Absorption and bioavailability of glucosamine in the rat

The objective of this study was to determine reasons behind the low oral (p.o.) bioavailability of glucosamine. By using male Sprague-Dawley rats, the movement of glucosamine through everted gut, the effect of dose and glucose, and inhibition of a glucose transporter (GLUT2) by quercetin were studied. Glucosamine pharmacokinetics and the effect of dosing, route of administration, food and antibiotic to eradicate gut microflora was also studied. Both in vitro and in vivo studies demonstrated linear absorption kinetics for glucosamine. Absorption from duodenum was the greatest. Glucose had no effect on the transport, whereas quercetin significantly reduced the extent of glucosamine transport. Intraperitoneal doses were completely absorbed, whereas p.o. doses demonstrated low bioavailability, indicating the gut as the site of presystemic loss. Food had no significant effect on glucosamine pharmacokinetics. Antibiotic treatment resulted in strong trends towards increased bioavailability with significant increase in fecal recovery. Incubation of glucosamine with faeces resulted in a significant loss. Glucosamine's low bioavailability is, at least in part, due to its dependence on a transport-facilitated absorption and presystemic loss brought about by the gut microflora.     

Absorption, metabolism and elimination of pempidine in the rat

Pempidine (1,2,2,6,6-pentamethylpiperidine) is a ganglion blocking agent introduced recently for the treatment of hypertension by oral administration of its hydrogen tartrate. It can be estimated colorimetrically by coupling with methyl orange, or fluorimetrically by reaction with eosin in xylene, the limits of sensitivity being 0.5 μg./ml. and 0.001 μg./ml. respectively. These methods, combined with appropriate extraction techniques, were suitable for estimating pempidine in aqueous solutions of its salts, in biological fluids and the like, and for investigating the biochemical properties of the drug when given orally to rats in amounts similar to those used clinically.

When administered orally to rats pempidine was rapidly absorbed, the maximum concentration in plasma being attained after 30 min. The drug was preferentially taken up by erythrocytes and a red cell/plasma partition ratio of about 1.2 established with clinical doses. Pempidine was soon distributed throughout the body, including the cerebrospinal fluid, and the highest concentrations were found in kidney, spleen and liver. Pempidine also entered the foetus and passed thence into the amniotic fluid. Protein-binding of the drug occurred only to a very limited extent and there was little evidence that it was metabolized. Pempidine was excreted rapidly in urine during 24 hr. following oral administration.

     

Absorption, metabolism and excretion of 14C-sultopride in the rat

Rats received (14C)-Sultopride (St) in doses of 20 mg/kg by ip. and oral route. After ip.-administration, urinary elimination was 62% of administered dose in 72 hours, fecal excretion, 25% in 96 hours. Conversely, at 120 hours after oral administration, renal elimination was 46% and fecal elimination 34%. From these data 75% absorption of St in rat intestine may be deduced. From total excreted radioactivity (feces plus urine; ip. route) 35% is due to unchanged St. Seven metabolites were isolated from the urine. By comparison of isolated compounds with chemically synthesized putative metabolites using spectrophotometric and radiometric TLC scanning procedures 5 metabolites were identified: O-desmethylated St (DMSt; 20% of total radioactivity excreted), sulfon-desethylated St (SDESt; 13%), 5-pyrrolidine-oxo St (OSt; 3%), the product of hydrolysis of the central amide bond (MESS; 4%) and the secondary metabolite O-desmethyl-oxo St (ODMST; less than 1%). Two metabolites both minor (1% or less), remained unidentified. In guinea-pigs, metabolism of St leads almost exclusively to OSt while in mice, to DMSt.     

