Plasma Concentrations Of Radioactivity Research Articles

Disposition of the Aldose Reductase Inhibitor AL01576 in Rats

The disposition of the aldose reductase inhibitor AL01576 was studied in rats following intravenous and oral dosing. Single 4mg/kg intravenous bolus and oral doses of [14C] AL01576 were administered and levels of radioactivity in blood, excreta, and various tissues were determined over a 168-h period. The decline of radioactivity in blood was quite similar for the two routes of administration, with an apparent half-life of ~30 h. At 120 to 144 h, a second, slower elimination phase began that was not fully characterized in the 168-h duration of the study. The HPLC analysis of plasma samples revealed intact AL01576 as the only compound in plasma. The mean plasma parent and radioactivity concentrations are in agreement; suggesting the absence of or an insignificant amount of metabolite in the plasma. The urinary and fecal excretion rate data showed a kinetic pattern similar to that of blood radioactivity. Fecal excretion was the primary route of elimination following both intravenous and oral dosing, accounting for 59% of the administered intravenous dose and 61% of the oral dose. Urinary excretion accounted for 32% of the intravenous dose and 29% of the oral dose. Negligible amounts of radioactivity were recovered as expired 14CO2. Experiments with bile-duct cannulated rats confirmed that the major route of elimination of the drug is biliary excretion. The pattern of distribution of [14C] AL01576 in tissues was quite similar following the two routes of administration. Tissue radioactivity concentration peaked at 4 h (the first sampling time) following both routes of administration in all tissues except the Gl tract. The highest radioactivity concentrations at 4 and 24 h were in the Gl tract, kidney, adrenals, and liver. At 168 h, the highest concentrations of radioactivity were found in the testes, kidneys, lungs, and adrenals, although the recovery from these four tissues combined represented <0.5% of the administered dose. After intravenous dosing, the recovery of radioactivity in the selected tissues (blood, liver, kidney, lung, brain, heart, spleen, testes, muscle, eyes, adrenals, skin, fat, and Gl tract) measured was 82, 75, 13, and 4% of the administered dose at 4, 24, 72, and 168 h, respectively. Overall, the data suggest that AL01576 is readily absorbed when administered orally, is distributed throughout the body tissues, is excreted predominantly by the feces through biliary excretion, and has a low systemic clearance and a long biologic half-life.

Studies on the metabolic fate of S-3460. (II). Absorption, distribution and excretion after repeated subcutaneous administration to rats.

The absorption, distribution and excretion of S-3460 in male rats were studied following 7- or 28-day period of daily subcutaneous administration of 3H-S-3460 or 14C-S-3460 at 0.5 mg/kg. 1. The concentrations of radioactivity in plasma and blood 24 hr after daily administration rose with increasing of dosing times, and its concentration after the 28 th dose was 4.3 and 17 times higher than that after a single dose, respectively. Thus, it seems that the accumulation in plasma is low while that in blood is significantly high. Tissue concentration of radioactivity also rose and reached plateau levels by the 28 th dose in most tissues except for the blood, kidney and spleen. 2. The concentrations of radioactivity in the plasma, blood and most tissues after repeated administration of 3H-S-3460 were slightly higher than those after a single dose, but the disappearances were significantly slow. In some tissues, the levels after 3H-S-3460 administration differed from those after 14C-S-3460 administration. This may have been due to detachment of 3H from the 1, 2 position of 3H-S-3460. Tissue levels of radioactivity in female rats were lower than those in male rats and transfer of radioactivity with blood cell was also low. 3. Excretion of radioactivity into the urine and feces was almost constant during repeated administration and that after the 7 th or 28 th dose was similar to that after a single dose. Most of the radioactivity was excreted via the feces in both male and female rats.

