Tissue distribution and excretion of CDRI-81/470 in rats

Methyl-N[5 [[4-(2-pyridinyl)-1-piperazinyl]carbonyl]- 1H-benzimidazol-2-yl] carbamate (CDRI-81/470) is a broad spectrum anthelmintic agent, effective against both intestinal and systemic parasitism. Tissue distribution and excretion of CDR1-81/470 were studied in rats after a single oral dose of 100 mg kg(-1) CDRI-81/470. One of the metabolites was identified in pilot studies as its N-decarboxylate derivative and characterized by synthesis. HPLC assay methods for the simultaneous estimation of CDRI-81/470 and its N-decarboxylate derivative in tissues, bile, urine, and faeces were developed and validated. The parent compound was quantitated in all major tissues and organs up to 48 h post-dose. Among the tissues other than serum, the highest concentrations of CDRI-81/470 were found in liver, whereas only trace levels were found in brain. Approximately 3% of the administered dose was excreted unchanged in urine at 120 h postdose, whereas approximately 7% was recovered in faeces. The contribution of the biliary route for the excretion of parent compound was less than 0.5%. The N-decarboxylate derivative was quantitated in faeces (1-4%) and bile ( < 0.1%) but was absent in serum, tissues, and urine. An additional metabolite was isolated from bile and characterized as the pyridinyl-5-hydroxy derivative of CDRI-81/470. CDRI-81/470 showed rapid absorption and distribution into all major organs and tissues, and underwent extensive metabolism in rats. Two metabolites in bile were identified and characterized by synthesis.     

Oral absorption, metabolism and excretion of 1-phenoxy-2-propanol in rats

1. This study was designed to determine the absorption, metabolism and excretion of 1-phenoxy-2-propanol in Fischer 344 rats following oral administration in an effort to bridge data with other propylene glycol ethers. 2. Rats were administered a single oral dose of 10 or 100 mg kg(-1) 14C-1-phenoxy-2-propanol as a suspension in 0.5% methyl cellulose ether in water (w/w). Urine was collected at 0-12, 12-24 and 24-48 h and faeces at 0-24 and 24-48 h post-dosing and the radioactivity was determined. Urine samples were pooled by time point and dose level and analysed for metabolites using LC/ESI/MS and LC/ESI/MS/MS. 3. The administered doses were rapidly absorbed from the gastrointestinal tract and excreted. The major route of excretion was via the urine, accounting for 93 +/- 5% of the low and 96 +/- 3% of the high dose. Most of the urinary excretion of radioactivity occurred within 12 h after dosing; 85 +/- 2% of the low and 90 +/- 1% of the high dose. Total faecal excretion remained < 10%. Rats eliminated the entire administered dose within 48 h after dosing; recovery of the administered dose ranged from 100 to 106%. Metabolites tentatively identified in urine were conjugates of phenol (sulphate, glutathione) with very low levels (< 2%) of hydroquinone (glucuronide), conjugates of parent compound (glucuronide, sulphate) and a ring-hydroxylated metabolite of parent. There was no free parent compound or phenol in non-acid-hydrolysed urine. In acid-hydrolysed urine, 61% of the dose was identified as phenol and 13% as 1-phenoxy-2-propanol. Although the parent compound was stable to acid hydrolysis, some of the phenol in acid hydrolysed urine may have arisen from degradation of acid-labile metabolite(s) as well as hydrolysis of phenol conjugates. 4. Rapid oral absorption, metabolism and urinary excretion of 1-phenoxy-2-propanol in rats were similar to other propylene glycol ethers.     

