Absorption,Metabolism, and Excretion of 2,3:4,5-Bis(2-Butylene) Tetrahydro-2 Furaldehyde (Mgk R11)in the Rat

Abstract

Experiments were conducted in four groups of rats to determine the absorption, distribution, metabolism, and excretion (ADME) patterns following oral administration of [formyl-¹⁴C] 2,3:4,5-bis(2-butylene) tetrahydro-2 furaldehyde (MGK R11).

Ten rats (five males and five females) were used in each of the four experiments. Fasted rats were administered [for-myl-¹⁴C] MGK R11 at a single oral dosage of 65 mg/kg, at a single oral dosage of 1000 mg/kg, and at a daily oral dosage of 65 mg/kg of nonradiolabeled compound for 14 days followed by a single dose of ¹⁴C-labeled compound at 65 mg/kg. Rat blood kinetics were determined in the fourth group following a single oral dose of 65 mg/ kg. Each animal was administered approximately 12–14 μCi of radioactivity.

Urine and feces were collected from 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 30 min in both the males and females, indicating very rapid absorption. The decline of radioactivity from blood followed a biphasic elimination pattern. The first half-life was 1.36 h for males and 1.18 h for females. In the second phase, the half-life was 21 h for males and 26 h for females.

Female rats excreted 67.21-86.85% of the radioactivity in urine and 13.99–28.08% in feces, whereas male rats excreted 50.19–64.37% of the administered radioactivity in urine and 31.43–40.94% in feces. Tissue residues of ¹⁴C ranged between 0.47% and 1.09% of the administered dose. The total mean recovered radioactivity of the administered dose in the four definitive studies ranged between 92% and 101%. No parent compound was detected in the urine.

Three major and one minor metabolite was isolated by high-performance liquid chromatography (HPLC) and identified by gas chromatography/mass spectrometry (GC/MS). One major metabolite was formed by oxidation of the aldehyde moiety to the carboxylic acid. A second metabolite was the glucuronic acid conjugate of the carboxylic acid and the third was formed by reduction of the aldehyde moiety of MGK R11 to an alcohol followed by glucuronic acid conjugation. The minor metabolite was the unconjugated alcohol derivative of MGK R11.

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.     

Absorption,distribution, metabolism and excretion of gemigliptin,a novel dipeptidyl peptidase IV inhibitor,in rats

Abstract

1.?The absorption, distribution, metabolism and excretion of a novel dipeptidyl peptidase IV inhibitor, gemigliptin, were examined following single oral administration of ¹⁴C-labeled gemigliptin to rats.

2.?The ¹⁴C-labeled gemigliptin was rapidly absorbed after oral administration, and its bioavailability was 95.2% (by total radioactivity). Distribution to specific tissues other than the digestive organs was not observed. Within 7 days after oral administration, 43.6% of the administered dose was excreted via urine and 41.2% was excreted via feces. Biliary excretion of the radioactivity was about 17.7% for the first 24?h. After oral administration of gemigliptin to rats, the in vivo metabolism of gemigliptin was investigated with bile, urine, feces, plasma and liver samples.

3.?The major metabolic pathway was hydroxylation, and the major circulating metabolites were a dehydrated metabolite (LC15-0516) and hydroxylated metabolites (LC15-0635 and LC15-0636).     

Biotransformation and mass balance of faldaprevir,a hepatitis C NS3/NS4 protease inhibitor in rats

Abstract

1.?The metabolism, pharmacokinetics, excretion and tissue distribution of a hepatitis C NS3/NS4 protease inhibitor, faldaprevir, were studied in rats following a single 2?mg/kg intravenous or 10?mg/kg oral administration of [¹⁴C]-faldaprevir.

2.?Following intravenous dosing, the terminal elimination t_1/2 of plasma radioactivity was 1.75?h (males) and 1.74?h (females). Corresponding AUC_0–∞, CL and V_ss were 1920 and 1900?ngEq?·?h/mL, 18.3 and 17.7?mL/min/kg and 2.32 and 2.12?mL/kg for males and females, respectively.