2,2,4-Trimethylpentane-induced nephrotoxicity: I. Metabolic disposition of TMP in male and female Fischer 344 rats

2,2,4-Trimethylpentane (TMP), a component of unleaded gasoline, causes nephrotoxicity in male, but not in female, rats. In the present study, male and female Fischer 344 rats were treated with a single oral dose of [14C]TMP (4.4 mmol/kg; 2 μCi/mmol). Radiolabeled material in kidney, liver, and plasma was determined at 4, 8, 12, 24, and 48 hr after dosing. Maximum concentration of TMP-derived radioactivity in kidney, liver, and plasma of male rats was found after 12 hr (1252, 1000, and 403 nmol eq/g, respectively), whereas those measured in females were found after 8 hr (577, 1163, and 317 nmol eq/g, respectively). A selective retention of the TMP-derived radiolabel in the kidneys of male rats was noted when peak tissue concentration was expressed as a percentage of administered dose. Kidney concentrations of TMP-derived radiolabel increased in a nonlinear, but dose-dependent, manner; the kidney to plasma ratio was greater at low doses than at higher doses. Increased retention of radiolabel material in the kidney was associated with a significant increase in renal concentration of the male-rat-specific protein, α2u-globulin, 24 and 48 hr after TMP administration. Total radioactivity collected in urine 48 hr after TMP administration was similar in males and females (32 and 31% of dose). Identification and quantitation of the urinary metabolites of TMP showed that both male and female rats metabolize TMP via the same pathway and at a similar rate. Female rats, however, excreted more conjugates of 2,4,4-trimethyl-2-pentanol in urine than males. 2,4,4-Trimethyl-2-pentanol was the major metabolite present in the male rat kidney, but was absent in the female rat kidney. The renal retention of 2,4,4-trimethyl-2-pentanol appears to account for the delayed clearance observed in the disposition of [14C]TMP-derived radiolabel. Based on the concomitant accumulations in renal α2u-globulin concentration and renal 2,4,4-trimethyl-2-pentanol concentration, an association is speculated between these two components. The male-rat-specific accumulation of 2,4,4-trimethyl-2-pentanol may therefore reflect the accumulation of a “metabolite-α2u-globulin” complex. This may be relevant to the male-rat-specific nephrotoxicity produced by TMP.

Studies on the metabolic disposition of ethyl eicosapentaenoate(EPA-E) in rats and dogs.

Plasma level, tissue distribution and excretion of ethyl eicosapentaenoate(EPA-E) were studied after oral administration of 14C-uniformly labelled EPA-E to rats and dogs and the following results were obtained. 1. The maximum concentration of radioactivity in plasma was obtained at 6-9 hr and at 24hr after dosing in rats and dogs, respectively. The elimination of radioactivity from plasma was biphasic. 2. The radioactivity administered to rats was mainly excreted in expired air. 3. The cumulative biliary excretion of radioactivity was 2.9 % of the dose within 24 hr. 4. The concentration of radioactivity in each tissue reached maximum at 9-24hr after dosing except for brain, fat, skin, muscle and aorta in which the concentration reached maximum at 1 week and subsequently decreased gradually. The elimination rate of radioactivity from each tissue was almost as same as that from plasma or a little slower. 5. Foeto-placental transfer of radioactivity in the pregnant rats at 12 and 19 days of gestation was observed but its extent was low. 6. The milk level of radioactivty in the lactating rats reached maximum at 24 hr and was 6-14 times higher than that in the maternal blood after 24hr. 7. Radioactive substances in plasma were mainly bound to plasma protein in rats and dogs. 8. During daily repeated administration to rats, the concentration of radioactivity in plasma at 24hr after every dosing reached plateau level within the 12 days but that in each tissue increased with increase in the number of doses. No remarkable difference in elimination half-lives of radioactivity in each tissue between the single and repeated dosing was observed.

Blood concentration, distribution, metabolism and excretion of nitroglycerin in rat. Comparison of single and repeated i.v. infusion.

