Salah M. El Dareer

Disposition of decabromobiphenyl ether in rats dosed intravenously or by feeding

The disposition of 14C-labeled decabromobiphenyl ether (DBBE) in male Fischer rats dosed by feeding (0.025-5.0% of the diet) or intravenously (1 mg/kg) was determined. For rats dosed by feeding, intestinal absorption of DBBE was evident in that the intact compound was present in extracts of liver. For these rats, the size of the liver increased with increasing concentration of DBBE in the diet. Liver contained a maximum of 0.449% of the administered radioactivity at 24 h after feeding rats a diet containing 0.0277% [14C]DBBE; no other organ or tissue contained more than 0.26%. The total amount of radioactivity found in tissues was less than 1% of the dose. Of the radioactivity recovered in the feeding experiments, more than 99% was in the feces and gut contents at 72 h; a maximum of 0.012% of the dose was in the urine. In the feces of rats fed [14C]DBBE, there were three metabolites, which together comprised 1.5-27.9% of the radioactivity. Since absorption was minimal, most of the metabolism of [14C]DBBE apparently took place in the gastrointestinal tract. The metabolites increased in percent of total radioactivity with the content of DBBE in the diet, an indication that enzyme induction in intestinal bacteria may have occurred at the higher doses. More extensive metabolism of [14C]DBBE occurred after intravenous administration; only 37% of the radioactivity in the feces was unchanged DBBE. At 72 h after dosing, fecal excretion accounted for 70% of the dose; only 0.129% appeared in the urine. Muscle retained 12.9% and skin 7.25% of the radioactivity administered. In 4 h, rats with biliary cannulas excreted in the bile 7.17% of the intravenously administered radioactivity; less than 1% was excreted as intact DBBE. Biliary excretion was apparently the major route for elimination of the intravenously administered compound. The rapid excretion and extensive metabolism of DBBE, relative to other polyhalogenated compounds, are advantageous properties that may allow it to be used in place of structurally similar compounds presently employed in industrial applications.

Disposition of 2‐hydroxy‐4‐methoxybenzophenone in rats dosed orally, intravenously, or topically

Administration to rats of oral doses of [14C]-2-hydroxy-4-methoxybenzophenone (HMB) in the range of 3.01-2570 mg/kg revealed that a dose-dependent elimination process was operative at the highest dose. Urinary excretion (63.9-72.9% of the dose in 72 h) was the major route for elimination of radioactivity. An intravenous dose (4.63 mg/kg) distributed rapidly throughout the body of rats and appeared in the urine in an amount (67.4%) similar to those for the oral doses. Rats absorbed large portions of doses of [14C]HMB administered topically, either as an ethanolic solution (50, 200, or 800 micrograms/rat) or formulated in a lotion (50 micrograms/rat). For rats with biliary cannulas, 36.6% of the radioactivity of an intravenous dose (4.46 mg/kg) appeared in the bile in 4 h; the initial half-life for biliary elimination was 40 min. In the bile, at least five radioactive components, none of which was intact HMB, were present. The two major components were glucuronides of HMB and demethylated HMB, and a third was probably a sulfate ester of hydroxylated HMB. In urine, there were nine radioactive components, two of which were unchanged HMB and its glucuronide.

Identification of metabolites of 9-β-d-arabinofuranosyl-2-fluoroadenine, an antitumor and antiviral agent

Analysis of blood from a dog given a 400 mg/m2 dose of 9-beta-D-arabinofuranosyl-2-fluoroadenine (2-F-araA) led to the identification of parent drug and a major metabolite, 9-beta-D-arabinofuranosyl-2-fluorohypoxanthine. 2-Fluoroadenine, a toxic derivative of 2-F-araA, was not detected in blood within the limits of detection, suggesting that parent drug was absorbed and distributed without systemic exposure to this toxic derivative. Parent drug, 2-fluoroadenine, and 9-beta-D-arabinofuranosyl-2-fluorohypoxanthine were identified in urine of dog, monkey, and mouse.

