Excretion Of Dose Research Articles

Disposition of orally administered atuliflapon, a novel 5-lipoxygenase-activating protein inhibitor in healthy participants.

In this study, the mass balance, pharmacokinetics (PK) and metabolism of atuliflapon, a novel 5-lipoxygenase-activating protein inhibitor, were investigated in healthy male subjects. A single oral dose of 200 mg [14C]atuliflapon suspension was administered to six healthy male subjects. Mass balance, PK and metabolite profiles of atuliflapon were analyzed using radioactivity monitoring and liquid chromatography with mass spectrometry analysis. The safety of atuliflapon was assessed during the study. Atuliflapon was rapidly absorbed with a median tmax of 1.5 h, followed by a biphasic decline in plasma exposure rendering a terminal half-life of ~20 h. Unchanged atuliflapon was the predominant radioactive component in plasma, accounting for 40.1% of the total drug-related exposure (DRE), while a direct N-glucuronide was the only metabolite exceeding 10% of DRE, accounting for 20.9%. Renal excretion of intact atuliflapon accounted for <1% of the administered dose. In total 85.2% of administered radioactivity was recovered over 312 h with 79.3% and 5.9% in feces and urine, respectively. Parent atuliflapon contributed to approximately 40% of the recovered dose in excreta, while metabolites resulting from phase 1 oxidative pathways accounted for more than 30% of the excreted dose. Overall, a single oral dose of 200 mg [14C]atuliflapon suspension was well tolerated in healthy male subjects. The human metabolism and disposition data obtained will support future development and submissions of atuliflapon as a potential candidate drug for the treatment of cardiovascular, cardiorenal, and respiratory indications.

A Phase I Study To Determine the Absolute Bioavailability and Absorption, Distribution, Metabolism, and Excretion of Capivasertib in Healthy Male Participants.

An open-label, single-center, phase I study was conducted to determine the absolute bioavailability and absorption, distribution, metabolism, and excretion of capivasertib-a potent, selective AKT serine/threonine kinase inhibitor-in healthy males. In part 1, six participants received a single oral dose of capivasertib (400 mg; tablets) followed by a [14C]-radiolabeled intravenous microdose of capivasertib (100 μg). After a 14-day washout, five of the participants proceeded to part 2 and received a single oral dose of [14C]capivasertib (400 mg; solution). In part 1, median time of maximum observed concentration for capivasertib was 1.7 hours, geometric mean terminal elimination half-life was 12.9 hours, and absolute bioavailability was estimated at 28.6% (90% confidence interval, 23.9 to 34.2). In part 2, a high proportion of the administered radioactivity was recovered over the 168-hour sampling period [mean recovery: 95.1% (feces, 50.4%; urine, 44.7%)]. Unchanged capivasertib in urine accounted for 7.4% of the total dose and 21.1% of the systemically available drug. Geometric mean renal clearance was 8.3 L/h, suggesting active tubular secretion. Twelve metabolites were identified in plasma. M11 (AZ14102143)-the glucuronide conjugate of capivasertib, inactive as an AKT serine/threonine kinase inhibitor-was the most abundant, accounting for a mean 78.4% of the plasma drug-related area under the curve. Of 22 metabolites identified in excreta, M11 was the most abundant (mean 28.2% of administered dose), indicating direct glucuronidation as one of the major routes of metabolism. No new safety concerns were identified. SIGNIFICANCE STATEMENT: This study provides characterization of the pharmacokinetics of capivasertib-a potent, selective AKT serine/threonine kinase (AKT) inhibitor-including absolute bioavailability, mass balance, and metabolic fate in humans; the findings are being used to inform further clinical development. Absolute bioavailability was estimated at 28.6%, and mean recovery of the administered dose in excreta over 168 hours was 95.1%. M11 (AZ14102143)-the glucuronide conjugate, inactive as an AKT inhibitor-was the most abundant identified metabolite in plasma and excreta.

