Metabolism and disposition of a thiazolobenzimidazole active against human immunodeficiency virus-1.

This study was undertaken to evaluate the disposition of the thiazolobenzimidazole, 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole (TZB), which has promising antiviral activity. For mice, the maximum tolerated intravenous dose of TZB was 50 mg/kg. An HPLC procedure developed for TZB was used to determine the distribution of the drug. TZB showed no measurable binding to plasma proteins. With intravenous dosing, the kinetic values for TZB in plasma and in each of five tissues were similar in that there was an initial, short alpha-phase (1.8-7.2 min) and a longer beta phase (38-68 min). The concentrations in liver were higher than those in plasma and other tissues. For mice dosed subcutaneously with TZB, the AUC value for plasma was considerably lower than that for mice dosed intravenously; mice dosed intraperitoneally had higher plasma levels of the drug than after oral or subcutaneous dosing. No intact drug could be detected in the plasma of mice dosed topically. After intravenous, oral, or subcutaneous dosing, urinary excretion of intact TZB was < 2% of the dose. Of several vehicles tested in an attempt to increase the plasma levels of unchanged TZB in mice dosed orally, 40% hydroxypropyl beta-cyclodextrin was most effective. Two metabolites present in plasma and urine of mice were tentatively identified as the axial and equatorial sulfoxide isomers of TZB; a third, minor metabolite, was tentatively designated as the sulfone. Although the compound has activity against HIV-1, its low solubility and extensive metabolism reduce its potential for clinical use.

Disposition and metabolism of carbovir in mice dosed intravenously or orally.

To determine the disposition of carbovir and [3H]carbovir in mice, HPLC and thin-layer chromatographic assays were developed and mice were dosed iv and by gavage. Carbovir had no lethal effect at iv doses up to 500 mg/kg and was stable for 24 hr in mouse plasma at temperatures ranging from 0-37 degrees C. Binding to plasma proteins was minimal. Following an iv dose of 500 mg/kg of carbovir or [3H] carbovir, elimination phases with half-lives of 26-37 min (alpha) and 206-330 min (beta) were observed for plasma. For mice dosed with 27 mg/kg of [3H]carbovir, however, only a single phase with a half-life of 17 min was noted. Of several tissues examined, kidney contained the highest concentration of radioactivity. For the high dose, 19.0 +/- 2.6% was excreted in the urine in 24 hr as unchanged carbovir and 42.2 +/- 2.4% as metabolites; for the low dose, 54.5 +/- 6.1% was excreted as carbovir and 26.5 +/- 5.0% as metabolites. When mice were dosed orally with 500 mg/kg, plasma concentrations of carbovir were low. The initial plasma half-life for carbovir was 69 min; the terminal half-life was 822 min. Urinary excretion of unchanged carbovir was 21.3 +/- 7.1%. These results indicate that clearance of high doses of carbovir is limited and that its absorption is poor after oral dosing.

Disposition of 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine in mice.

Mice 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 of 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.(ABSTRACT TRUNCATED AT 250 WORDS)

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-(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.

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 sucrose octa-isobutyrate in rats, dogs and monkeys.

The disposition of 200 mg/kg of 14C-labelled sucrose octa-isobutyrate (14C-SOIB), a component of sucrose acetate isobutyrate (SAIB), a beverage emulsion stabilizer, was studied in rats, dogs and monkeys. After oral administration of 14C-SOIB to three rats, 3-15% of the dose was excreted as volatile products, 1-2% appeared in urine and 78-93% was recovered in faeces. In dogs, recoveries of radiolabel in CO2, urine and faeces were approximately 1%, less than 2% and 77-94%, respectively. Monkeys excreted the majority of the dose in faeces; less than 2% of the administered radioactivity was eliminated in either CO2 or urine. The biliary excretion of radiolabel from 14C-SOIB was negligible in rats and monkeys; however, in dogs, 3-10% of the dose was excreted into bile. It was demonstrated by chromatographic analyses of faeces that 14C-SOIB was more extensively hydrolysed in the gastro-intestinal tract of rats and dogs than in monkeys. The results indicate that after oral administration, rats and dogs absorb SOIB following hydrolysis of the sugar ester in the gut. The proportion of the dose that is absorbed by the rat is oxidized to CO2. In the dog, little of the absorbed product is oxidized; rather, it is circulated through an enterohepatic pathway. In contrast, in the monkey, SOIB is not detectably hydrolysed in the gut or absorbed. These findings show that there is a species difference in the disposition of SOIB; the most salient findings relate to a difference in the disposition of SOIB in the dog compared with the rat.

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.

Disposition of 9-aminoacridine in rats dosed orally or intravenously and in monkeys dosed topically.