Absorption, distribution, metabolism and excretion of p-bromophenylacetylurea in the female rat

1. This study has investigated absorption, distribution, metabolism and excretion of p-bromophenylacetylurea (BPAU) in the F344 female rat. BPAU and its metabolites were determined by HPLC. 2. Following a single p.o. dose of 150 mg/kg BPAU, the absorbed fraction of dosed BPAU was 65.9% and its half-life in the blood was 9.4 h. The relative distribution of BPAU (tissue/serum ratio) at 6 h (peak time point) after a single i.p. dose of 150 mg/kg BPAU was spinal cord (4.6+/-0.2) > liver (3.7+/-0.1) > brain (2.9+/-0.1) (mean+/-SD, n = 5), and they were significantly different from each other (p < 0.05). BPAU in spinal cord reached the highest level. 3. Absorbed BPAU was metabolized in vivo into three major metabolites. N'-hydroxy-p-bromophenylacetylurea (M1) was a dominant metabolite in tissues, whereas 4-(4-bromophenyl)-3-oxapyrrolidine-2,5-dione (M2) reached a high concentration in blood. N'-methyl-p-bromophenylacetylurea (M3) was mainly found in the urine. All three metabolites were excreted via the urine and together accounted for 87% of absorbed BPAU. 4. This study provides a basic understanding of BPAU absorption, distribution, metabolism and elimination in rat.     

Absorption,distribution, metabolism and excretion of p-bromophenylacetylurea in the female rat

1. This study has investigated absorption, distribution, metabolism and excretion of p-bromophenylacetylurea (BPAU) in the F344 female rat. BPAU and its metabolites were determined by HPLC. 2. Following a single p.o. dose of 150?mg/kg BPAU, the absorbed fraction of dosed BPAU was 65.9% and its half-life in the blood was 9.4 h. The relative distribution of BPAU (tissue/serum ratio) at 6 h (peak time point) after a single i.p. dose of 150?mg/kg BPAU was spinal cord (4.6 +/- 0.2) &;gt; liver (3.7 +/- 0.1) &;gt; brain (2.9 +/- 0.1) (mean +/- SD, n = 5), and they were significantly different from each other (p&;lt;0.05). BPAU in spinal cord reached the highest level. 3. Absorbed BPAU was metabolized in vivo into three major metabolites. N'-hydroxy- p-bromophenylacetylurea (M1) was a dominant metabolite in tissues, whereas 4-(4-bromophenyl)-3-oxapyrrolidine-2,5-dione (M2) reached a high concentration in blood. N'-methyl-p-bromophenylacetylurea (M3) was mainly found in the urine. All three metabolites were excreted via the urine and together accounted for 87% of absorbed BPAU. 4. This study provides a basic understanding of BPAU absorption, distribution, metabolism and elimination in rat.     

Pharmacokinetics, bioavailability, metabolism, tissue distribution and urinary excretion of gamma-L-glutamyl-L-dopa in the rat

gamma-L-Glutamyl-L-dopa (gludopa) is believed to be a dopamine prodrug specific for the kidney. Its pharmacokinetics have been studied in the rat given 50 mg kg-1 intravenously (i.v.) and 60 mg kg-1 intraperitoneally (i.p.). By the i.v. route, elimination followed apparent first order kinetics and was biphasic with a t 1/2 alpha of 7 min and terminal half-life of 67 min. After i.p. administration absorption was rapid (t 1/2 ab 6 min), elimination was monophasic with a terminal half-life almost identical following i.v. dosing (65 min), and bioavailability was 40%. In tissues (liver and kidney) gludopa was biotransformed to four intact catecholic products (L-dopa, dopamine, DOPAC and gamma-L-glutamyl-dopamine) which appeared quickly (peaks at 15 min) and which were almost completely cleared by 4 h. Dopamine was the major kidney metabolite accounting for 69% of total catechol content with an AUC 31 times greater than in liver where it accounted for only 34% of total catechols. In rat urine eight major metabolites (5.7% of the dose) and at least 12 minor metabolites were detected of all of which 85% was dopamine. A higher percentage of the dose was excreted as intact catechols in man (15.7%) but fewer metabolites were detected (L-dopa, dopamine, DOPAC). It is confirmed that gludopa is kidney specific in rat but that the pharmacological effects of dopamine are likely to be short lived due to rapid clearance. Gludopa appears to be less dopamine specific in man.     

Absorption, metabolism and excretion of safrole in the rat and man.