We have synthesized 14C-labelled nitroglycerin (GTN) to study the blood concentration, distribution, metabolism and excretion of GTN after i. v. administration in Wistar rats. 1) The concentration of radioactivity in plasma reached the maximum level at the end of i. v. infusion for 1 hr and then it decreasedin a biexponential manner. Half lives of α and β phase were 2.59 and 28.11 hrs, respectively. The half life after repeated infusion showed the same value for α phase, but its value at β phase was increased twice as compared with single infusion. It was suggested that the metabolites of longer half life, which were formed by the repeated infusion, have circulated in a whole body for a long period at time. 2) Total excretion of radioactivity in urine, expired air and feces was about 73 % of dose during 72 hrs after a single infusion, and approximately 27 % remained in a whole body. Similar results were obtained in multiple infusion studies. 3) Urinary metabolites found during 24 hrs after administration were mono-and dinitroglycerin (GMN and GDN), glucuronide, glycerol and unknown components. One may suspect that glycerol was metabolized to 14CO2 via the Krebs cycle. 4) The distribution of GTN in tissues and organs showed that the maximum concentration at the end of infusion or 1 hr after the end of infusion both in single and repeated administration. It decreased relatively fast until 4 hrs after the end of infusion, and thereafter a decay of concentration was quite slow. At 24 hrs after the end of infusion, remained radioactivity was 10 ?? 40 % and 40 ?? 60 % of the maximum concentration after a single and repeated infusion, respectively. This shows the accumulation of radioactivity by the repeated infusion. The entity of this accumulated subustance may be considered as the glucuronide of GDN and GMN, and glycerol which have a weak toxicity.

Disposition and Pharmacokinetics of 14C-Nitrendipine in Healthy Volunteers

Six healthy male volunteers were each given a single 20 mg dose of 14C-labeled nitrendipine as an oral suspension. Urine, feces, and plasma were collected after dosing and assayed for total radioactivity. Urine and plasma were also assayed by capillary gas chromatography for nitrendipine and five metabolites. A mean of 77 ± 7.3% of the dose was excreted in the urine over 96 h, 70% was excreted within 24 h, and 76% within 48 h of dosing. The 48 h cumulative urinary excretion of nitrendipine metabolites accounted for 42 ± 4%, of the dose. Thus, ∼ 55% of the radioactivity excreted in the urine was present in the form of measured metabolites. Fecal recovery of radioactivity accounted for 8.1 ± 4.0% of the dose. Total recovery of radioactivity in urine and feces collected over 96 h was 85.1 ± 8.1% of the dose. When mean plasma levels of unchanged nitrendipine and five metabolites were compared with the concentration of total radioactivity in plasma, nitrendipine accounted for 2.4%, and the five metaolites for 80% of the total radioactivity in plasma detected 0–12 h after dose. The highest concentrations of nitrendipine, metabolites, and total radioactivity were attained between 0.5 and 1.5 h after dosing. The results show that on the average at least 77% of the dose was absorbed after oral administration, and only 8% of the dose was excreted in the feces. Most of the radioactivity in plasma and urine was attributed to nitrendipine and five metabolites.

Regional blood-brain barrier transport of glucose after portacaval anastomosis.

The regional influx of glucose across the blood-brain barrier was measured in rats 5 to 6 weeks after a portacaval anastomosis or sham operation. D-[14C]Glucose was infused intravenously for 15 sec while arterial blood was sampled continuously for measurement of plasma radioactivity and glucose concentration. Brain tissue radioactivity was measured by quantitative autoradiography. Glucose influx and plasma clearance (permeability times surface area; PS) were calculated from the net disintegrations per minute per gram in brain, the plasma radioactivity integral, and the plasma glucose concentration. In shunted rats influx was decreased by about 22% (in the brain as a whole) compared to that in controls. This decrease was almost entirely due to the decrease in plasma glucose concentrations (27%). The PS, normalized to take plasma concentrations into account, showed a slight decrease in most of the brain except the telencephalon. For the brain as a whole this decrease amounted to 11%. The regional PS and glucose utilization are known to be coupled and the relationship between these was the same in sham-operated and shunted rats. The decrease in PS observed in shunted rats was commensurate with their lower rates of glucose use; thus, the transport process of glucose from plasma to brain appeared to be unaffected by portacaval shunting.