Investigation of diurnal changes in the disposition of theophylline

The mechanism of observed temporal variations in plasma theophylline concentrations has been investigated. Eight healthy volunteers were given both oral and intravenous doses of theophylline (5 mg/kg) at 09.00 h and 21.00 h under controlled conditions. Regular plasma concentration measurements were made following each dose in order to determine the diurnal and nocturnal disposition of the drug. Plasma theophylline concentrations at 0.5 h following each oral dose were 6.9 +/- 0.8 micrograms/ml, a.m., and 3.9 +/- 0.6 microgram/ml, p.m. (P less than 0.05). Time to peak concentration was 1.69 +/- 0.28 h, a.m.; 2.13 +/- 0.23 h, p.m. (P less than 0.05). Values for ka were not significantly different, however. Overall bioavailability, volume of distribution and systemic clearances, calculated for the 12 h period after each dose, did not differ significantly between day and night. Diurnal variations in theophylline disposition do not appear to be the result of changes in metabolism or excretion, but may reflect minor differences in absorption.     

LC determination of the anti-ischemic and anti-hypertensive agent CDRI-93/478 in rat serum

CDRI-93/478 is a potent anti-ischemic and anti-hypertensive agent. This compound is in advanced stage of pre-clinical trials. A high-performance liquid chromatographic (HPLC) method was developed for the analysis of CDRI-93/478 in rat serum, a species used for safety evaluation. The HPLC analysis, applicable to 1 ml volumes of serum, involved double extraction of serum samples with diethyl ether at alkaline pH followed by separation on a spheri-5 cyano column and the use of fluorescence detector at excitation wavelength 250 nm and emission wavelength 372 nm. The method was sensitive with a limit of quantitation of 10 ng ml(-1) in rat serum and the recovery was more than 84%. The linearity was satisfactory as indicated by correlation of >0.99, in addition to the visual examination of the calibration curves. The precision and accuracy were acceptable as indicated by relative standard deviation (R.S.D.) ranging from 1.73 to 9.51%, bias values ranging from -7.31 to 8.68%. Moreover, CDRI-93/478 was stable in rat serum after being subjected to three freeze-thaw cycles. In-process stability evaluation showed the stability of the compound in processed samples lasted up to 168 h. The assay was found to be sensitive, specific, accurate, precise, and reliable for use in pharmacokinetic or toxicokinetic studies.     

Pharmacokinetics, biliary excretion, and tissue distribution of novel anti-HIV agents, cosalane and dihydrocosalane, in Sprague-Dawley rats.

Cosalane and dihydrocosalane are potent inhibitors of HIV replication with a broad range of activity. The purpose of this study was to investigate: 1) the pharmacokinetic disposition of both cosalane and dihydrocosalane in male Sprague-Dawley rats, and 2) biliary excretion, enterohepatic circulation, and tissue distribution of cosalane after i.v. and/or oral administration. Animals were administered i.v. (10 mg/kg) cosalane or dihydrocosalane through a jugular vein to obtain plasma profiles. Dose dependence of cosalane was studied over a dose range of 1.0 to 10 mg/kg. The extent of enterohepatic recycling, biliary excretion, and tissue distribution were studied after i.v. administration. Both cosalane and dihydrocosalane exhibited a biexponential disposition with very long half-lives of 749 +/- 216 and 1016 +/- 407 min, along with very large volumes of distribution 23.1 +/- 4.4 and 24.4 +/- 2. 5 liter/kg, respectively. Both cosalane (nondetectable) and dihydrocosalane (<1%) showed very poor oral bioavailability. The biliary and renal excretions of cosalane were found to be negligible with no detectable metabolites either in urine or bile. After oral administration, more than 87% of the cosalane dose was excreted in the feces as the parent compound. Also, cosalane was sequestered significantly in liver with quantifiable levels in all tissues tested, even 48 h after the dose was administered. Therefore it was concluded that the poor oral bioavailability of cosalane may be due to its poor enterocytic transport coupled with sequestration in liver parenchymal cell membrane layers.     

Pharmacokinetics of pemoline in plasma, saliva and urine following oral administration.