The metabolic disposition of different doses of [14C] safrole were studied in rat and man. In both species, small amounts of orally administered safrole were absorbed rapidly and then excreted almost entirely within 24 h in the urine. In the rat, when the dose was raised from 0.6 to 750 mg/kg, a marked decrease in the rate of elimination occurred as only 25% of the dose was excreted in the urine in 24 h. Furthermore, at the high dose level, plasma and tissue concentrations of both unchanged safrole and its metabolites remained elevated for 48 h probably indicating impairment of the degradation/excretion pathways. The main urinary metabolite in both species was 1,2-dihydroxy-4-allylbenzene which was excreted in a conjugated form. Small amounts of eugenol or its isomer 1-methoxy-2-hydroxy-4-allylbenzene were also detected in rat and man. 1'-Hydroxysafrole, a proximate carcinogen of safrole, and 3'-hydroxyisosafrole were detected as conjugates in the urine of the rat. However, in these investigations we were unable to demonstrate the presence of the latter metabolites in man.     

Absorption,metabolism and excretion studies on clavulanic acid in the rat and dog

1. At least one third of an oral dose of sodium [G-¹⁴C]clavulanate was absorbed by rat and dog. Excretion of radioactivity was rapid in both species.

2. In addition to urinary and faecal excretion of radioactivity, appreciable elimination of ¹⁴CO₂ occurred, particularly in the rat. This was produced in part by the action of the gut microflora.

3. In the rat, only a small proportion of the radioactive dose was secreted in the bile.

4. The major metabolite in urine was identified as l-amino-4-hydroxybutan-2-one. Clavulanic acid was also a major component in urine.     

Sex differences in the pharmacokinetics, oxidative metabolism and oral bioavailability of oxycodone in the Sprague-Dawley rat

1. The pharmacokinetics and oxidative metabolism of oxycodone were investigated following intravenous and oral administration in male and female Sprague-Dawley (SD) rats. 2. High-performance liquid chromatography (HPLC)-electrospray ionization (ESI)-tandem mass spectrometry (MS-MS) was used to quantify plasma concentrations of oxycodone and its oxidative metabolites noroxycodone and oxymorphone following administration of single bolus intravenous (5 mg/kg) and oral (10 mg/kg) doses of oxycodone. 3. The mean (+/-SEM) clearance of intravenous oxycodone was significantly higher in male than female SD rats (4.9 +/- 0.3 vs 3.1 +/- 0.3 L/h per kg, respectively; P < 0.01). Mean areas under the plasma concentration versus time curves (AUC) for oxycodone were significantly higher in female than male SD rats following intravenous (approximately 1.6-fold; P < 0.01) and oral (approximately sevenfold; P < 0.005) administration. 4. The oral bioavailability of oxycodone was low (at 1.2 and 5.0%, respectively) in male and female SD rats, a finding consistent with high first-pass metabolism. Noroxycodone : oxycodone AUC ratios were significantly higher in male than female SD rats after intravenous (approximately 2.4-fold; P < 0.005) and oral (approximately 12-fold; P < 0.005) administration. 5. Circulating oxymorphone concentrations remained very low following both routes of administration. Noroxycodone : oxymorphone AUC ratios were greater in male than female SD rats after intravenous (approximately 13- and fivefold, respectively) and oral (approximately 90- and sixfold, respectively) administration. 6. Sex differences were apparent in the pharmacokinetics, oxidative metabolism and oral bioavailability of oxycodone. Systemic exposure to oxycodone was greater in female compared with male SD rats, whereas systemic exposure to metabolically derived noroxycodone was higher in male than female SD rats. 7. Oral administration of oxycodone to the SD rat is a poor model of the human for the study of the pharmacodynamic effects of oxycodone.     

Absorption,distribution, metabolism and excretion of telmesteine,amucolitic agent,in rat

1. The metabolism and disposition of telmesteine, a muco-active agent, have been investigated following single oral or intravenous administration of ¹⁴C-telmesteine in the Sprague–Dawley rat.

2. ¹⁴C-telmesteine was rapidly absorbed after oral dosing (20 and 50mg kg^-1) with an oral bioavailability of > 90% both in male and female rats. The C_max and area under the curve of the radioactivity in plasma increased proportionally to the administered dose and those values in female rats were 30% higher than in male rats.