3.?After oral dosing, t_1/2 and AUC_0–∞ for plasma radioactivity were 1.67 and 1.77?h and 11?300 and 17?900 ngEq?·?h/mL for males and females, respectively.

4.?In intact rats, ≥90.17% dose was recovered in feces and only ≤1.08% dose was recovered in urine for both iv and oral doses. In bile cannulated rats, 54.95, 34.32 and 0.27% dose was recovered in feces, bile and urine, respectively.

5.?Glucuronidation plays a major role in the metabolism of faldaprevir with minimal Phase I metabolism.

6.?Radioactivity was rapidly distributed into tissues after the oral dose with peak concentrations of radioactivity in most tissues at 6?h post-dose. The highest levels of radioactivity were observed in liver, lung, kidney, small intestine and adrenal gland.     

Absorption,distribution and excretion of nilvadipine,a new dihydropyridine calcium antagonist,in rats and dogs

1. The absorption, distribution and excretion of nilvadipine have been studied in male rats and dogs after an i.v. (1 mg/kg for rats, 0.1 mg/kg for dogs) and oral dose (10 mg/kg for rats, 1 mg/kg for dogs) of ¹⁴C-nilvadipine.

2. Nilvadipine was rapidly and almost completely absorbed after oral dosing in both species; oral bioavailability was 4.3% in rats and 37.0% in dogs due to extensive first-pass metabolism. The ratios of unchanged drug to radioactivity in plasma after oral dosing were 0.4–3.5% in rats and 10.4–22.6% in dogs. The half-lives of radioactivity in plasma after i.v. and oral dosing were similar, i.e. 8–10h in rats, estimated from 2 to 24 h after dosing and 1.5 d in dogs, estimated from 1 to 3 d. In contrast, plasma concentrations of unchanged drug after i.v. dosing declined biexponentially with terminal phase half-lives of 1.2 h in rats and 4.4 h in dogs.

3. After i.v. dosing to rats, radioactivity was rapidly distributed to various tissues, and maintained in high concentrations in the liver and kidneys. In contrast, after oral dosing to rats, radioactivity was distributed mainly in liver and kidneys.

4. With both routes of dosing, urinary excretion of radioactivity was 21–24% dose in rats and 56–61% in dogs, mainly in 24 h. After i.v. dosing to bile duct-cannulated rats, 75% of the radioactive dose was excreted in the bile. Only traces of unchanged drug were excreted in urine and bile.     

Absorption and Mass Balance of Mgk R11 and Mgk R11 Formulated with Deet,Mgk 264, and Mgk 326 Following an 8 Hour Dermal Exposure in Human Volunteers

Abstract

Dermal absorption and excretion of MGK R11 [2,3:4,5-bis(2-butylene) tetrahydro-2 furaldehyde, McLaughlin Gormley King Company, Minneapolis, MN] was studied using [¹⁴C]MGK R11 either by itself or formulated with DEET (N,N-diethyl-m-toluamide), MGK 264 (N-octylbicycloheptene dicarboximide), and MGK 326 (di-n-propyl-isocinchomeronate). Each of these two formulations was tested on four young, healthy male volunteers, using a single topical application on the forearm under nonocclusive conditions for an 8 h period. Blood from the ipsilateral and contralateral arms, urine, and feces were collected at selected intervals during the 8 h application and through a 120 h postapplication period. The application area was also tape-stripped to determine if any of the test material accumulated in the stratum corneum. These samples provided data that permitted some insight into the kinetics of penetration and elimination processes of MGK R11. Urine samples, swabs, and skin rinse samples were analyzed by high-performance liquid chromatography (HPLC) to characterize the metabolic profile, identify the major metabolites, and determine the metabolic pathway.