The metabolic disposition of 14C-ciramadol in humans.

Twelve subjects received single 15 mg oral doses of 14C-ciramadol. Excretion of the dose occurred almost entirely by the renal route (93.5 +/- 11.7 (S.D.)% of the dose), and only 0.7 +/- 0.6% of the dose was recovered in faeces indicating that absorption was essentially complete. More than 90% of the amount recovered in urine was excreted within 24 h after dosing. Unchanged drug accounted for 43.9 +/- 6.5% of the dose, while a phenolic glucuronide conjugate was the only major urinary metabolite accounting for a further 37.9 +/- 7.8%. A second glucuronide that was conjugated with the alicyclic ring was also identified but constituted only 2.3 +/- 0.6% of the dose. Concentrations of radioactivity in plasma reached a peak at 2 h after dosing and declined with a terminal disposition half life of 4.9 h. Only ciramadol and the aryl-O-glucuronide were detected in substantial amounts in plasma. Renal clearance of ciramadol amounted to 298 +/- 54 ml/min suggesting tubular secretion in addition to glomerular filtration.

The disposition of clavulanic acid in man.

Following oral administration of potassium 14C-clavulanate to four human subjects, at least 73% of the radioactive dose was absorbed. The mean absolute bioavailability was 64%. Absorption was rapid with peak plasma concentrations of radioactivity and clavulanic acid (2-6 micrograms/ml) occurring between 45 min and three hours after dosing. Values for the volume of distribution at steady-state and terminal half-life of clavulanic acid in the plasma were 12.01 and 0.8 h respectively. Following intravenous administration of clavulanic acid to the same subjects, the clearance, and volume of distribution at steady-state were 0.21 l/min, and 12.01, respectively. Clavulanic acid was the major radioactive component present in 0-24 h urine following oral dosing (23% of the dose). The two major metabolites were 2,5-dihydro-4-(2-hydroxyethyl)-5-oxo-1H-pyrrole-3-carboxylic acid (15% of the dose) and 1-amino-4-hydroxybutan-2-one (8.8% of the dose). Clavulanic acid and 1-amino-4-hydroxybutan-2-one were the major components in plasma following oral administration (52 and 21% of plasma radioactivity respectively at two hours after dosing). The major route of excretion of radioactivity following oral administration was via the urine (73% of the dose). Most of this radioactivity was excreted in the first 24 h after dosing (68% of the dose). The renal clearance of clavulanic acid was 0.1 l/min. Elimination of radioactivity also occurred via the expired air (17% of the dose) and the faeces (8% of the dose).

Prostaglandin F-2 alpha is transferred from the uterus to the ovary in the sheep by lymphatic and blood vascular pathways.

[3H]Prostaglandin F-2 alpha (PGF-2 alpha) was infused into a uterine lymphatic vessel or a uterine vein for up to 1 h, or injected into the uterine lumen of anaesthetized non-pregnant sheep 7-15 days after oestrus. After an intraluminal injection, labelled PGF-2 alpha was recovered in uterine lymph and peak radioactivity was reached 50 min after injection. [3H]PGF-2 alpha infused at a constant rate into a uterine lymphatic vessel resulted in a maximum concentration of radioactivity in plasma which was 5.6- and 1.7-fold higher in the adjacent utero-ovarian and ovarian vein, respectively, than in carotid arterial plasma. Estimation of the amount of infusate transferred from a lymphatic into ovarian venous blood gave a value (0.4%) similar to that for transfer from a uterine vein (0.3%). Evidence for local transfer was substantiated by the presence of significantly higher concentrations of 3H-labelled compounds in the ovary and corpus luteum adjacent to the site of intra-lymphatic infusion compared with those in the opposite organs. The concentrations in the adjacent ovary and corpus luteum were significantly greater when an intra-lymphatic rather than intra-uterine vein infusion was adopted. The results show that [3H]PGF-2 alpha is transferred locally from uterine lymphatic vessels into the adjacent ovary, corpus luteum and ovarian vein.