1 Pemoline concentrations were measured in plasma and saliva following a single oral dose (37.5 or 50.0 mg) to healthy volunteers. In addition urinary excretion rates and cumulative urinary excretion of the parent compound and its oxazolidinedione metabolite were determined. 2 The plasma curves exhibited a mean elimination half-live of 11.0 +/- 1.2 h (n=4). Peak levels were reached at 2.7 +/- 0.6 h (n=4). The saliva concentrations were about 50% lower than the corresponding plasma concentrations during the elimination phase. During the absorption phase irregularities in the saliva to plasma concentration ratios were observed. 3 In urine 47.0 +/- 8.4% of the dose (n=6) administered was excreted as unchanged drug and only 3.7 +/- 0.8% (n=3) as the oxazolidinedione metabolite. Urinary half-lives were slightly shorter than the corresponding plasma half-lives.     

Extremely low bioavailability of magnesium lithospermate B, an active component from Salvia miltiorrhiza, in rat

We assessed the bioavailability of magnesium lithospermate B (MLB), a main polyphenolic component of Salvia miltiorrhiza and a potent antioxidant having various pharmacological activities, to evaluate its action in vivo. The plasma concentrations of lithospermic acid B (LSB) showed a biexponential decrease after intravenous administration of MLB to rats at doses of 4 and 20 mg/kg. The values of area under the concentration-time curve (AUC; 87.8 +/- 10.9 and 1130 +/- 329 microg.min/mL), total body clearance (CL (tot); 55.52 +/- 7.07 and 23.51 +/- 5.98 mL/min/kg), and distribution volume at steady state (V (ss); 7.60 +/- 1.03 and 3.61 +/- 1.16 L/kg) suggested non-linear pharmacokinetics between the two doses. After oral administration of MLB at a high dose of 100 mg/kg, the mean AUC was barely 1.26 +/- 0.36 microg.min/mL. Absolute bioavailability of MLB was calculated to be 0.0002 from the AUC values after both intravenous dosing at 20 mg/kg and oral dosing at 100 mg/kg. The extremely low bioavailability was caused mainly by poor absorption from the rat gastrointestinal tract; about 65 % of the dose was retained in the tract even 4 h after oral administration, and most of the dose was retained even 20 min after infusion in an in situ jejunal loop experiment. Urinary and biliary excretion of LSB were only 0.70 % +/- 0.26 % and 5.10 % +/- 2.36 %, respectively, over a 30 h time period after intravenous injection despite the large CL (tot) and V (ss) values, and were much less (0.010 % +/- 0.001 % and 0.12 % +/- 0.04 %) after oral dosing. These findings suggest that extensive metabolism, including a first-pass effect, and wide distribution of LSB besides the poor absorption contributed significantly to the extremely low systemic bioavailability.     

Toxicokinetics of 14C-endosulfan in male Sprague-Dawley rats following oral administration of single or repeated doses

Endosulfan (ES), an organochlorine (OC) insecticide that belongs to the cyclodiene group, is one of the most commonly used pesticides to control pests in vegetables, cotton, and fruits. The toxicokinetics of 14C-endosulfan following oral administration of a single dose of 5 mg/kg body weight was investigated in male Sprague-Dawley rats. Three rats were sacrificed 30 min, 1 h, 2 h, 4 h, and 8 h after dosing. 14C-endosulfan radioactivity was detected in all tissues at each time point. In a separate experiment urine and feces were collected for 96 h. The total radioactivity recovered in the excreta for 4 days was 106.8% +/- 26.2%, with fecal elimination the major route of elimination route (94.4% +/- 21.4%). The cumulative excretion in the urine for 4 days was 12.4% +/- 4.8%. Radioactivity 8 h after administration was highest in gastrointestinal (GI) tract tissue (20.28 +/- 16.35 mg ES eq./L) and lowest in muscle (0.18 +/- 0.06 mg ES eq./L). The toxicokinetic parameters obtained from 14C-endosulfan-derived radioactivity in blood were distribution half-life (T1/2 x) = 31 min and terminal elimination half-life (T1/2 y) = 193 h. Blood concentration reached its maximum (Cmax) of 0.36 +/- 0.08 mg ES eq./L 2 h after the oral dose. Endosulfan was rapidly absorbed into the GI tract in rats, with an absorption rate constant (ka) of 3.07 h(-1).     