Following administration of [14C]-labeled 9-aminoacridine ([14C]9AA) hydrochloride either orally or intravenously to rats, the excretion of radioactivity was similar, with 20-26% of the dose appearing in the urine and 57-68% in the feces. The pattern of tissue distribution was also similar for the two routes. This information suggests that absorption of the oral doses was extensive and that, for both routes of administration, biliary excretion accounted for most of the radioactivity in the feces. Biliary excretion of radioactivity derived from [14C]9AA was confirmed in an experiment involving rats with inserted biliary cannulas. For these rats, 49.5% of the dose administered appeared in the bile in 4 h. The major urinary and biliary metabolite of [14C]9AA of rats was identified as an O-beta-glucuronide of hydroxylated 9AA. Absorption of 9AA through the skin could not be conclusively demonstrated. For monkeys dosed topically with [14C]9AA, only small amounts of radioactivity (a total of less than 0.8% of the dose) appeared in the urine and various tissues in 24 h.

Disposition of 2-mercaptobenzimidazole in rats dosed orally or intravenously.

The disposition of [14C]-labeled 2-mercaptobenzimidazole (MBI) in male Fischer-344 rats dosed orally (49 or 0.5 mg/kg) or intravenously (0.5 mg/kg) was determined. Absorption of the oral dose was evident, since, in 72 h, most of the radioactivity administered by either route appeared in the urine. Smaller amounts appeared in the feces. In 4 h, 12% of the radioactivity from an intravenous dose of 0.5 mg/kg was excreted in the bile of rats with biliary cannulas. For rats dosed intravenously, the half-life for disappearance of unchanged MBI from plasma was 125 min. In contrast, the terminal half-life for loss of radioactivity from blood was 83 h. The concentration of total radioactivity was higher in liver and kidney tissue than in blood. One of the major urinary metabolites was identified as benzimidazole, and a minor component was tentatively identified as unchanged MBI. Neither of these could be detected in bile.

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.

Disposition of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-phosphate in mice and dogs.

The metabolic disposition of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-phosphate (2-F-araAMP) has been studied in mice and dogs after iv administration. Following injection of 40 mg/m2 into mice, serum levels of 2-F-araAMP fell, with apparent half-lives of 0.7 mins for the alpha phase and 21 mins for the beta phase. Rapid dephosphorylation of the compound resulted in high levels of the nucleoside, 9-beta-D-arabinofuranosyl-2-fluoroadenine (2-F-araA), which disappeared from serum in two phases, with half-lives of 31 and 114 mins. 9-beta-D-Arabinofuranosyl-2-fluorohypoxanthine (2-F-araHx) was also present in serum. After administration of 500 mg/m2 of 2-F-araAMP to mice, the apparent half-lives for the parent compound were 2.5 and 27 mins. Serum levels of 2-F-araA fell, with apparent half-lives of 36 and 185 mins. Tissue distribution studies revealed that, in mice administered 40 mg/m2, the liver, kidney, and spleen contained the highest levels of 2-F-araAMP. For most tissues, elimination of 2-F-araAMP occurred exponentially but at a slower rate than in serum. As in serum, the major tissue metabolite was 2-F-araA; other metabolites identified were 2-F-araHx, 2-fluoroadenine (2-F-A), and polyphosphorylated derivatives of 2-F-araA. In mice dosed with 500 mg/m2, the tissue distribution of metabolites was similar, but the levels were about tenfold higher. With both doses, 2-F-araAMP, 2-F-araA, and 2-F-araHx were recovered in urine. In dogs administered 40 mg/m2, serum levels of 2-F-araAMP fell rapidly in an initial phase of 5 mins and in a second phase of 30 mins. As in mice, the major serum metabolite was 2-F-araA, which disappeared in two phases of 16 and 97 mins. After administration of 500 mg/m2 to dogs, the apparent half-lives for 2-F-araAMP in serum were 9 and 51 mins. For 2-F-araA, a single phase of disappearance of 89 mins was evident. In dog serum, as compared with mouse serum, a greater percentage of the administered compound was metabolized to 2-F-araHx. During 24 hrs following administration of either 40 or 500 mg/m2 of 2-F-araAMP to dogs, less than 2% of the dose was excreted in urine as unchanged drug. Approximately equal percentages of 2-F-araA and 2-F-araHx were recovered in urine after both doses. The levels of 2-F-A in urine comprised about 2% of the radioactivity after administration of either the low or the high dose. The studies demonstrate that 2-F-araAMP undergoes rapid dephosphorylation in both mice and dogs. Deamination of the dephosphorylated product is more rapid in dogs than in mice.

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.

Identification of metabolites of 9-beta-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 indicine N-oxide in mice and monkeys.