Absorption, tissue distribution, and excretion of 3H-labeled arbaprostil in the male rat.

A single dose of arbaprostil-11 beta-3H (4 micrograms/kg) was administered orally to male rats. A maximum plasma radioactivity concentration equivalent to 2.5 to 2.8 nanograms of the prostaglandin per ml was reached at 30 minutes and was maintained until 120 minutes after drug administration. The plasma drug disappearance half-life was 2.6 hours. These results along with data from tissue distribution studies suggested a rapid uptake of radiolabeled arbaprostil by the glandular stomach tissue followed by an apparent zero-order release of drug-related radioactivity from this tissue "reservoir" into the plasma. Drug-related radioactivity was excreted rapidly, with 96 to 99% of the urinary excretion and 82 to 97% of the fecal excretion being completed within 24 hours. A total of 49.6 +/- 3.5% of the orally administered dose was excreted in the urine and 46.7 +/- 3.9% in the feces. No radioactive residues were detected in the animals at the end of the 120 hour specimen collection period. The metabolic stability of the 11 beta-tritium label and the suitability of arbaprostil-3H for use in human studies was demonstrated.

Comparison of the plasma and urinary metabolites of [3H]-econazole nitrate in the monkey and pregnant and non-pregnant rat

Concentrations of total radioactivity, unchanged econazole, and extractable metabolites in plasma, and chromatographic patterns of radioactive components in urine, have been determined after single oral doses of [3H]-econazole nitrate to nonpregnant rats and monkeys (10 mg/kg) and pregnant rats (10 and 50 mg/kg). Plasma3H-concentration-time profiles were qualitatively similar for all groups of rats in that each exhibited two distinct maxima, whereas the corresponding monkey profiles only exhibited a single maximum. Concentrations declined relatively slowly and radioactivity was still detectable at 48 hours (rats) or 120 hours (monkeys). Little or no unchanged econazole was present in the plasma of either species after the lower dose, but notable concentrations were found in pregnant rats receiving the higher dose. Most of the extractable radioactivity in plasma was associated with three metabolites which had suffered oxidative biotransformation in the imidazole ring. Concentrations of these metabolites were generally lower in monkey plasma than in rat plasma. Renal excretion appeared to be a more important route of elimination of the dose for the monkey than for the rat, and although no unchanged econazole was excreted in this way by either species, their patterns of urinary metabolites exhibited several important differences. Thus, monkey urine contained a greater proportion of the glucuronide (or sulphate) conjugates of metabolites which had lost thep-chlorobenzyl group as well as having suffered oxidation of the heterocyclic ring, whereas rat urine contained more of a less polar metabolite tentatively identified as econazole-N-oxide.

Dopamine β-hydroxylase: Determination of half-life and appearance in lymph fluid after IV injection of 125I-DBH into rats

A 4 day half-life of dopamine beta-hydroxylase (DBH) was determined for rats injected IV with 125I-rat DBH from the slow exponential component of radioactivity appearing in plasma, urine, feces and combined urine and feces. Half-life estimates for 125I-rat DBH injected IV into WKY and SHR animals did not differ from Sprague Dawley (Zivic Miller) rats. Radioactivity declined in parallel in plasma, urine and feces following IV 125I-rat DBH administration and each radioactivity falloff curve could be resolved into two components. The slow phase of the decline of radioactivity excreted into urine and feces from which DBH half-life was calculated occurred between 5 and 25 days after 125I-rat DBH injection. The early fast phase which is associated with distribution of the exogenous protein in body fluids and tissues continued for approximately the first 140 hr after DBH injection. The distribution characteristics of IV administered active bovine DBH and 125I-rat DBH into the lymphatic system were examined. After active bovine DBH or 125I-rat DBH was injected IV into rats, active DBH or radioactivity, respectively, appeared in lymph fluid (thoracic duct) within 20 min; reached peak concentrations within 90 min, and thereafter, declined in parallel with the plasma concentration. The concentration of radioactivity in plasma and lymph fluid were found to be unequal at 9 hr but were equivalent 68–75 hrs after IV injection of 125I-rat DBH. Based on the amount of active DBH or radioactivity which accumulates in lymph fluid it is clear that'a substantial amount (> 50%) of the DBH in blood circulates through the lymphatic channels. Analysis of parallel experiments with labelled serum albumin indicate that use of these methods to study plasma proteins do provide sensitive measures of biological half-life and lymphatic distribution characteristics. Specifically for DBH, the results of our study suggest that DBH normally circulates in plasma and lymph fluid with a biological half-life of 4 days.