Systemic lanthanum is excreted in the bile of rats

Lanthanum carbonate is a non-calcium-based oral phosphate binder for the control of hyperphosphataemia in patients with chronic kidney disease Stage 5. As part of its pre-clinical safety evaluation, studies were conducted in rats to determine the extent of absorption and routes of excretion. Following oral gavage of a single 1500 mg/kg dose, the peak plasma lanthanum concentration was 1.04+/-0.31 ng/mL, 8 h post-dose. Lanthanum was almost completely bound to plasma proteins (>99.7%). Within 24h of administration of a single oral dose, 97.8+/-2.84% of the lanthanum was recovered in the faeces of rats. Comparing plasma exposure after oral and intravenous administration of lanthanum yielded an absolute oral bioavailability of 0.0007%. Following intravenous administration of lanthanum chloride (0.3 mg/kg), 74.1+/-5.82% of the dose (96.9+/-0.50% of recovered lanthanum) was excreted in faeces in 42 days, and in bile-duct cannulated rats, 10.0+/-2.46% of the dose (85.6+/-2.97% of recovered lanthanum) was excreted in bile in 5 days. Renal excretion was negligible, with <2% of the intravenous dose recovered in urine. These studies demonstrate that lanthanum undergoes extremely low intestinal absorption and that absorbed drug is predominantly excreted in the bile.     

Pharmacokinetics and in-situ absorption studies of a new anti-allergic compound 73/602 in rats

Compound 73/602 (AA) is a structural analogue of vasicinone, an alkaloid present in the leaves and roots of Adhatoda vasica (Acanthaceae). It possesses potent antiallergic activity in mice, rats and guinea pigs. The pK(a) of AA was determined to be 2.87+/-0. 19 by UV spectrophotometry. The absorption kinetics of this compound were studied in-situ using a rat gut technique at pH 2.6 and 7.4. The rate of absorption at pH 2.6 (0.0288+/-0.004 min(-1)) was slightly less than at pH 7.4 (0.035+/-0.0008 min(-1)). This characteristic behavior was attributed to the low pK(a) of AA, a weekly basic compound, where nearly 35% of the compound remained in the unionized form at pH 2.6. Also, the return of compound into the mucosal lumen from the blood capillaries over a period of 2 h after administering a 2 mg dose in tail vein was less than 0.3%. Hence it was concluded that entero-enteric circulation of AA did not contribute significantly to the in-situ absorption rates. Pharmacokinetic parameters of AA were determined in male rats after administering a single 10 mg/kg intravenous dose (i.v.) and 50 mg/kg oral bolus dose. Following i.v. administration the initial decline in serum concentration was rapid with half-life of 20.2 min. After a single oral dose the concentration-time data of AA in rats was best described by a one-compartment model with equal first order absorption and apparent elimination rate constants. The half-life of the decline in serum concentration of AA following oral administration was 50.6 min, indicating absorption rate limiting disposition at the high dose given. Comparison of AUC of oral and i. v. data indicates that only about 60% of the oral dose reach the systemic circulation.     

In situ absorption and protein binding characteristics of CDRI-85/92, an antiulcer pharmacophore

CDRI-85/92, a new antiulcer drug, acts as a proton pump inhibitor arresting the secretion of acid in the stomach. The absorption kinetics of CDRI-85/92 was evaluated in situ using rat intestinal recirculation perfusion method. The experiment was conducted at pH 2.6 and 7.4 representing the acidic and the mild alkaline environment, which the drug experiences through the GIT during oral treatment. The rate of absorption was the same (0.12h(-1)) at pH 2.6 and 7.4, thus suggesting equal absorption profile of the CDRI-85/92 throughout the GIT irrespective of the pH. Equal rates of absorption can also be correlated with the presence of acidic and basic groups in the structure of CDRI-85/92.Protein binding studies of CDRI-85/92 using ultrafiltration were conducted in vitro and in vivo. Protein binding was found to be in the range of 31.49-32.91% both in in vitro and in vivo (employing 5-min post dose samples of rat serum after 20 mgkg(-1) i.v. treatment of CDRI-85/92). The binding was found to be linear in the concentration range of 156.25-2000 ngml(-1) (r(2)>0.99).     