MGK R11, either by itself or formulated, was poorly absorbed through the skin as shown by the amount of radioactivity excreted in the urine and the very low plasma radioactivity level in the ipsilateral plasma. When dosed by itself, approximately 8% of the dose was excreted in the urine. In contrast, only 3% of the formulated MGK R11 was excreted in the urine. Approximately 0.3% of the dose was excreted in the feces. There was no evidence of accumulation of MGK R11 in the skin, as evidenced by low amounts of radioactivity in the tape strippings. A significant portion of the dosed radioactivity was recovered from the dome covering the dosing site amounting to 67% of the compound by itself or 27% of the formulated product, indicating a difference of volatility depending on the formulation. The rest of the external radioactivity was present in the swabs. Total recovery of the applied radioactivity was 89.9% and 99.5% for MGK R11 and the formulated product, respectively. Radiochemical analyses of the swab composites indicated a 30% degradation of parent compound in the one-component swabs and no degradation in the four-component swabs. Absorbed MGK R11 was completely metabolized prior to its excretion in the urine to two metabolites that accounted for 95% of the urinary metabolites. The major metabolic pathway is by oxidation of the aldehyde to the corresponding acid or reduction of the aldehyde to the corresponding alcohol followed by conjugation to produce the glucuronide.     

The Fate of Ultra-Low Viscosity 14C-Hydroxypropyl Methylcellulose in Rats Following Gavage Administration

ABSTRACT

The disposition of ¹⁴C-Hydroxypropyl methylcellulose (HPMC) with a viscosity of 2.25 centipoise was studied in male and female Sprague-Dawley rats following a single 500 mg/kg body weight gavage dose, or five consecutive daily doses. Recoveries for the single dose were: feces, >99%; urine, ～1%; carcass and tissues, ?0.2%; expired air, 0.07%; and bile, 0.05%. Plasma radioactivity had a monophasic excretion half-life of approximately 2 hours for either sex. The majority of the residual radioactivity in the tissues was found in the gastrointestinal tract. The absorbed radioactivity in the urine, based on thin layer chromatography (TLC) analyses, represented methyl ethers of glucose and oligomers; this amounted to 0.56% recovered in a study in which urine samples were isolated from possible contamination by radioactivity in the feces. The 0.56% correlated well with the 0.53% portion of the original dosing solution which consisted of cellulose units with an average molecular weight of < 1000. Recovery of radioactivity in the feces of rats on the 5-day dosing regimen was 97% and 102% for males and females, respectively, without any evidence for accumulation in tissues. Approximately 1% was recovered in the urine. Thus, the results of this work show that ultra-low viscosity 2.25 centipoise HPMC was only minimally absorbed with essentially all of a single 500 mg/kg gavage dose, or 5 daily consecutive doses, being excreted unabsorbed in the feces.     

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.     

Biotransformation and mass balance of tipranavir, a nonpeptidic protease inhibitor, when co-administered with ritonavir in Sprague-Dawley rats

In this study, tipranavir (TPV) biotransformation and disposition when co-administered with ritonavir (RTV) were characterized in Sprague-Dawley rats. Rats were administered a single intravenous (5 mg kg(-1)) or oral (10 mg kg(-1)) dose of [(14)C]TPV with co-administration of RTV (10 mg kg(-1)). Blood, urine, faeces and bile samples were collected at specified time-points over a period of 168 h. Absorption of TPV-related radioactivity ranged from 53.2-59.6%. Faecal excretion was on average 86.7% and 82.4% (intravenous) and 75.0% and 82.0% (oral) of dosed radioactivity in males and females, respectively. Urinary excretion was on average 4.06% and 6.73% (intravenous) and 9.71% and 8.28% (oral) of dosed radioactivity in males and females, respectively. In bile-duct-cannulated rats, 39.8% of the dose was recovered in bile. After oral administration, unchanged TPV accounted for the majority of the radioactivity in plasma (85.7-96.3%), faeces (71.8-80.1%) and urine (33.3-62.3%). The most abundant metabolite in faeces was an oxidation metabolite R-2 (5.9-7.4% of faecal radioactivity, 4.4-6.1% of dose). In urine, no single metabolite was found to be significant, and comprised <1% of dose. TPV when co-administered with RTV to rats was mainly excreted in feces via bile and the parent compound was the major component in plasma and faeces.     