The absorption and excretion of the peripheral vasodilator 14C-mecinarone, (14C-6809 MD) in rat, dog and man.

Oral doses of the peripheral vasodilator mecinarone (6809 MD), administered as the 14C-compound, were well absorbed from the gastrointestinal tract of rats, dogs and humans. Much of the dose was excreted in 24 by rats and dogs, but more slowly by humans. In 5 days, rats, dogs and humans excreted in the urine and faeces respectively means of 3.3 and 95.9%, 13.2 and 80.3%, and 22.0 and 60.8%. The proportions of radioactivity excreted in urine and faeces after intravenous doses were similar to those after oral doses, means of 3.1 and 85.0% respectively by rats and 16.8 and 78.3% by dogs. Radioactivity present in the faeces was probably mainly excreted in bile; rats (n = 2) excreted a mean of 52.3, 19.8 and 3.9% in bile, faeces and urine after oral doses. Plasma concentrations of radioactivity after oral doses reached a maximum at 1 h in rats (mean 126 ng equiv/ml), at 1 to 2 h in dogs (mean 784 ng equiv/ml) and at 1.5 to 2 h in humans (mean 547 ng equiv/ml. Only a small proportion of this radioactivity (10-30%) represented unchanged drug. When "normalised" for dose/bodyweight differences, those levels were in the ratio 1 : 7 : 32 (rat less than dog less than man). Areas under plasma radioactivity concentration-time curves after oral doses to rats and dogs were about 25% and 53% respectively of those after corresponding intravenous doses. Only about 20% of the radioactivity in the plasma of dogs at 2 min after an intravenous dose represented unchanged drug. These data suggest that 6890 MD was probably rapidly biotransformed in rat, dog and man.

Transplacental stimulation of lung development in the fetal rabbit by 3,5-dimethyl-3'-isopropyl-L-thyronine.

The effect of thyroid hormone on maturation of fetal rabbit lung was studied with maternal treatment using 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT), a synthetic analogue of triiodothyronine. To investigate the in vivo kinetics and distribution of DIMIT, we prepared [3H]DIMIT and injected both pregnant rats (18-21 d gestation) and rabbits (25 d gestation). In the rat, maximal concentrations of radioactivity in maternal plasma, fetal plasma, and amniotic fluid occurred within 10 min, 1-2 h, and 4-6 h, respectively, after intramuscular injection. After 7 h the concentration of radioactivity in fetal plasma was 163 and 71% of the maternal level in rats and rabbits, respectively, indicating that DIMIT readily crosses the placenta. We treated pregnant rabbits for 1-2 d with DIMIT in doses of 0.5-3 mg/kg per d and examined the fetuses at 26 and 27 d gestation. Treatment did not affect fetal growth or viability. In fetal liver, DIMIT increased the activity of NADPH cytochromeac reductase by 64% and decreased the glycogen content by 73% compared to controls. The rate of choline incorporation by lung minces increased in dose-dependent manner to a maximum of +104% at 3 mg/kg DIMIT; this does stimulated by 38% the activity of lung phosphatidic acid phosphatase (PAPase), a corticosteroid-responsive enzyme, but there was no increase in tissue PAPase activity at most lower doses of DIMIT that enhanced choline incorporation. Treated lungs had 38% less glycogen tha controls, but there was no effect on tissue levels of DNA, protein, or phospholipid. DIMIT treatment increased the amount of total phospholipid (+163%). saturated phosphatidylcholine (+330%), and PAPase activity (+134%) in lung lavage fluid. The DIMIT effects on both choline incorporation by lung minces and phospholipid content of lavage fluid were substantially greater than what had occurred with an optimal dose of betamethasone. DIMIT also increased corticosteroid binding capacity in fetal plasma and produced a dose-dependent increase (maximal threefold) in total and free corticoids of both maternal and fetal plasma. It is estimated that elevated endogenous corticoids probably account for less than one-third of the increases in phospholipid synthesis and secretion observed at the higher doses of DIMIT. These data indicate that administration of DIMIT to pregnant rabbits accelertes maturation of the surfactant system in fetal lung. The magnitude of the effects on phospholipid synthesis and secretion, along with the minimal effect of PAPase activity in fetal lung tissue, suggest that thyroid hormones affect different biochemical processes from those influenced by glucocorticoids.