The pharmacokinetics of nitrendipine. I. Absorption, plasma concentrations, and excretion after single administration of [14C]nitrendipine to rats and dogs

[14C]nitrendipine (3-ethyl 5-methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate, Bay e 5009, Baypress, Bayotensin) was administered to rats and dogs (intravenously, orally, intraduodenally, 0.5-50 mg/kg) in order to investigate absorption, disposition, and excretion of parent compound and metabolites. The absorption of radioactivity following oral administration of [14C]nitrendipine was rapid and almost complete in both species. Maximum concentrations of total radioactivity in plasma were reached after 1.2 (rat) or 0.7 h (dog). The radioactivity was eliminated from plasma with terminal half-lives of 57 (rat) and 188 h (dog) during an observation period up to 10 and 9 days, respectively. Unchanged nitrendipine contributed to the AUC of total radioactivity only 8-9% after intravenous and 1-2% after oral administration. The bioavailability of nitrendipine after oral administration amounted to 12% in rats and 29% in dogs due to a strong first pass elimination process. About two thirds of the radioactivity administered were excreted via faeces, one third via urine. Distinct sex-differences in the excretion pattern could be found in rats but not in mice. They were attributed to well-known sex differences of the metabolic capacities in rat liver. In rats the radioactivity excreted via bile (about 75% of the dose) was subject to a marked entero-hepatic circulation, about 50% of the amount excreted being reabsorbed. The radioactive residues in the body were low (0.5% of the dose after 2 days in rats; less than or equal to 0.6% after 9 days in dogs).     

Disposition of orally and intravenously administered methyltetrahydrofuran in rats and mice

The disposition of [14C]methyltetrahydrofuran (14C-MTHF) in rats and mice was determined by following changes in the radioactivity in tissue and excreta with time after dosing. MTHF administered orally (1, 10, or 100 mg/kg) or intravenously (1 mg/kg) to either rats or mice was rapidly metabolized and excreted with <8% (mice) or 8-22% (rats) of the dose remaining in the body after 24 h (1 and 10 mg/kg doses) or 72 h (100 mg/kg dose). Based on recovery of radioactivity in excreta (other than feces) and tissues (other than the gastrointestinal [GI] tract), absorption of orally administered MTHF was essentially complete (93-100%). There were no overt signs of toxicity observed at any dose studied. The major route of excretion in mice was in urine followed by exhaled CO2. In rats the major route of excretion was exhaled CO2 followed by urinary excretion. The excretion of exhaled volatile organic compounds (VOC) was dose-dependent in both species; at lower doses exhaled VOC represented 1-5% of dose, but at the highest dose (100 mg/kg) this proportion rose to 14% (mice) and 27% (rats). Analysis of the VOCs exhaled at the high dose indicated that the increase was due to exhalation of the parent compound, 14C-MTHF. Analysis of urine showed three highly polar peaks in the mouse urine and two polar peaks in the rat urine. Because the 14C label in MTHF was in the methyl group, the polar metabolites were considered likely due to the one-carbon unit getting into the metabolic pool and labeling intermediate dietary metabolites.     