Pharmacokinetics, metabolism, and excretion of licogliflozin, a dual inhibitor of SGLT1/2, in rats, dogs, and humans

Absorption, metabolism, and excretion (AME) of licogliflozin, a sodium-glucose co-transporters (SGLTs) 1 and 2 inhibitor, were studied in male rats, dogs, and healthy male volunteers and reported. Oral absorption of licogliflozin was rapid (t max < 1 h) with absorption estimated at 87%, 100% and 77% in rats, dogs and humans, respectively. Excretion of licogliflozin-related radioactivity was rapid and nearly complete following oral administration with total radioactivity recovery ranging from 73% in dogs, 92.5% in humans, to 100% in rats. Dose-related radioactivity was excreted in both urine and faeces with urinary excretion playing a slightly more important role in humans (∼56%) than in animal species (∼19–41%). Elimination of licogliflozin was predominantly via metabolism with the majority of the radioactivity dose (∼54–74%) excreted as metabolites across species. The principal biotransformation pathways involved direct glucuronidation and oxidation across all species. In humans, direct glucuronidation to M17 and M27 was the major pathway observed, accounting for ∼38% of the dose in excreta while oxidative metabolism also contributed to >29% of the dose in excreta. Oxidative pathways were predominant in animal species.

Correlation of the in vitro biotransformation of H3B-6527 in dog and human hepatocytes with the in vivo metabolic profile of 14C-H3B-6527 in a dog mass balance study

1. H3B-6527 is an orally available covalent small molecule inhibitor of FGFR4 undergoing evaluation in adults with hepatocellular carcinoma. Absorption, metabolism, transport and elimination of H3B-6527 were investigated in vitro and in a 14C-H3B-6527 beagle dog mass balance study.2. Following intravenous dosing in dogs, unchanged 14C-H3B-6527 represents only 1.6% of the total dose in excreta. The low amount of radioactivity in the dog urine (4.9% of the administered dose), suggests that renal elimination is a minor pathway of clearance for H3B-6527. A majority of the radioactivity was observed in the feces up to 5 days after dose administration, suggesting that drug-related material was secreted in the bile, and that H3B-6527 clearance was mostly driven by metabolism.3. In vitro, H3B-6527 is a substrate of GSTs, CYP3A and P-glycoprotein.4. The major pathways of metabolism were similar in human and dog hepatocytes, and occurred via glutathione (GSH) conjugations and sequential hydrolysis, N-deethylation and hydroxylation.5. The metabolic profile of H3B-6527 was qualitatively similar in dog hepatocytes and plasma/excreta.Trial registration: ClinicalTrials.gov identifier: NCT02834780.

Metabolic Disposition of [Women 14 C] Ulipristal Acetate in Healthy Premenopausal

Introduction: Ulipristal acetate (UPA) is a novel selective progesterone receptor modulator for the treatment of benign gynaecological conditions such as uterine myoma. The disposition of [ 14 C] UPA was determined in five healthy premenopausal women after administration of a single oral dose of 20 mg (59 μCi). Materials and Methods: The single dose study allocated 5 healthy women of reproductive age to receive a single radio labelled dose of 20 mg (59 μCi) UPA. After dosing, blood, plasma, urine and faecal samples were collected for up to 11 days and analysed for concentrations of radioactivity. UPA metabolite profiles in plasma were determined by high-performance liquid chromatography with radioactivity flow detection; metabolite structures were confirmed by liquid chromatography-mass spectrometry. Results: UPA was rapidly absorbed, exhibiting a mean peak plasma concentration of 141 ng/mL at 0.7 hours post-dose. Plasma radioactivity maxima were observed 0.9 hours post-dose at 281ng equivalents/mL. The total mean recovery of the radioactive dose in excreta was 78.8%, with the majority recovered in faeces (72.5%) and only a small fraction (6.4%) in urine. UPA was extensively metabolised. Radio-chromatograms of plasma revealed that oxidative demethylation was the major metabolic pathway, most likely via cytochrome P450 isoenzyme3A4. At peak plasma radioactivity, the majority of circulating radioactivity was constituted by parent (58.0%), N-monodemethylated UPA (PGL4002 (20.5%)) and N-didemethylated UPA (PGL4004) eluting together with PGL4002+2H (8.3%). Unchanged UPA was not present in faeces, but PGL4002, hydroxylated PGL4004 and UPA +2H, UPA +2O -2H, as well as acetylated or glucuronidated UPA were identified. Conclusion: After oral administration in healthy premenopausal women, UPA was rapidly absorbed, extensively metabolized via oxidative demethylation, and excreted predominantly in faeces.