Pharmacokinetics of oral acetylcysteine: absorption, binding and metabolism in patients with respiratory disorders.

The fate of an oral 100 mg dose of 35S-acetylcysteine, a mucolytic agent, was studied in 10 patients with respiratory disorders, 5 of whom underwent pneumonectomy or lobectomy a few hours after administration of the drug. In the 5 nonoperated patients, plasma radioactivity concentrations were maximal after 2 to 3 hours and remained high after 24 hours; about 22% of radioactivity was excreted in urine after 24 hours. In the 5 operated patients, plasma radioactivity concentrations were comparable with those in the nonoperated patients. Lung tissue radioactivity concentrations after 5 hours were comparable with those in plasma, while the presence of small amounts of radioactivity in the bronchial secretions indicates that acetylcysteine passes into the mucus. Total radioactivity after 5 hours consisted of free, unchanged drug and metabolites (about 22% of total in plasma, 48% in lung tissue), unchanged drug bound to protein by means of labile disulphide bridges (about 14% in plasma, 47% in lung tissue), and drug firmly bound to protein (about 64% in plasma, 5% in lung tissue). Oral acetylcysteine is rapidly absorbed and slowly excreted and is available in the lung in an active form for at least 5 hours at high concentrations.

The conversion of [formula omitted]-norgestrel-3-oxime-17-acetate to [formula omitted]-norgestrel in female rhesus monkeys

Single intragastric 0.5 mg/kg doses of 14C- d -norgestrel-3-oxime-17-acetate were given to female rhesus monkeys. Rapid absorption was evidenced by peak concentrations of radioactivity in plasma and whole blood within three hours. A multiphasic decline in concentrations of radioactivity then followed. At three and six hours after drug administration, two major metabolites, d -norgestrel and d -norgestrel-3-oxime, and at least five minor metabolites were detected in plasma fractions containing unconjugated metabolites. These accounted for approximately 40% of the plasma radioactivity. d -Norgestrel was also found in plasma fractions containing conjugated metabolites although the major conjugated biotransformation product was a glucuronide of d -3α,5β-tetrahydronorgestrel, previously shown to be the major metabolite of d-norgestrel in humans and the African green monkey. The presence of d-norgestrel was confirmed by chemical ionization mass spectrometric analysis. No d -norgestrel-17-acetate or d -norgestrel-3-oxime-17-acetate was detected in any plasma specimen. d -Norgestrel-3-oxime-17-acetate thus appears to be a “pro drug” that is rapidly deacetylated to d -norgestrel-3-oxime, which is then hydrolyzed to d -norgestrel. Further metabolism of the d -norgestrel was indicated by comparing the plasma metabolite patterns obtained after administration of either d -norgestrel-3-oxime-17-acetate or d -norgestrel to female rhesus monkeys.

Identification of an N-oxide as the major metabolite of the analgesic O-(diethylaminoethyl)-4-chlorobenzaldoxime hydrochloride in dogs.