Pharmacokinetics of a ginseng saponin metabolite compound K in rats

The absorption, dose-linearity and pharmacokinetics of compound K, a major intestinal bacterial metabolite of ginsenosides, were evaluated in vitro and in vivo. Using the Caco-2 cell monolayers, compound K showed moderate permeability with no directional effects, thus suggesting passive diffusion. After intravenous dose (i.v.; 1, 2, and 10 mg/kg), no significant dose-dependency was found in Cl (17.3-31.3 ml/min/kg), Vss (1677-2744 ml/kg), dose-normalized AUC (41.8-57.8 microg.min/ml based on 1 mg/kg) and t1/2. The extent of urinary excretion was minimal for both i.v. and oral doses. The extent of compound K recovered from the entire gastrointestinal tract at 24h were 24.4%-26.2% for i.v. doses and 54.3%-81.7% for oral doses. Following oral administration (doses 5-20 mg/kg), dose-normalized AUC (based on 5 mg/kg) was increased at the 20 mg/kg dose (85.3 microg.min/ml) compared with those at lower doses (4.50-10.5 microg.min/ml). Subsequently, the absolute oral bioavailability (F) was increased from 1.8%-4.3% at the lower doses to 35.0% at the 20 mg/kg dose. The increased F could be related to the saturation of carrier-mediated hepatic uptake and esterification of compound K with fatty acids in the liver.     

Intravenous pharmacokinetics, oral bioavailability and dose proportionality of ragaglitazar, a novel PPAR-dual activator in rats

Pharmacokinetics of ragaglitazar (a novel phenoxazine derivative of aryl propanoic acid), a potent insulin sensitizing and lipid-lowering compound was studied in Wistar rats. A single dose of 1, 3 or 10 mg/kg of ragaglitazar was given orally to male rats (n=4 per dose level) to evaluate dose proportionality. In another study, a single intravenous bolus dose of ragaglitazar was given to rats (n=4) at 3 mg/kg dose following administration through the lateral tail vein in order to obtain the absolute oral bioavailability and clearance parameters. Blood samples were drawn at predetermined intervals and the concentration of ragaglitazar in plasma was determined by a validated HPLC method. Plasma concentration versus time data were generated following oral and intravenous dosing and pharmacokinetic analysis was performed using non-compartmental analysis. The results revealed that Cmax and AUC(0-infinity) increased more than proportionally to the administered oral doses. As dose increased in the ratio of 1:3:10, the mean Cmax and AUC(0-infinity) increased in the ratio of 1:3.2:13 and 1:3.2:16, respectively. After intravenous administration the systemic clearance and volume of distribution of ragaglitazar in rats were 139+/-30 ml/h/kg and 463+/-51 ml/kg, respectively (mean+/-SD). Plasma concentrations declined mono-exponentially following intravenous administration and elimination half-life (t1/2) was about 2.6 h and not significantly different (p > 0.05) from the value from oral administration. Mean residence time (MRT) values for ragaglitazar were found to be 4.15+/-0.52 h (3.5 to 4.6 h). Absolute oral bioavailability of ragaglitazar across the doses tested was in the range of 68%-93%. In conclusion, ragaglitazar exhibits promising pharmacokinetic properties in rats.     

Pharmacokinetic evaluation of LASSBio-579: an N-phenylpiperazine antipsychotic prototype

This work aimed to investigate the pharmacokinetics of the N-phenylpiperazine antipsychotic prototype LASSBio-579 and to compare the results with those described for its bioisosteric derivative LASSBio-581. LASSBio-579 was administered to male Wistar rats as a 10 mg kg(-1) intravenous bolus and 30 and 60 mg kg(-1) intraperitoneal and 60 mg kg(-1) oral doses, and plasma concentrations were determined by a validated LC-MS/MS method. Individual plasma concentration-time profiles were evaluated by non-compartmental and compartmental analysis, using WinNonlin. LASSBio-579 plasma protein binding was 93 +/- 4%. After intravenous administration of 10 mg kg(-1), the Vd(ss) (0.6 +/- 0.2 L kg -1) and the t(1/2) (5.2 +/- 1.1 h) determined were smaller than those obtained after extravascular routes, but the CL(tot) (0.23 +/- 0.05 Lh(-1)kg(-1)) was statistically similar (alpha = 0.05). The intraperitoneal and oral bioavailability was around 1.7% and 0.6%, respectively. The plasma profiles obtained after intravenous and intraperitoneal administration of the compound were best fitted to a three-compartment and two-compartment lag-time open model, respectively. Brain tissue showed low penetration (6.3%) and t(1/2) of 1.1 h. Both the limited bioavailability and the lower brain penetration of LASSBio-579, in comparison with the LASSBio-581, suggest that its CNS activity may be due to a high receptor binding affinity or to a specific distribution into brain structures.     