Disposition of 2-mercaptobenzothiazole and 2-mercaptobenzothiazole disulfide in rats dosed intravenously, orally, and topically and in guinea pigs dosed topically

To determine the metabolic disposition of [14C]-2-mercaptobenzothiazole (MBT) and [14C]-2-mercaptobenzothiazole disulfide (MBTS), male and female rats were dosed topically. Topical doses were 36.1 micrograms/animal for [14C]MBT and 33.6 micrograms/animal for [14C]MBTS. Although more MBT passed through the skin than MBTS and although, relative to rats, guinea pigs absorbed a greater percentage of the dose (33.4% compared to 16.1-17.5% of the MBT and 12.2% compared to 5.94-7.87% for MBTS), the disposition of radioactivity derived from the two compounds was similar. Washing of the skin removed more of the radioactivity from guinea pigs than from rats. For both sexes of rats dosed intravenously with [14C]MBT (0.602 mg/kg) or [14C]MBTS (0.571 mg/kg), disposition of the compounds was similar. In 72 h, 90.9-101% of the dose appeared in the urine and 3.79-15.1% in the feces. At this time, a small portion of the administered radioactivity (1.52-1.96% of the dose) remained associated with erythrocytes. Oral dosing of rats for 14 d with unlabeled MBT (0.510 mg/kg.d) prior to a single dose of [14C]MBT (0.503 mg/kg) or with unlabeled MBTS (0.521 mg/kg.d) prior to a single dose of [14C]MBTS (0.730 mg/kg). For both sexes, disposition of the compounds was similar. At 96 h after dosing, a small portion of the administered radioactivity (1.20-1.69% of the dose) remained associated with erythrocytes, most of which was bound to the membranes. For both compounds and sexes, 60.8-101% of the radioactivity administered appeared in the urine and 3.46-9.99% in the feces in 96 h. At the time, only trace amounts of radioactivity remained in tissues other than blood. Of these tissues, thyroid contained the highest concentration. In the urine, there was a detectable MBT or MBTS, but there were two metabolites, one of which was identified as a thioglucuronide derivative of MBT. The other was possibly a sulfonic acid derivative of MBT. In conclusion, there were similarities in absorption, distribution, and metabolism of [14C]MBT and [14C]MBTS in rats and in guinea pigs, indicating that [14C]MBTS was readily converted to [14C]MBT.

Disposition of 2′, 3′-dideoxyadenosine and 2′, 3′-dideoxyinosine in mice

SummaryMice were dosed with [3H]2′,3′-dideoxyadenosine ([3H]ddA) in three procedures: intravenously, intraperitoneally, and interperitoneally following a dose of 2′ -deoxycoformycin (dCF). For mice dosed intravenously, the content of radioactivity in plasma and tissue samples were essentially constant after 30 min. Of the radioactivity in plasma and brain samples collected between 30 min and 24 hr, more than 94% was present as 3H2O, indicating that most of the tritium from [3H]ddA had exchanged with water. No intact ddA was detected, and the deamination product, 2′,3′ -dideoxyinosine (ddI), was present only transiently. In the urine, the major radioactive material was [3H]ddI. Also detected were 3H2O and small amounts of [3H]hypoxanthine and [3H]ddA. Following intraperitoneal doses to mice, levels of radioactivity in plasma, liver, and kidney increased to a maximum by 15–30 min after dosing but dropped to essentially constant levels thereafter, again indicating that the tritium had exchanged with water. At 5, 15, and 30 min after dosing, ddI was the major radioactive component in plasma. Only small amounts of ddA were present. When dCF was administered 24 hr prior to intraperitoneal [3H]ddA, levels of radioactivity in plasma, liver, and kidney reached a maximum at 30 to 60 min after dosing and decreased to essentially constant levels thereafter. The dCF transiently inhibited the deamination of ddA to ddI, since, in plasma, [3H]ddA was the main radioactive component at 5 and 15 min after dosing. Comparison of HPLC assays based on radioactivity detection and UV absorbance showed that they were equivalent for measuring ddA and ddI in samples derived from dosed mice. Therefore, exchange of tritium must have occurred at a metabolic step beyond ddI.For mice dosed intravenously and orally with unlabeled ddI, there was evidence of a saturated process. Nevertheless, for the high and low intravenous doses of ddI, the percent of dose excreted in the urine as unchanged drug was the same.

Some biochemical characteristics of L1210 cell lines resistant to 6-mercaptopurine and 6-thioguanine and with increased sensitivity to methotrexate.