1. After oral administration to dogs of the analgesic O-(diethylaminoethyl)-4-chloro[7-14C]benzaldoxime hydrochloride together with piperazine hydrochloride (2:1, w/w), at a dose of 4.5 mg/kg, the radioactivity was well absorbed and rapidly excreted. During 5 days, 81 percent of the dose (ca. 50 percent in 12 h) was excreted in urine and 10 percent in faeces. 2. Rates and routes of excretion of radioactivity were not altered in animals pre-treated with the drug for fourteen days. 3. Peak mean plasma concentrations of radioactivity (5.5 microgram equiv./ml) occurred at 90 min after an oral dose and were higher than those at 2 min following an equivalent intravenous (3.4 microgram equiv./ml) or rectal (4.0 microgram equiv./ml) dose which gave a max. at 45 min. 4. The drug was rapidly and extensively metabolized and no unchanged drug was detected in the plasma or urine. The major urinary metabolite was the N-oxide of the parent compound accounting for 34 percent and 23 percent dose excreted in the urine of males and females respectively during 12 h after administration.

Urinary metabolites and disposition of the antiarrhythmic agent 2′-[2-(diisopropylamino) ethoxy] propylbenzyl alcohol hydrochloride in the rat

An oral dose of 10 mg/kg of the antiarrhythmic drug14C-2′-[2-(diisopropylamino)ethoxy]propylbenzyl alcohol to rats was mainly eliminated within 2 days. During 5 days, means of 62% and 30% of the dose were excreted in the urine and faeces respectively, and less than 1% remained in the carcass. Mean plasma concentrations of radioactivity reached a maximum (0.12% dose/ml) at about 30 min, and parent drug represented less than 15% of the plasma radioactivity at 30 min and could not be detected after 4 hr. After an oral dose, radioactivity was mainly confined to the gastrointestinal tract, liver and kidneys and was not detected in any tissues at 96 hr. After an intravenous dose of 10 mg/kg concentrations were highest in the brain, brown fat, lungs, adrenals, kidneys, liver and salivary glands, and at 4 hr radioactivity could only be detected in the large intestine. Five major radioactive components were detected in rat urine and three metabolites have been identified by mass spectrometry as the products of dealkylation (loss of N-isopropyl and O-diisopropylaminoethyl) and oxidation in the butyl side-chain.

Release and elimination of 14C-fluphenazine enanthate and decanoate esters administered in sesame oil to dogs.

The rates of release of 14C-fluphenazine enanthate and 14C-fluphenazine decanoate were compared in two groups of five male dogs. Each dog was given a single dose (2 mg/kg im) of either the enanthate or decanoate ester in sesame oil. The times required to attain maximum concentrations of radioactivity in plasma were 3.8 +/- 0.5 days (+/-SE) for the enanthate ester and 10.6 +/- 1.1 days for the decanoate ester (p less than 0.001); maximum concentrations of radioactivity in the plasma at these times were 16.7 +/- 1.1 and 11.1 +/- 1.2 ng/ml, respectively (p less than 0.01). However, 35 days after dosing, the concentrations of radioactivity in plasma were greater for the decanoate ester than for the enanthate ester. The times required for 50% of the dose to be excreted in the urine and feces were 7.8 +/- 0.5 days for the enanthate ester and 22.6 +/- 4.4 days for the decanoate ester (p less than 0.05). The total amounts excreted in 35 days were 85.4 +/- 1.8 and 68.8 +/- 6.6% of the dose for the enanthate and decanoate esters, respectively; the average half-times for the rates of release of radioactivity from depot and body, as calculated from the data for total excretion, were 5.55 days for the enanthate ester and 15.4 days for the decanoate ester. Thirty-five days after dosing, the amount of the dose present in the injection site was 4.6 +/- 1.6% for the enanthate ester and 18.6 +/- 5.7% for the decanoate ester. Two groups of six dogs each were protected against the emetic effects of apomorphine more than twice as long by the decanoate ester than by the enanthate ester after the subcutaneous administration of single 8-mg/kg doses of either drug in sesame oil (p less than 0.05). Based on measurements of total radioactivity, it was concluded that the decanoate ester was released from the depot at less than one-half the rate of the enanthate ester.