Pharmacokinetic study of triptolide, a constituent of immunosuppressive chinese herb medicine, in rats

Triptolide is a potential anti-immune agent, and has shown multi-organic toxicity, however its toxic mechanism remained undiscovered. This paper aimed at characterizing the pharmacokinetic profiles of triptolide in rats to provide the clue to approach the toxic mechanism. The absorption, distribution, metabolism and excretion of triptolide were investigated in male Sprague-Dawley rats after single doses of oral and i.v. administration. After oral administration of 0.6, 1.2 and 2.4 mg/kg, the concentration of triptolide in plasma reached the maximum within 15 min, and declined rapidly with an elimination half-life from 16.81 to 21.70 min. The triptolide kinetics was fitted into one-compartment model after i.v. administration. Oral absolute bioavailability was 72.08% at the dose of 0.6 mg/kg. Triptolide was also rapidly distributed and eliminated in all selected tissues. Less than 1% triptolide of the dose was recovered from the bile, urine or feces as parent drug within 48 h. While triptolide could not be detected in tissues and plasma at 4 h post dose, rats in the group C (oral: 1.2 mg/kg) and D (oral: 2.4 mg/kg) showed obvious toxic response to triptolide and some of rats even died out. It was indicated that triptolide was metabolized extensively, eliminated rapidly, and also showed that the toxicity produced by the triptolide was lag behind the exposure concentration.     

Pharmacokinetics of NS-49, a phenethylamine class alpha 1A-adrenoceptor agonist. 1st communication: absorption and excretion in rats after a single administration of 14C-NS-49.

The absorption and excretion of NS-49 ((R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide hydrochloride, CAS 137431-04-0), a phenethylamine class alpha 1A-adrenoceptor agonist, were studied in rats after a single administration of 14C-NS-49. In addition, the protein binding of this drug was investigated in vivo and in vitro. After oral administration of 14C-NS-49 (1 mg/kg) to male rats, the radioactivity concentrations in the blood and plasma reached maximums within 1 h, then decreased biexponentially with respective elimination half-lives of 25.4 and 11.9 h. Most of the plasma radioactivity was due to unchanged NS-49, indicating of the poor metabolism of this drug in rats. The results of the in situ absorption study using the intestinal loop method showed that 14C-NS-49 was well absorbed from the small intestine. Systemic availability was high (86%), as determined by a comparison of the areas under the plasma concentration-time curves of unchanged NS-49 for oral and intravenous administrations. Food affected the absorption of NS-49. There were no significant sex-related differences in the plasma concentration profiles after the intravenous administration of 14C-NS-49 (p > 0.05). NS-49 was primarily eliminated by renal excretion, 76% and 62% of the dose being excreted unchanged in the urine after intravenous and oral administrations, respectively. The absorption rate, determined on the basis of the urinary excretion of radioactivity, was 83%, being almost the same as the systemic availability. First-pass metabolism of NS-49, therefore, is considered to be very limited in rats. The excretion of radioactivity in the bile within 48 h after the oral administration of 14C-NS-49 (1 mg/kg) was 5.9% of the dose, and the excretion of radioactivity in the exhaled air after the intravenous administration (0.2 mg/kg) was negligible. The percentage of 14C-NS-49 bound to serum proteins in vitro was less than 15% in all the animal species tested. The percentage of radioactivity bound to rat serum proteins after the oral administration of 14C-NS-49 (1 mg/kg) was 16-21%.     

