volunteers on a low sodium diet. Urinary steroids were measured with specific radioimmunoassays after extraction and chromatography (F and E) or after dilution (THF and THE). Excretion of cortisol (124 +/-41 nmol/day) was significantly lower on Day 2 (86 +/- 27 nmol/day, p < 0.01) and Day 7 (85 +/- 25 nmol/day, p < 0.01) of sodium restriction. On the same samples calculated ratios of THF/F (55 +/- 15; 61 +/- 22; 68 +/- 21) and E/F (2.5 +/- 0.6; 2.8 +/- 1.4; 3.0 +/- 1.3) reflecting the activity of 5 beta-reductase and 11 beta-hydroxysteroid dehydrogenase, respectively, showed significant increases in the former on both Days 2 and 7 and for the latter only on Day 7. This study supports the notion that sodium restriction decreases urinary cortisol excretion and provides evidence that increased activity of 5 beta-reductase and lowered metabolism by 11 beta-HSD are presumably the mechanisms of this decrease.     

Modulators of the protein kinase C system influence biliary excretion of cationic drugs

To investigate whether hepatobiliary transport of organic cations is under regulatory control, we studied transport of tri-n-butylmethylammonium in the isolated perfused rat liver and in isolated rat hepatocytes. Transport was investigated in the presence of modulators of the protein kinase C and the cyclic AMP second-messenger system. In the isolated perfused rat liver, it was observed that compounds modulating protein kinase C activity clearly affected the biliary excretion process of the cation tri-n-butylmethylammonium. Phorbol 12-myristate 13-acetate, a compound that directly stimulates protein kinase C, elevated the biliary excretion rate of tri-n-butylmethylammonium in a concentration-dependent manner, reaching a twofold increase at 60 nmol/L of the phorbol ester. The inactive derivative 4 alpha-phorbol 12, 13-didecanoate (60 nmol/L) did not show any effect. Vasopressin (48 nmol/L), a receptor-mediated activator of protein kinase C, stimulated the excretion rate of the cation by about 50%. Staurosporin (1 mumol/L), an inhibitor of protein kinase C, clearly decreased the biliary excretion rate of the cation and also blocked its stimulation by phorbol 12-myristate 13-acetate. Neither phorbol 12-myristate 13-acetate nor vasopressin (at concentrations ranging from 10(-9) to 10(-6) mol/L) affected the initial uptake velocity of tri-n-butylmethylammonium in isolated hepatocytes and isolated perfused livers, whereas staurosporin (1 mumol/L) showed only a modest inhibition of the uptake of the cation. It is inferred that the effect of protein kinase C modulators on hepatobiliary transport of organic cations occurs at the level of carrier-mediated transport in the canalicular membrane.(ABSTRACT TRUNCATED AT 250 WORDS)