3. Telmesteine was distributed over all organs except for brain and the tissue/plasma ratio of the radioactivity 30min after dosing was relatively low with a range of 0.1–0.8 except for excretory organs.

4. Excretion of the radioactivity was 86% of the dose in the urine and 0.6% in the faeces up to 7 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 3% for the first 24 h. The unchanged compound mainly accounted for the radioactivity in the urine and plasma.

5. Telmesteine was hardly metabolized in microsomal incubations. A glucuronide conjugate was detected in the urine and bile, but the amount of glucuronide was less than 6% of excreted radioactivity.     

Absorption, distribution, excretion and metabolism of orally administered 14C-beta-cyclodextrin in rat

The absorption, distribution, excretion and metabolism of orally administered universally labelled 14C-beta-cyclodextrin and 14C-glucose were compared in rat. The maximum radioactivity of the blood derived from 14C-beta-cyclodextrin was observed between 4th and 11th h and the value of the maximum in different experiments ranged between 5 and 17 0/00 of the total administered radioactivity. Following 14C-glucose treatment radioactivity reached the maximum within half-an-hour, with values of 15 to 82 0/00. In the 8th h after a high dose (313.5 mg/kg) of beta-cyclodextrin no more than 3-50 ppm beta-cyclodextrin was detectable in the blood by HPLC. After 14C-beta-cyclodextrin treatment 4.2-4.8% of the administered total radioactivity was excreted by the urine and about the same quantity (2-3.6%) in case of 14C-glucose. No specific accumulation was observed after 14C-beta-cyclodextrin treatment in the different organs. The large intestine contained 10-15% of the cyclodextrin radioactivity while this value was only 2% in case of 14C-glucose. Following p.o. administration of different doses of 14C-beta-cyclodextrin the radioactivity peak was detected in the exhaled air between the 4-6th and 6-8th h, respectively, depending on the administered doses, while in case of 14C-glucose treatment it was observed within 2 h. The total radioactivity exhaled by 14C-beta-cyclodextrin treated animals in 24 h was 55 to 64% of the administered radioactivity and 58% in case of 14C-glucose. It is assumed that beta-cyclodextrin is metabolized in rats slower but similarly to glucose, therefore p.o. administered beta-cyclodextrin cannot induce toxic symptoms.     

Absorption, distribution, metabolism and excretion of the cholecystokinin-1 antagonist dexloxiglumide in the rat.

Single oral doses of 14C-dexloxiglumide were rapidly and extensively absorbed in rats, and eliminated more slowly by females than by males. The respective half-lives were about 4.9 and 2.1 h. Following single intravenous doses, dexloxiglumide was characterised as a drug having a low clearance (6.01 and about 1.96 ml/min/kg in males and females respectively), a moderate volume of distribution (Vss, 0.98 and about 1.1 L/kg in males and females respectively) and a high systemic availability. It was extensively bound to plasma proteins (97%). Dexloxiglumide is mainly cleared by the liver. Its renal clearance was minor. In only the liver and gastrointestinal tract, were concentrations of 14C generally greater than those in plasma. Peak 14C concentrations generally occurred at 1-2 h in males and at 2-4 h in females. Tissue 14C concentrations then declined by severalfold during 24 h although still present in most tissues at 24 h but only in a few tissues (such as the liver and gastrointestinal tract) at 168 h. Decline of 14C was less rapid in the tissues of females than in those of males. Single intravenous or oral doses were mainly excreted in the faeces (87-92%), mostly during 24 h and more slowly from females than from males. Urines contained less than 11% dose. Mean recoveries during 7 days when 14C was not detectable in the carcass except in one female rat ranged between 93-101%. Biliary excretion of 14C was prominent (84-91% dose during 24 h) in the disposition of 14C which was also subjected to facile enterohepatic circulation (74% dose). Metabolite profiles in plasma and selected tissues differed. In the former, unchanged dexloxiglumide was the major component whereas in the latter, a polar component was dominant. Urine, bile and faeces contained several 14C-components amongst which unchanged dexloxiglumide was the most important (eg. up to 63% dose in bile). LC-MS/MS showed that dexloxiglumide was metabolised mainly by hydroxylation in the N-(3-methoxypropyl)pentyl sidechain and by O-demethylation followed by subsequent oxidation of the resulting alcohol to a carboxylic acid.     