Absorption,Distribution, Metabolism,and Excretion of N-Octylbicycloheptene Dicarboximide (MGK 264) Administered Orally to Rats

Abstract

Experiments were conducted in four groups of rats to determine the absorption, distribution, metabolism, and excretion (ADME) patterns following oral administration of [hexyl-1-¹⁴C] N-octylbicycloheptene dicarboximide (MGK 264).

Ten rats (five males and five females) were used in each of the four experiments. Fasted rats were administered fhexyl-1-¹⁴C] MGK 264 at a single oral dose of 100 mg/kg, at a single oral dose of 1000 mg/kg, and at a daily oral dose of 100 mg/kg of nonradiolabeled compound for 14 days followed by a single dose of ¹⁴C-labeled compound at 100 mg/kg. Rat blood kinetics were determined in the fourth group following a single oral dose of 100 mg/kg. Each animal was administered 18-30 μCi radioactivity.

Urine and feces were collected for all groups at predetermined time intervals. Seven days after dose administration, the rats were euthanized and selected tissues and organs were harvested. Samples of urine, feces, and tissues were subsequently analyzed for ¹⁴C content.

In the blood kinetics study, radioactivity peaked at approximately 4 h for the males and 6 h for the females. The decline of radioactivity from blood followed a monophasic elimination pattern. The half-life of blood radioactivity was approximately 8 h for males and 6 h for females.

Female rats excreted 71.45-73.05% of the radioactivity in urine and 20.87-25.28% in feces, whereas male rats excreted 49.49-63.49% of the administered radioactivity in urine and 31.76-46.67% in feces. Total tissue residues of radioactivity at 7 days ranged from 0.13 to 0.43% of the administered dose for all dosage regimens. The only tissues with ¹⁴C residues consistently higher than that of plasma were the liver, stomach, intestines, and carcass. The total mean recovered radioactivity of the administered dose in the studies ranged between 93.1 and 97.4%. No parent compound was detected in the urine.

Four major metabolites and one minor metabolite were isolated from the urine by high-performance liquid chromatography (HPLC) and identified by gas chromatography/mass spectometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS). The four major metabolites were shown to be carboxylic acids produced by either ω-1 oxidation or β-oxidation of the side chain and oxidation of the norbornene ring double bond. The minor metabolite was the carboxylic acid of the intact norbornene ring.

The gender of the animals affected the rate, route of excretion, and metabolic profile. The urinary excretion rate was faster in females than in males and the amount excreted was also greater in female rats.     

Excretion of nitrofurantoin in dog hepatic bile

1. After the intravenous administration of nitrofurantoin sodium to dogs at nitrofurantoin doses of 1.5-24.0 mg/kg, a substantial amount of nitrofurantoin is excreted in bile. The bile to blood drug ratios were about 200. A marked hydrocholeretic effect which correlated directly with the amount of nitrofurantoin administered was also observed.2. The excretion of nitrofurantoin in bile and the hydrocholeretic effect were linear with the dose of drug over the range 1.5-12.0 mg/kg. Maximum increases in hepatic bile flows were usually from 5-10 ml/0.5 h, while average control bile flow was 1.6 ml +/- S.D. 0.6/0.5 hours. The lowest dose at which the hydrocholeretic effect was still detectable was 0.09 mg/kg.3. Apparent saturation of the biliary excretion system for nitrofurantoin and the hydrocholeretic mechanism occurred after a dose of 24.0 mg/kg. Saturation of the urinary system for nitrofurantoin excretion was noted after a dose of 6.0 mg/kg.4. Biliary nitrofurantoin recoveries ranged from 16.5% +/- S.D. 4.2 to 22.6% +/- S.D. 4.7 for the 6 h period after doses of 1.5, 3.0, and 6.0 mg/kg. Urinary nitrofurantoin recoveries for the same interval ranged from 24.1% +/- S.D. 6.6 to 36.2% +/- S.D. 8.3.5. In comparison to values obtained in normal dogs, only about one-tenth of the drug excretion in bile and about one-fifth of the hydrocholeretic effect were obtained after intravenous drug administration to dogs with hepatic impairment induced by CCl(4).