Sex differences in the metabolism and excretion of nilvadipine,a new dihydropyridine calcium antagonist,in rats

1. The metabolic profiles of nilvadipine in the urine and bile of male and female rats were studied after i.v. dosing with 1?mg/kg of the ¹⁴C-labelled compound.

2. Excretion rates of the dosed radioactivity in male and female rats, respectively, in the first 48?h were 8.41% and 59.1% in bile, 12.0% and 36.9% in urine, and 2.5% and 3.6% in faeces.

3. Comparison of biliary and urinary excretion for each radioactive metabolite after dosing with ¹⁴C-nilvadipine, showed marked sex-related differences in the excretion routes of several metabolites. In male rats, metabolite M3, having a free 3-carboxyl group on the pyridine ring, was not excreted in urine, but in female rats urinary excretion of M3 accounted for 4.7% of the dose. One reason for the lower urinary excretion of radioactivity by males than by females was that the main metabolite, M3, was not excreted in the urine of the male rats.

4. To clarify the sex difference in the route of excretion of M3, this metabolite (M3) was given i.v. to rats. No excretion of the metabolite was observed in urine of male rats within 24?h but, in marked contrast, 41.5% of the dose was excreted in urine of females in the same period.     

The biotransformation of [14C]lormetazepam in dogs,rabbits, rats and rhesus monkeys

1. After oral or intravenous doses (0.25?mg/kg) of [¹⁴C]lormetazepam to rats, most of the urinary radioactivity was associated with polar components and < 1% dose was excreted as unconjugated lormetazepam. About 30% of an oral dose was excreted in rat bile as a conjugate of lormetazepam and about 50% dose as polar metabolites. Plasma also contained mainly polar metabolites, and unchanged lormetazepam represented at most 10% of total plasma radioactivity after an oral dose.

2. Almost all the radioactivity in dog, rhesus monkey and rabbit urine, after oral or intravenous doses (0.5–0.7?mg/kg) of [¹⁴C]lormetazepam, was associated with conjugated material. In the dog there were only two major components, conjugates of lormetazepam and lorazepam (N-desmethyl-lormetazepam) which accounted for about 24% and 14% respectively of the oral dose in the 0–24?h urine. The same two conjugated components were also present in dog bile. Conjugated lormetazepam was the only major component in monkey and rabbit urine and accounted for about 60% dose in the 0–24?h urine of each species, while conjugated lorazepam accounted for only about 0.5% and 4% respectively.

3. Dog and monkey plasma contained mostly conjugated material after oral and intravenous doses (0.05–0.07?mg/kg of [¹⁴C]lormetazepam. Dog plasma after an oral dose contained conjugates of both lormetazepam and lorazepam with peak concn. at 1?h of 130 and 47 ng/ml respectively. Concn. of these conjugates in plasma declined with apparent terminal half-lives of about 17 and 27?h respectively after oral doses, and 13?h in both cases after intravenous doses. Conjugated lormetazepam was the only major component in monkey plasma representing a peak concn. of 180 ng/ml at 1?h after an oral dose, and declined with an apparent terminal half-life of about 11?h after oral or intravenous doses.

4. Lormetazepam crosses the placental ‘barrier’ of rabbits: its concn. in the foetus were similar to those in maternal plasma after intravenous doses.     

Metabolism,excretion and pharmacokinetics of [14C]glasdegib (PF-04449913) in healthy volunteers following oral administration

1.?The metabolism, excretion and pharmacokinetics of glasdegib (PF-04449913) were investigated following administration of a single oral dose of 100?mg/100 μCi [¹⁴C]glasdegib to six healthy male volunteers (NCT02110342).

2.?The peak concentrations of glasdegib (890.3?ng/mL) and total radioactivity (1043 ngEq/mL) occurred in plasma at 0.75?hours post-dose. The AUC_inf were 8469?ng.h/mL and 12,230 ngEq.h/mL respectively, for glasdegib and total radioactivity.