Clinical disposition, metabolism and in vitro drug–drug interaction properties of omadacycline

1. Absorption, distribution, metabolism, transport and elimination properties of omadacycline, an aminomethylcycline antibiotic, were investigated in vitro and in a study in healthy male subjects.2. Omadacycline was metabolically stable in human liver microsomes and hepatocytes and did not inhibit or induce any of the nine cytochrome P450 or five transporters tested. Omadacycline was a substrate of P-glycoprotein, but not of the other transporters.3. Omadacycline metabolic stability was confirmed in six healthy male subjects who received a single 300 mg oral dose of [14C]-omadacycline (36.6 μCi). Absorption was rapid with peak radioactivity (∼610 ngEq/mL) between 1–4 h in plasma or blood. The AUClast of plasma radioactivity (only quantifiable to 8 h due to low radioactivity) was 3096 ngEq h/mL and apparent terminal half-life was 11.1 h. Unchanged omadacycline reached peak plasma concentrations (∼563 ng/mL) between 1–4 h. Apparent plasma half-life was 17.6 h with biphasic elimination. Plasma exposure (AUCinf) averaged 9418 ng h/mL, with high clearance (CL/F, 32.8 L/h) and volume of distribution (Vz/F 828 L). No plasma metabolites were observed.4. Radioactivity recovery of the administered dose in excreta was complete (>95%); renal and fecal elimination were 14.4% and 81.1%, respectively. No metabolites were observed in urine or feces, only the omadacycline C4-epimer.

Pharmacokinetics, metabolism and excretion of [14C]-lanicemine (AZD6765), a novel low-trapping N-methyl-d-aspartic acid receptor channel blocker, in healthy subjects

1. (1S)-1-phenyl-2-(pyridin-2-yl)ethanamine (lanicemine; AZD6765) is a low-trapping N-methyl-d-aspartate (NMDA) channel blocker that has been studied as an adjunctive treatment in major depressive disorder. The metabolism and disposition of lanicemine was determined in six healthy male subjects after a single intravenous infusion dose of 150 mg [14C]-lanicemine.2. Blood, urine and feces were collected from all subjects. The ratios of Cmax and AUC(0–∞) of lanicemine to plasma total radioactivity were 84 and 66%, respectively, indicating that lanicemine was the major circulating component with T1/2 at 16 h. The plasma clearance of lanicemine was 8.3 L/h, revealing that lanicemine is a low-clearance compound. The mean recovery of radioactivity from urine was 93.8% of radioactive dose.3. In urine samples, 10 metabolites of lanicemine were identified. Among which, an O-glucuronide conjugate (M1) was the most abundant metabolite (∼11% of the dose in excreta). In plasma, the circulatory metabolites were identified as a para-hydroxylated metabolite (M1), an O-glucuronide (M2), an N-carbamoyl glucuronide (M3) and an N-acetylated metabolite (M6). The average amount of each of metabolite was less than 4% of total radioactivity detected in plasma or urine.4. In conclusion, lanicemine is a low-clearance compound. The unchanged drug and metabolites are predominantly eliminated via urinary excretion.

Pharmacokinetics, Metabolism, and Excretion of the Antidiabetic Agent Ertugliflozin (PF-04971729) in Healthy Male Subjects

The disposition of ertugliflozin (PF-04971729), an orally active selective inhibitor of the sodium-dependent glucose cotransporter 2, was studied after a single 25-mg oral dose of [(14)C]-ertugliflozin to healthy human subjects. Mass balance was achieved with approximately 91% of the administered dose recovered in urine and feces. The total administered radioactivity excreted in feces and urine was 40.9% and 50.2%, respectively. The absorption of ertugliflozin in humans was rapid with a T(max) at ∼1.0 hour. Of the total radioactivity excreted in feces and urine, unchanged ertugliflozin collectively accounted for ∼35.3% of the dose, suggestive of moderate metabolic elimination in humans. The principal biotransformation pathway involved glucuronidation of the glycoside hydroxyl groups to yield three regioisomeric metabolites, M4a, M4b, and M4c (∼39.3% of the dose in urine), of which M4c was the major regioisomer (∼31.7% of the dose). The structure of M4a and M4c were confirmed to be ertugliflozin -4-O-β- and -3-O-β-glucuronide, respectively, via comparison of the HPLC retention time and mass spectra with authentic standards. A minor metabolic fate involved oxidation by cytochrome P450 to yield monohydroxylated metabolites M1 and M3 and des-ethyl ertugliflozin (M2), which accounted for ∼5.2% of the dose in excreta. In plasma, unchanged ertugliflozin and the corresponding 4-O-β- (M4a) and 3-O-β- (M4c) glucuronides were the principal components, which accounted for 49.9, 12.2, and 24.1% of the circulating radioactivity. Overall, these data suggest that ertugliflozin is well absorbed in humans, and eliminated largely via glucuronidation.