L1210 cells resistant to 6MP and 6TG exhibit increased sensitivity to MTX compared to the parent line. The differential response of parent and purine analog-resistant cell lines to MTX is not due to host influences, for both L1210/6MP and L1210/6TG cell lines are cross-resistant to 6-MeMPR, an inhibitor of de novo synthesis, and cultured L1210/6MP cells are more sensitive to MTX than the parent cell line. Following treatment of tumor-bearing mice with MTX, the drug concentration in L1210/6TG cells was about 50% greater than in L1210/0 cells for 24 hr and may account, wholly or in part, for the increased sensitivity of the L1210/6TG cell line to MTX. L1210/6MP cells, however, accumulated less MTX than L1210/0 cells, indicating that an equivalent mechanism is not operative in these cells. DHFR activity in L1210/6TG cells was the same as that in L1210/0 cells, but activity in L1210/6MP cells was lower by 60%. Cultured L1210/6MP cells also exhibited a deficiency in DHFR activity as compared to the parent cell line. The sensitivity of the enzyme to MTX was the same for all three cell lines propagated in vivo. Therefore, the increased sensitivity of the L1210/6MP cell line to MTX may be due, in part, to decreased DHFR activity. Significantly lower levels of GTP + GDP and CTP in 6TG-resistant cells than in parent cells 4 hr after the administration of MTX to tumor-bearing mice may be related to the increased MTX sensitivity of these cells. Our results indicate that the observed alterations in drug sensitivity are associated with more than one biochemical change and that these changes are different in the two purine analog-resistant cell lines.

Disposition of 2‐(2‐quinolyl)‐1,3‐indandione (d. c. yellow #11) in rats dosed orally or intravenously

The disposition of 2-(2-quinolyl)-1,3-indandione (D. C. yellow #11, DCY) in male Fischer rats dosed intravenously or by feeding was determined. For rats given [14C]DCY in the feed (0.00044-0.41% of the diet), recovery of radioactivity during the 24-h dosing period and the 72-h period thereafter ranged from 89.1 to 93.9% for feces and from 4.98 to 6.25 for urine. Tissues contained only trace amounts. Following intravenous dosing with [14C]DCY (0.93 mg/kg), radioactivity distributed readily into most tissues; maximum amounts were present at 5 min, the earliest time of assay. Maximum amounts of radioactivity in fat, skin, and gut tissue, however, were present at 30 min after dosing. These three tissues also had relatively long alpha phases for the elimination of radioactivity. In 24 h after intravenous dosing, rats excreted 81.1% of the dose in the feces and 16.0% of the dose in the urine. For rats fitted with biliary cannulas, 54.5% of the dose, all of which was metabolites of [14C]DCY, was recovered in the bile in 4 h. Associated with the rapid and extensive biliary excretion of metabolites of intravenously administered [14C]DCY was the appearance of large amounts of radioactivity in the feces and also, at intermediate time points, in the liver, gut contents, and gut tissue. In conclusion, rats rapidly distribute, metabolize, and excrete [14C]DCY.

Investigations on the basis for the differential toxicity of hexachlorocyclopentadiene administered to rats by various routes

The differential disposition of hexachlorocyclopentadiene (HCCP) following oral administration, as contrasted to inhalation or intravenous administration, may account for its lower toxicity by this route. Following an intravenous dose of [14C]HCCP to rats at 0.59 mg/kg, 39.0% of the radioactivity remained in the tissues at 72 h; after inhalation of vapors of [14C]HCCP (1.3-1.8 mg/kg), this amount was 11.5%. After oral doses of 4.1 or 61 mg/kg, however, the amount was only 2.4%. No detectable amount of intact HCCP was present in the lungs or kidneys of rats exposed to the chemical by inhalation, and only about 1% was converted to CO2, regardless of the route of administration. The chemical reactivity of HCCP with biological materials was evident in in vitro experiments, in which HCCP became bound to components of whole blood, plasma, liver homogenates, fecal homogenates, and intestinal contents. Thus, the lower toxicity of oral doses of HCCP may be related to its reaction with intestinal contents and its lack of absorption into tissues, in substantial amounts, as the intact, reactive form.