3.?Mean recovery of [¹⁴C]glasdegib-related radioactivity in excreta was 91% of the administered dose (49% in urine and 42% in feces). Glasdegib was the major circulating component accounting for 69% of the total radioactivity in plasma. An N-desmethyl metabolite and an N-glucuronide metabolite of glasdegib represented 8% and 7% of the circulating radioactivity, respectively. Glasdegib was the major excreted component in urine and feces, accounting for 17% and 20% of administered dose in the 0–120?hour pooled samples, respectively. Other metabolites with abundance <3% of the total circulating radioactivity or dose in plasma or excreta were hydroxyl metabolites, a desaturation metabolite, N-oxidation and O-glucuronide metabolites.

4.?Elimination of [¹⁴C]glasdegib-derived radioactivity was essentially complete, with similar contribution from urinary and fecal routes. Oxidative metabolism appears to play a significant role in the biotransformation of glasdegib.     

Metabolism and disposition of the flame retardant plasticizer, tri-p-cresyl phosphate, in the rat

The metabolism and disposition of tri-p-cresyl phosphate (TPCP) were studied in the rat after a single oral administration of [methyl-14C] TPCP. At a dosage of 7.8 mg/kg, most of the administered radioactivity was excreted in the urine (41%) and feces (44%) in 7 days. For 3 days, the expiratory excretion as 14CO2 amounted to 18% of the radioactivity, but was reduced to 3% by treatment of the animal with neomycin. In separate rats, the biliary excretion amounted to 28% of the dose in 24 hr. At a dose of 89.6 mg/kg, the radioactivity was excreted in urine (12%) and feces (77%) in 7 days, and the expired air (6%) in 3 days. At 24, 72, and 168 hr after oral administration, the concentration of radioactivity was relatively high in adipose tissue, liver, and kidney. The major urinary metabolites were p-hydroxybenzoic acid, di-p-cresyl phosphate (DCP), and p-cresyl p-carboxyphenyl phosphate (1coDCP). The biliary metabolites were DCP, 1coDCP, and the oxidized triesters, di-p-cresyl p-carboxyphenyl phosphate (1coTPCP), and p-cresyl di-p-carboxyphenyl phosphate (2coTPCP). The main fecal metabolite was TPCP, and the others were similar to those of bile. Following oral administration, TPCP was absorbed from the intestine, distributed to the fatty tissues, and moderately metabolized to a variety of products of oxidation and dearylation of TPCP, which were then excreted in the urine, feces, bile, and expired air. The intestinal microflora appeared to play an important role in degrading biliary metabolites to 14CO2 through the enterohepatic circulation in rats.     

The Disposition of 10–10′ Oxybisphenoxarsine (OBPA) in Rats,Rabbits and Guinea Pigs

ABSTRACT

The disposition of 10–10’ oxybisphenoxarsine (OBPA), a potent, wide spectrum anti-microbial agent widely used in plastics, was investigated in rats, guinea pigs and rabbits. All animals were given a single dose of [U- ¹⁴C]OBPA by gavage. Urine and feces were collected daily for 7 days, at which time the animals were sacrificed and tissue samples removed for analysis. In all three species, approximately 90% of the administered dose was excreted within 7 days. The rabbits and guinea pigs excreted about 58% via the feces and 32% via the urine. The rats, however, excreted 82% via the feces and 10% via the urine. There were significant differences in the tissue distribution of radioactivity between the three species. The most prominent difference was that the erythrocytes of the rat retained 3.2% of the administered radiolabel while only 0.08% and 0.03% of the dose remained in the erythrocytes of the guinea pig and rabbit, respectively.     

Metabolism and excretion of CP-122,721, a non-peptide antagonist of the neurokinin NK1 receptor,in dogs: Identification of the novel cleaved product 5-trifluoromethoxy salicylic acid in plasma