Pharmacokinetics and metabolism of [14C]anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in humans

1. The disposition of anagliptin, an orally active, highly selective dipeptidyl peptidase-4 inhibitor, was investigated after a single oral dose of 100 mg/1.92 MBq [14C]anagliptin to six healthy men. Almost all the dose (98.2%) was recovered within 168 h: 73.2% in urine and 25.0% in faeces.2. Anagliptin was rapidly absorbed, with peak plasma concentrations of unchanged drug attained at a mean time of 1.8-h postdose. Mean fraction of the dose absorbed was >73%. Unchanged drug and a carboxylate metabolite (M1) were the major components in plasma, accounting for 66.0 and 23.4% of total plasma radioactivity area under the curve, respectively.3. Anagliptin was incompletely metabolized, with about 50% dose eliminated as unchanged drug (46.6% in urine and 4.1% in faeces). Metabolism to M1 accounted for 29.2% of the dose. No other metabolite accounted for >1% dose in excreta or yielded measurable systemic exposure. Terminal half-life of anagliptin and M1 was 4.37 and 9.88 h, respectively. Renal clearance of unbound anagliptin and unbound M1 far exceeded glomerular filtration rate, indicating active renal elimination: that might reflect the fact that anagliptin may be a substrate of OAT1, OAT3, MDR1 and MRP2, and M1 a substrate of OAT3, BCRP, MRP2 and MRP4.

Disposition and Metabolism of LY2452473, a Selective Androgen Receptor Modulator, in Humans

The disposition and metabolism of isopropyl N-[(2S)-7-cyano-4-(2-pyridylmethyl)-2,3-dihydro-1H-cyclopenta[b]indol-2-yl]carbamate (LY2452473; a selective androgen receptor modulator) in humans was characterized after a single 15-mg (100 μCi) oral dose of [¹⁴C]LY2452473 to six healthy male subjects. LY2452473 was absorbed rapidly (time to reach maximum plasma concentration for both LY2452473 and total radioactivity was 2-3 h) and cleared slowly (plasma terminal t(½) of 27 h for LY2452473 and 51 h for the total radioactivity). LY2452473 and metabolites S5 (acetylamine) and S12 (hydroxylation on the cyclopentene) were major circulating entities in plasma, accounting for approximately 42, 21, and 35% of the total radioactivity exposure, respectively, as calculated from relative area under the concentration versus time curves from zero to 48 h derived from the plasma radiochromatograms. The radioactive dose was almost completely recovered after 312 h with 47.9% of the dose eliminated in urine and 46.6% in feces. Minimal LY2452473 was detected in excreta, indicating that metabolic clearance was the main route of elimination. Multiple metabolic pathways were observed with no single metabolic pathway accounting for more than 30% of the dose in excreta. Metabolite S10 (a diol across the cyclopenta-indole linkage) was the largest excretory metabolite (approximately 14% of the dose). S10 displayed interesting chemical and chromatographic properties, undergoing conversion to the corresponding epoxide under acidic conditions and conversion back to the diol under neutral conditions. An in vitro phenotyping approach indicated that CYP3A4 was the largest contributor to LY2452473 depletion.

Abstract A134: Pharmacokinetics and metabolism of iniparib for the treatment of metastatic triple-negative breast cancer (TNBC).