Absorption and metabolism of procaine by the rat small intestine

Summary The aim of this study was to obtain information about the absorption of procaine in the rat small intestine (Fisher-Parsons preparation). In the range from 0.25–10 mmol · l^–1 procaine in the luminal perfusate, much more of the unchanged drug was absorbed in segments of the ileum than of the duodenum and jejunum. Besides procaine, two metabolites, p-aminobenzoic acid (PABA) and acetylated p-aminobenzoic acid (AABA), formed in the intestinal mucosa, appeared in the absorbate. With increasing substrate concentration in the perfusate the PABA in the absorbate increased considerably in all three segments; from 0.75 mmol · l^–1 procaine upwards the PABA produced was highest in the jejunum. AABA formed in the mucosa and measured in the absorbate did not increase in the same manner with increasing substrate concentration; in the absorbate of jejunal segments the amount of AABA was significantly higher than in duodenal and ileal segments. Taking into account that in rats the microclimate of the ileum differs considerably from that of the upper part of the small intestine, the marked difference observed in the absorption of procaine between ileal segments on the one side, and duodenal and jejunal segments on the other, can be explained on the basis of the non-ionic diffusion theory.Send offprint requests to H. P. Büch at the above address     

Absorption rate limited metabolism of salicylate in man: a consideration in bioavailability assessment

To study the effect of absorption rate on the urinary excretion of the unchanged salicycic acid and its consequence on bioavailability tests, 500 mg tablets of a regular (A) and two slow-dissolved (B and C) acetylsalicylic acid were administered to 8 volunteers in a cross-over fashion. Salicylic acid in plasma and urine and total metabolitas in urine were determined. Comparison of area under plasma level-time curves (AUC) failed to show any significant differences between 3 products. How-ever, the flow dissolution rate caused reduction in maximum plasma levels and delayed the time of their occurrence. The cumulative total metabolites (∑Mu) and salicylic acid (as % of ∑Mu) were significantly less following administration of B and C. It is concluded that the extent of absorption of slow-dissolved tablets is significantly lower than regular product although it is not reflected on the observed AUCs. Therefore, when salicylate products being tested have different absorption rates, the cumulative excretion of total metabolites seems to be a more valid measure of the relative extent of bioavailability than AUC. The reduction in the cumulative salicylic acid (as % of ∑Mu) excreted in the urine may indicate an absorption rate limited metabolism phenomenon.     

Absorption,distribution, metabolism and excretion of telmesteine,a mucolitic agent,in rat

1. The metabolism and disposition of telmesteine, a muco-active agent, have been investigated following single oral or intravenous administration of (14)C-telmesteine in the Sprague-Dawley rat. 2. (14)C-telmesteine was rapidly absorbed after oral dosing (20 and 50 mg kg(-1)) with an oral bioavailability of >90% both in male and female rats. The C(max) and area under the curve of the radioactivity in plasma increased proportionally to the administered dose and those values in female rats were 30% higher than in male rats. 3. Telmesteine was distributed over all organs except for brain and the tissue/plasma ratio of the radioactivity 30 min after dosing was relatively low with a range of 0.1-0.8 except for excretory organs. 4. Excretion of the radioactivity was 86% of the dose in the urine and 0.6% in the faeces up to 7 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 3% for the first 24 h. The unchanged compound mainly accounted for the radioactivity in the urine and plasma. 5. Telmesteine was hardly metabolized in microsomal incubations. A glucuronide conjugate was detected in the urine and bile, but the amount of glucuronide was less than 6% of excreted radioactivity.     

Absorption, distribution, metabolism, and elimination of 8-2 fluorotelomer alcohol in the rat.