The disposition of tritium-labeled indicine N-oxide (INO) was evaluated in mice and rhesus monkeys. Disappearance of INO from the serum of BDF1 mice given iv doses of 100 or 500 mg/kg occurred with an initial half-life of about 11 mins followed by a second phase greater than 100 mins. At 2 hrs after iv injection of mice, the highest concentrations of INO were present in kidney, liver, and intestine. In CDF1 mice bearing P388 leukemia cells and injected ip with a dose of 500 mg/kg, INO was found, in equal concentrations, in cells of the parent line, which is resistant to INO, and in cells of a line resistant to cyclophosphamide but sensitive to INO. Serum levels of INO in these mice decreased with an initial half-life of about 20 mins. For monkeys given iv doses of 24, 2.4 of 0.24 mg/kg, INO disappeared from the serum in three phases, with average half-lives of 3, 32, and 180 mins, respectively. Half-lives for the two observed phases of urinary excretion were 40 and 240 mins. In 24 hrs, both mice and monkeys excreted greater than 80% of the doses unchanged.

Disposition of thymidine administered as large doses to rats and mice.

Blood and urine levels of thymidine and its catabolic product, thymine, have been determined for mice and rats given a single large dose of thymidine and for rats during and after infusion of large amounts of this drug. For mice given a bolus dose (400 mg/kg, 1.2 g/m2), two phases of elimination of thymidine from blood were evident, an initial phase (half-life = 4 mins) and a longer second phase (half-life = 17 mins). The initial (2-min) level in blood was 2.8 mM. For rats given an equivalent dose (150 mg/kg, 1.2 g/m2), three phases with half-lives of 2, 29, and 365 mins were observed. The initial (5-min) concentration in the blood was 0.6 mM. More of a dose of [2-14C]thymidine was converted to CO2 by rats than by mice. For both species, small amounts of radioactivity from this labeled compound became associated with macromolecules of the small intestine. Following infusion of rats with thymidine at rates of 300 and 600 mg/kg/hr for 24 hrs (60 and 120 g/m2, respectively), steady-state blood levels were approximately 0.7 and 1.5 mM, respectively. When the infusions were stopped, a phase with a half-life of 35 mins and a longer phase of indeterminate length were noted for each dose. Elimination of metabolically formed thymine from the blood of rats and excretion into the urine was mediated by a process that was apparently saturated.

Disposition of 5-methyltetrahydrohomofolate and methotrexate in rats.

The pharmacologic disposition of [methyl-14C]5-methyltetrahydrohomofolate (MTHHF) and [3H]methotrexate (MTX) has been studied in rats after iv doses of 25 mg/kg. Thin-layer chromatography and high-pressure liquid chromatography were used to separate the parent compounds from possible products. In rat serum, levels of MTHHF decreased with half-lives of 7 and 55 mins; for MTX, the corresponding values of half-lives were 14 and 54 mins. No metabolites of MTHHF or MTX were found in the samples assayed. At 3, 6, and 24 hrs after administration of MTHHF or MTX, liver, kidney, and small intestine contained concentrations of the drugs greater than those in serum. In rats with cannulated bile ducts, 16% of 60% of the doses of MTHHF and MTX, respectively, were excreted in the bile within 4 hrs. In 24 hrs, 51% of the dose of MTHHF and 41% of the dose of MTX were excreted in the urine of rats without bile cannulas. During the same time, fecal excretion accounted for 21% of the dose of MTHHF and 17% of the dose of MTX. The data indicate that enterohepatic circulation is probably extensive for MTX but less so for MTHHF.

Disposition of 9-beta-D-arabinofuranosyl-2-fluoroadenine in mice, dogs, and monkeys.

The metabolic disposition of 9-beta-D-arabinofuranosyl-2-fluoroadenine (2-F-AraA) has been studied in mice, dogs, and monkeys after iv administration. Following injection of 2-F-AraA (30 mg/m2) into mice, serum levels fell with apparent half-lives of 17 min for the alpha-phase and 72 min for the beta-phase. For dogs given the same dose, these values were less than 5 and 112 min, and, for monkeys, 26 and 125 min, respectively. A higher concentration of metabolites was present in the serum of dogs than in the serum of mice and monkeys. Phosphorylated derivatives of 2-F-AraA were present in each of several mouse tissues examined; liver contained the highest concentration. In 24 hr, mice excreted more than half of the administered compound in the urine as unchanged 2-F-AraA. For dogs given a dose of 400 mg/m2, a single phase of disappearance of the drug (t1/2 = 130 min) was observed. For a single monkey, there were two phases, with half-lives of 15 min and 6.7 hr. In the urine, monkeys excreted about half of either dose as parent compound; but dogs excreted only about one-fourth as unchanged drug. These data indicate that 2-F-AraA is extensively metabolized by dogs but less so by mice and monkeys.