Abstract Background: Iniparib (BSI-201) is an investigational anticancer agent whose mechanism of action is under study. In breast cancer cell lines and xenograft models of TNBC, iniparib has anti-proliferative activity and potentiates the cell cycle effects of some DNA damaging agents. In a randomized, open-label phase 2 study in patients with metastatic TNBC (mTNBC), iniparib combined with gemcitabine (G) and carboplatin (C) improved efficacy outcomes compared with GC alone. In a confirmatory phase 3 study, GCI failed to meet pre-specified criteria for PFS and OS; however, an exploratory subset analysis suggested a potential benefit among 2nd/3rd line patients (O'Shaughnessy et al. ASCO 2011). Here we report the pharmacokinetic and metabolism results of two clinical studies. Methods and Results: In a Phase 1, open-label study (BEX11505; NCT01161836) following the administration of 400 mg [14C]-iniparib to 2 male and 5 female patients with solid tumors, approximately 73% of the radioactivity was excreted in urine and 16% in feces. Less than 0.5% of the dose in excreta was unchanged drug. Iniparib accounted for approximately 11% of the total radioactivity in plasma. Two metabolites, 4-iodo-3-amino-benzamide (IABM) and 4-iodo-3-amino-benzoic acid (IABA), which represent biotransformation through the nitro-reduction pathway, were only 0.4% and 1.9% of unchanged drug, respectively. The plasma t1/2 of iniparib averaged 11 minutes, while that of IABM and IABA was 0.8 h and 2.1 h, respectively. The major circulating metabolites of iniparib were products of iodine substitution with glutathione, followed by further metabolism mainly to the cysteine derivative (SAR291066) and the N-acetylated cysteine derivative (SAR289336). The sum of these three metabolites in plasma accounted for approximately 66% of the measured radioactivity. Other routes of metabolism included hydrolysis to form benzoic acid derivatives and further metabolism by glycine conjugation and nitro-reduction to IABM and IABA. The majority of the dose excreted via urine was as SAR291066 (31%) and SAR289336 (16%). In the phase 2 randomized trial (TCD11418; NCT01045304), iniparib was administered as a 60-min IV infusion either twice weekly on days 1, 4, 8, and 11 at 5.6 mg/kg (arm A) or weekly on days 1, and 8 at 11.2 mg/kg (arm B), in combination with gemcitabine/carboplatin every 3 weeks in women with mTNBC. Pharmacokinetic parameters of iniparib and its two metabolites (IABA and IABM) were calculated based on their plasma concentrations in 69 patients (n=34 in arm A; n=35 in arm B). Iniparib, IABA, and IABM levels following a single 11.2 mg/kg dose were higher than after a 5.6 mg/kg dose, with a 2-fold increase in dose resulting in a 1.57, 2.35, and 2.04-fold increase of AUC on Day 1 in Cycle 1. The t1/2 of iniparib was short, with geometric mean values of 19 min and 25.7 min for arms A and B, respectively. The t1/2 of IABA and IABM for arms A and B were; 1.75 h and 1.78 h, and 0.793 h and 0.814 h, respectively. There was no apparent accumulation of iniparib, IABA, and IABM after repeated iniparib dosing with the present dosing regimen. Conclusion: Iniparib is rapidly metabolized and cleared from plasma with a short t1/2 of 10–20 min and much of the drug being converted to inactive glutathione adducts. Evidence for biotransformation via nitro-reduction was seen by detection of IABM and IABA in plasma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A134.

Assessment of a Micropatterned Hepatocyte Coculture System to Generate Major Human Excretory and Circulating Drug Metabolites

Metabolism is one of the important determinants of the overall disposition of drugs, and the profile of metabolites can have an impact on efficacy and safety. Predicting which drug metabolites will be quantitatively predominant in humans has become increasingly important in the research and development of new drugs. In this study, a novel micropatterned hepatocyte coculture system was evaluated for its ability to generate human in vivo metabolites. Twenty-seven compounds of diverse chemical structure and subject to a range of drug biotransformation reactions were assessed for metabolite profiles in the micropatterned coculture system using pooled cryopreserved human hepatocytes. The ability of this system to generate metabolites that are >10% of dose in excreta or >10% of total drug-related material in circulation was assessed and compared to previously reported data obtained in human hepatocyte suspensions, liver S-9 fraction, and liver microsomes. The micropatterned coculture system was incubated for up to 7 days without a change in medium, which offered an ability to generate metabolites for slowly metabolized compounds. The micropatterned coculture system generated 82% of the excretory metabolites that exceed 10% of dose and 75% of the circulating metabolites that exceed 10% of total circulating drug-related material, exceeds the performance of hepatocyte suspension incubations and other in vitro systems. Phase 1 and phase 2 metabolites were generated, as well as metabolites that arise via two or more sequential reactions. These results suggest that this in vitro system offers the highest performance among in vitro metabolism systems to predict major human in vivo metabolites.