The metabolism and excretion of a potent and selective substance P receptor antagonist, CP-122,721, have been studied in beagle dogs following oral administration of a single 5?mg?kg^?1 dose of [¹⁴C]CP-122,721. Total recovery of the administered dose was on average 89% for male dogs and 95% for female dogs. Approximately 94% of the radioactivity recovered in urine and feces was excreted in the first 72?h. Male bile duct-cannulated dogs excreted a mean of ～56% of the dose in bile, ～11% in feces, and ～25% in urine. The sum of radioactivity in bile and urine indicates >80% of the [¹⁴C]CP-122,721-derived radioactivity was absorbed by the gastrointestinal tract. CP-122,721 was extensively metabolized in dogs, and only a small amount of parent CP-122,721 was excreted as unchanged drug. There were no significant gender-related quantitative/qualitative differences in the excretion of metabolites in urine or feces. The major metabolic pathways of CP-122,721 were O-demethylation, aromatic hydroxylation, and indirect glucuronidation. The minor metabolic pathways included: Aliphatic oxidation at the piperidine moiety, O-dealkylation of the trifluoromethoxy group, and N-dealkylation with subsequent sulfation and/or oxidative deamination. In addition, the novel cleaved product 5-trifluoromethoxy salicylic acid (TFMSA) was identified in plasma. These results suggest that dog is the most relevant animal species in which the metabolism of CP-122,721 can be studied for extrapolating the results to humans.     

Chlophentermine-induced abnormalcytoplasmic inclusions in peripheral blood cells of rats and guinea pigs.

The metabolic fate of [¹⁴C]gossypol was studied in the pig following a single oral dose of 6.7 mg/kg (3.7 μCi). Radioactivity was rapidly excreted from the animal body via feces. After 20 days, the total radioactivity recovered in the feces was 94.6% of the administered dose. A total of 2.1% of the radioactivity of administered dose was recovered in the expired CO₂ collected continually for 20 days. This indicates that decarbonilation of gossypol is not a major route of gossypol metabolism in the pig. Radioactivity was least excreted via urine; only 0.7% of the administered dose was recovered in the urine. One day after the administration, the tissues had 32.9% of the administered dose, which was decreased to 1.2% at 20 days. The conceptration of gossypol and its metabolites in the tissues (as indicated by radioactivity) was highest in the muscle, followed by liver, adipose tissues, and the blood. The half-life for the disappearance of radioactivity from the animal body following the administration of [¹⁴C]gossypol was 78 hr. Identification of metabolites was carried out by ultraviolet, infrared, and mass spectrometry in connection with thin-layer autoradiography. Compounds isolated from pig liver were characterized as gossypol, gossypolone, gossypolonic acid, demethylated gossic acid, and presumably apogossypol. Gossypol and metabolites may be conjugated to form glucuronides, sulfates, or hybrids.     

The Effect of Route of Administration on the Metabolic Fate of Terbutaline in the Rat

Abstract

1. The metabolic fate of [³H]terbutaline has been investigated in rats after oral, subcutaneous, intraperitoneal and intraportal administration (5 mg per kg).

2. About half the administered radioactivity was excreted in the urine and the remainder in faeces regardless of route of administration. Urinary excretion was essentially complete in 24 h, but an additional 10% of the dose was excreted in the 24–48 h faeces.

3. Only one metabolite, a glucuronide conjugate of terbutaline, was excreted in the urine along with unchanged drug. About 3% of the dose was excreted unchanged in urine following oral administration. Ratios of terbutaline glucuronide to free drug were 1 : 1, 2 : 1 and 13 : 1 after subcutaneous, intraperitoneal or intraportal, and oral administration respectively, suggesting that the orally administered drug is extensively conjugated in the intestinal mucosa.

4. Measurement of the mobility-pH profile by high-voltage paper electrophoresis was utilized to characterize the conjugate.     

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 [6]-shogaol,a pungent ingredient of <Emphasis Type="Italic">Zingiber officinale</Emphasis> Roscoe (Part I)