The absorption, distribution, metabolism, and elimination of [3-14C] 8-2 fluorotelomer alcohol (8-2 FTOH, C7F1514CF2CH2CH2OH) following a single oral dose at 5 and 125 mg/kg in male and female rats have been determined. Following oral dosing, the maximum concentration of 8-2 FTOH in plasma occurred by 1 h postdose and cleared rapidly with a half-life of less than 5 h. The internal dose to 8-2 FTOH, as measured by area under the concentration-time curve to infinity, was similar for male and female rats and was observed to increase in a dose-dependent fashion. The majority of the 14C 8-2 FTOH (> 70%) was excreted in feces, and 37-55% was identified as parent. Less than 4% of the administered dose was excreted in urine, which contained low concentrations of perfluorooctanoate (approximately 1% of total 14C). Metabolites identified in bile were principally composed of glucuronide and glutathione conjugates, and perfluorohexanoate was identified in excreta and plasma, demonstrating the metabolism of the parent FTOH by sequential removal of multiple CF2 groups. At 7 days postdose, 4-7% of the administered radioactivity was present in tissues, and for the majority, 14C concentrations were greater than whole blood with the highest concentration in fat, liver, thyroid, and adrenals. Distribution and excretion of a single 125-mg/kg [3-14C] 8-2 FTOH dermal dose following a 6-h exposure in rats was also determined. The majority of the dermal dose either volatilized from the skin (37%) or was removed by washing (29%). Following a 6-h dermal exposure and a 7-day collection period, excretion of total radioactivity via urine (< 0.1%) and feces (< 0.2%) was minor, and radioactivity concentrations in most tissues were below the limit of detection. Systemic availability of 8-2 FTOH following dermal exposure was negligible.     

Absorption and metabolism of the phenothiazine drug perazine in the rat intestinal loop

Jejunal loops of male rats were instilled with [³⁵S]perazine and venous Wood from the loops was collected. Plasma, erythrocytes, intestinal wall and intestinal contents were analysed for perazine and its metabolites by reverse isotope dilution; purification to constant specific radioactivity was carried out by thin-layer chromatography. Within 60 min, 57 per cent of the material appeared in blood, more than four-fifths in the form of unchanged perazine. The principal metabolites present in plasma were 3-hydroxyperazine glucuronide and perazine sulfoxide; besides the sulfoxide, red cells contained small quantities of desmethyl perazine. This metabolite was predominantly located in the intestinal wall which contained a total of 17 per cent of the administered radioactivity, mostly as unmetabolized perazine. Another 17 per cent was found in the intestinal contents and here the proportion of perazine sulfoxide -was one-third. Besides perazine as the major compound small amounts of hydroxyperazine glucuronide and desmethyl perazine and traces of perazine N-oxide were present in the intestinal lumen.     

Absorption, distribution, metabolism, and excretion of 1,2-dihydro-2,2,4-trimethylquinoline in the male F344 rat

1,2-Dihydro-2,2,4-trimethylquinoline (TMQ), an antioxidant used in the rubber industry, was readily absorbed from the gastrointestinal tract of the male Fischer 344/N rat and rapidly distributed throughout the body tissues. Absorption, distribution, metabolism, and excretion were not significantly affected by dose in the range 11.5-1150 mumol/kg. Following iv administration, the greatest amounts of TMQ-derived radioactivity were present in the high volume tissues including muscle, adipose, skin, liver, and blood. TMQ had no particular affinity for any tissue. TMQ-derived radioactivity was excreted primarily in urine (60-70%) and feces (20-30%) within 3 days after administration. Greater than 99% of the TMQ dose excreted in urine and feces was in the form of metabolites. Urine contained two major and ten minor metabolites while feces contained two major and four minor metabolites. The two major TMQ metabolites in urine were identified by NMR and mass spectroscopy as the O-sulfate conjugate of 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline and the monosulfate conjugate of 1,2-dihydro-1,6-dihydroxy-2,2,4-trimethylquinoline. In vitro studies with liver subcellular fractions suggest that most of the metabolites present in urine, feces, and bile are the products of mixed function oxidase activity and conjugates of these metabolites. Multiple exposure of rats to high TMQ doses (1150 mumol/kg) resulted in some bioaccumulation of TMQ-derived radioactivity in all tissues examined, but these residues did not persist when dosing was discontinued.