Disposition and Metabolism of Semagacestat, a γ-Secretase Inhibitor, in Humans

Semagacestat is a functional gamma-secretase inhibitor that has been shown to reduce the rate of formation of amyloid-beta in vitro and in vivo. This study was conducted to characterize the disposition of semagacestat in humans. After a single 140-mg dose of [(14)C]semagacestat administered as an oral solution to six healthy male subjects, semagacestat was rapidly absorbed (T(max) approximately 0.5 h) and eliminated from the systemic circulation (terminal t(1/2) approximately 2.4 h). The major circulating metabolites of semagacestat, M2 (hydrolysis of the amide bond proximal to the benzazepine ring) and M3 (benzylic hydroxylation of the benzazepine ring), accounted for approximately 27 and 10% of total radioactivity exposure, respectively, as calculated from relative area under the plasma concentration versus time curve from 0 to 24 h derived from the plasma radiochromatograms. The radioactive dose was almost completely recovered after 7 days postdose, with 87% of the dose in urine and 8% in feces. Unchanged [(14)C]semagacestat in urine accounted for approximately 44% of the dose, which indicates that renal excretion played an important role in elimination. Metabolites M2 and M3, with their related secondary metabolites, each accounted for approximately 20% of the dose in excreta. In vitro data indicate the formation of M3 is primarily mediated by CYP3A, with cDNA-expressed CYP3A5 approximately 2 times more efficient than CYP3A4 in forming M3. Thus, the relative content of CYP3A4 and CYP3A5 in humans will likely determine the formation clearance of M3 after exposure to semagacestat.

Metabolic Disposition of [14C]Bazedoxifene in Healthy Postmenopausal Women

Bazedoxifene is a selective estrogen receptor modulator under development for the prevention and treatment of osteoporosis. The disposition of [(14)C]bazedoxifene was determined in six healthy postmenopausal women after administration of a single oral dose of 20 mg (200 microCi). After dosing, blood was collected at frequent intervals, and urine and fecal samples were collected for up to 10 days. Aliquots of plasma, blood, urine, and fecal homogenates were analyzed for concentrations of radioactivity. Bazedoxifene metabolite profiles in plasma and feces were determined by high-performance liquid chromatography with radioactivity flow detection; metabolite structures were confirmed by liquid chromatography-mass spectrometry. Bazedoxifene was rapidly absorbed, exhibiting a mean peak plasma concentration of 3.43 ng/ml at 1.2 h postdose. The total mean recovery of the radioactive dose in excreta was 85.6%, with the majority recovered in feces (84.7%) and only a small fraction (0.81%) in urine. Radiochromatograms of plasma revealed that glucuronidation was the major metabolic pathway; little or no cytochrome P450-mediated metabolism was evident. The majority of circulating radioactivity was constituted by metabolites, with bazedoxifene-5-glucuronide being the predominant metabolite (up to 95%). Bazedoxifene-4'-glucuronide was a minor metabolite (up to 20%), and unchanged bazedoxifene represented 0 to 13% of the radioactivity in most plasma samples. Unchanged bazedoxifene was the major radioactive component in feces, however, reflecting unabsorbed drug and/or glucuronides that were hydrolyzed by intestinal bacterial enzymes. [(14)C]Bazedoxifene was generally well tolerated. These findings demonstrated that, after oral administration in healthy postmenopausal women, bazedoxifene was rapidly absorbed, metabolized via glucuronidation, and excreted predominantly in feces.

Metabolism of 2-ethylhexanoic acid administered orally or dermally to the female Fischer 344 rat1

1. Excretion balance studies were conducted with 2-ethylhexanoic acid (EHA) in the female Fischer 344 rat following single high (1 g kg) or low (0.1 g kg) oral doses of \\[2- Chexyl]EHA,following repeated oraldosing with unlabelled EHA and a final\\ [C]EHAoral dose at the low dose level, following dermal exposure with a high (1 g kg) and low (0.1 g kg) applied dose of \\ [C]EHA, and following a 1 mg kg i.v. dose of \\ [C]EHA. 2. Oral, i.v. and dermal doses were eliminated rapidly, predominantly in the urine during the first 24 h following dosing. 3. After oral dosing of 0.1 g kg, the mean peak blood level was 85.1 mu g equivalents EHA g. Maximum blood concentrations were detected at either 15 or 30 min in individual animals. After dermal application of 0.1 g kg, the mean peak blood level of 7.9 mu g equivalents EHA g was attained at 8 h. 4. Occlusive dermal exposure caused damage to the epidermis in the first 24 h after application and resulted in dermal absorption of 70% relative to i.v. dosing, based on the ratio of percent dose in excreta. 5. Dermal application followed by prompt washing of the skin resulted in recovery of 101.9% from the skin surface and 0.2% in the excreta. 6. The major urinary metabolites were the glucuronide of EHA, 2-ethyl-1,6- hexanedioic acid (namely 2-ethyladipic acid), 2-ethyl-5-hydroxyhexanoic acid, 2-ethyl-6- hydroxyhexanoicacidandethylketohexanoicacid.Evidencefor metabolismvia beta -oxidation was alsofound,consistent with the incorporationofEHAinto normalcellular intermediary metabolism.