To investigate the pharmacokinetics of [6]-shogaol, a pungent ingredient of Zingiber officinale Roscoe, the pharmacokinetic parameters were determined by using ¹⁴C-[6]-shogaol (labeled compound) and [6]-shogaol (non-labeled compound). When the labeled compound was orally administered to rats, the maximum plasma concentration (C _max) and the area under the curve (AUC) of plasma radioactivity concentration increased in a dose-dependent manner. When the labeled compound was orally administered at a dose of 10 mg/kg, 20.0 ± 1.8% of the radioactivity administered was excreted into urine, 64.0 ± 12.9% into feces, and 0.2 ± 0.1% into breath. Thus, more of the radioactivity was excreted into feces than into urine, and almost no radioactivity was excreted into breath. Furthermore, when the labeled compound was orally administered at a dose of 10 mg/kg, cumulative biliary radioactivity excretion over 48 h was 78.5 ± 4.5% of the radioactivity administered, and cumulative urinary radioactivity excretion over 48 h was 11.8 ± 2.7%, showing that about 90% of the dose administered orally was absorbed from the digestive tract and most of the fecal excretion was via biliary excretion. On the other hand, when the non-labeled compound [6]-shogaol was orally administered, the plasma concentration and biliary excretion of the unchanged form were extremely low. When these results are combined with those obtained with the labeled compound, it would suggest that [6]-shogaol is mostly metabolized in the body and excreted as metabolites.     

Studies on the toxicology of hexachlorobenzene

Female rats were dosed intraperitoneally with ¹⁴C-hexachlorobenzene. The drug was administered on 2 or 3 occasions. The total doses amounted to 260 and 390 mg/kg ¹⁴C-hexachlorobenzene, respectively. Urine and feces from the animals were collected over a period of 4 weeks after the first injection. Both excreta and some tissues of the animals were examined for their content of radioactivity and for hexachlorobenzene and its metabolites. Gas chromatography, isotope dilution analysis, and combined gas chromatography-mass spectrometry were used to identify the metabolites of hexachlorobenzene. In urine pentachlorophenol, tetrachlorohydroquinone, and pentachlorothiophenol were present as major metabolites. One of the isomers of tetrachlorothiophenol was present as a minor metabolite. In the feces pentachlorophenol and penta-chlorothiophenol only were identified.At the end of the experiment, carbon-14 excreted with urine and feces amounted to 7% and 27%, respectively, of the radioactivity administered.More than 90% of carbon-14 excreted in urine was contained in the major metabolites. In the feces about 30% of the excreted radioactivity was bound to metabolites and about 70% was contained in the unchanged drug, while in the tissues of the animals only pentachlorophenol was detected in measurable amounts, accounting for 10% of label in blood and less than 0.1% of carbon-14 determined in body fat. Total radioactivity contained in the metabolites detected in the animal body and in the excreta at the end of the experiment accounted for about 16% of the administered radioactivity.The authors thank Miss A. Springer and Mr. K. Wittkamp for their technical assistance.     

Disposition of 3,3′-dichlorobenzidine in the rat

The disposition of the carcinogen 3,3′-dichlorobenzidine (DCB) was studied in the male rat following oral administration. [¹⁴C]DCB was well absorbed by the rat with the maximum plasma radioactivity levels being found within 8 hr after dosing. The radioactivity was well distributed in the tissues 24 hr after administration with the highest levels found in the liver, followed by kidney, lung, and spleen. Repeated administration (six doses) of [¹⁴C]DCB to animals did not result in a substantial accumulation of ¹⁴C in the tissues. The elimination of radioactivity from the plasma, liver, kidney, and lung was biphasic showing an initial rapid decline (half-lives 1.68, 5.78, 7.14, and 3.85 hr, respectively) followed by a slower disappearance phase (half-lives 33.0, 77.0, 138.6, and 43.3 hr, respectively). Approximately half of the total ¹⁴C in the liver and kidney was covalently bound to cellular macromolecules 72 hr after dosing. [¹⁴C]DCB-derived radioactivity was extensively excreted by rats, mainly via the feces. Approximately 23–33% of the administered dose was recovered in the urine and 58–72% in the feces of rats within 96 hr. More than 65% of the administered ¹⁴C was eliminated in the bile of bile duct-cannulated rats within 24 hr after dosing. The radioactivity excreted in the urine and bile was primarily in the form of free (urine 71.2%, bile 25.5%) and conjugated (urine 19.6%, bile 57.9%) metabolites of DCB. Thus DCB is readily absorbed following oral administration, and then metabolized and excreted mainly via the feces.