Predominant Route Of Elimination Research Articles

Mass balance, metabolic disposition, and pharmacokinetics of a novel selective inhibitor of PI3Kδ [14C] SHC014748M in healthy Chinese subjects following oral administration.

SHC014748M is a potent, novel selective PI3Kδ isoform inhibitor and is proposed for the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. This study investigated the pharmacokinetics, mass balance, metabolism and excretion of SHC014748M in Chinese male subjects following a single oral dose of 150mg (100μCi) [14C] SHC014748M. Six healthy Chinese male subjects administrated an oral suspension of 150mg (100μCi) [14C] SHC014748M and the samples of blood, urine and feces were collected for measuring. Liquid chromatography-tandem mass spectrometry and liquid scintillation counter were utilized to obtain mass balance and the pharmacokinetic data. The median Tmax for [14C]-radioactivity was 1.6 ± 0.5h after the oral administration of [14C] SHC014748M and the mean Cmax was 3863 ± 354ngEq./mL in plasma, while the mean Cmax, t1/2 values and AUC0-∞ values for total radioactivity in whole blood were 2466 ± 518ngEq./mL, 32.2 ± 30.5h and 66,236 ± 44,232h * ng Eq./mL, respectively. Fecal excretion was proposed as the predominant elimination route, accounting for a mean of 90.68 ± 11.38% of the administered dose, whereas the mean urine excretion was 6.00 ± 1.48% within 336h post-dose. The proposed major metabolic pathway of [14C] SHC014748M in the human body were as follows: (I) monooxidation, (II) glucuronide acid conjugation, and (III) monoxide-hydrogenation. SHC014748M was absorbed, metabolized and excreted with unchanged SHC014748M as its main circulating component in plasma following oral administration. In addition, it was speculated that fecal excretion was the principal excretion pathway; meanwhile, monohydroxy, glucuronide conjugation, oxygen, and hydrogenation were the major clearance pathways of SHC014748M through urine and/or feces. The trial registration number: CTR20202505.

Metallobiochemistry of ultratrace levels of bismuth in the rat II. Interaction of 205+206Bi3+ with tissue, intracellular and molecular components

BackgroundKnowledge on Bi metabolism in laboratory animals refers to studies at “extreme” exposures, i.e. pharmacologically relevant high-doses (mg kg−1 b.w.) in relation to its medical use, or infinitesimal doses (pg kg−1b.w.) concerning radiobiology protection and radiotherapeutic purposes. There are no specific studies on metabolic patterns of environmental exposure doses (ultratrace level, μg kg−1 b.w.), becoming in this context Bi a “heavy metal fallen into oblivion”. We previously reported the results of the metabolic fate of ultratrace levels of Bi in the blood of rats [1]. In reference to the same study here we report the results of the retention and tissue binding of Bi with intracellular and molecular components. MethodsAnimals were intraperitoneally injected with 0.8 μg Bi kg−1 b.w. as 205+206Bi(NO)3, alone or in combination with 59Fe for the radiolabeling of iron proteins. The use of 205+206Bi radiotracer allowed the determination of Bi down to pg fg−1 in biological fluids, tissues, subcellular fractions, and biochemical components isolated by differential centrifugation, size exclusion chromatography, solvent extraction, precipitation, immunoprecipitation and dialysis. Main findingsAt 24 h post injection the kidney contained by far the highest Bi concentration (10 ng g−1 wt.w.) followed by the thymus, spleen, liver, thyroid, trachea, femur, lung, adrenal gland, stomach, duodenum and pancreas (0.1 to 1.3 ng g−1 wt.w.). Brain and testis showed smaller but consistently significant concentrations of the element (0.03 ng g−1 wt.w). Urine was the predominant route of excretion. Intracellularly, liver, kidney, spleen, testis, and brain cytosols displayed the highest percentages (35%–58%) of Bi of homogenates. Liver and testis nuclei were the organelles with the highest Bi content (24 % and 27 %). However, when the recovered Bi of the liver was recorded as percent of total recovered Bi divided by percent of total recovered protein the lysosomes showed the highest relative specific activity than in other fractions. In the brain subcellular fractions Bi was incorporated by neuro-structures with the protein and not lipidic fraction of the myelin retaining 18 % of Bi of the total homogenate. After the liver intra-subcellular fractionation: (i) 65 % of the nuclear Bi was associated with the protein fraction of the nuclear membranes and 35 % with the bulk chromatin bound to non-histone and DNA fractions; (ii) about 50 % of the mitochondrial Bi was associated with inner and outer membranes being the other half recovered in the intramitochondrial matrix; (iii) in microsomes Bi showed a high affinity (close to 90 %) for the membranous components (rough and smooth membranes); (iv) In the liver cytosol three pools of Bi-binding proteins (molecular size > 300 kDa, 70 kDa and 10 kDa) were observed with ferritin and metallothionein–like protein identified as Bi-binding biomolecules. Three similar protein pools were also observed in the kidney cytosol. However, the amount of Bi, calculated in percent of the total cytosolic Bi, were significantly different compared to the corresponding pools of the liver cytosol. ConclusionsAt the best of our knowledge the present paper represents the first in vivo study, on the basis of an environmental toxicology approach, aiming at describing retention and binding of Bi in the rat at tissue, intracellular and molecular levels.

Development and validation of a LC-MS/MS method for simultaneous determination of TQ-A3326 and its major metabolites in human plasma, urine and feces: application to pharmacokinetic assay

TQ-A3326 has been developed as a new drug by modifying the structure of daclatasvir with deuterium. The pharmacokinetics (PK) of TQ-A3326 in human remains unclear. The aim of the present study was to establish a LC-MS/MS method to investigate preliminarily the PK characteristics of TQ-A3326 and its major metabolites in healthy Chinese volunteers. All volunteers were administrated TQ-A3326 (60 mg). Plasma, feces and urine samples were extracted through protein precipitation. A rapid and sensitive LC-MS/MS method was successfully developed and applied to assess the PK properties of TQ-A3326. The AUC0-t and Cmax were 39516.3 ± 10778.5, 1034.6 ± 452.9 and 71.0 ± 49.5 ng·h·mL−1, and 1411.2 ± 325.4, 52.9 ± 16.4 and 1.8 ± 0.5 ng·mL−1, respectively, for TQ-A3326, M2-D and M4-D. Feces were the predominant route of elimination of TQ-A3326. M2-D was an abundant metabolite in feces and urine, representing 23.72% and 0.24% of the dose, respectively. The measurements of TQ-A3326 and its active metabolites would help to better understand the predominant route of elimination of the prototype drug, and provide meaningful information for further investigation of the bioactive mechanism of TQ-A3326 and its clinical applications.

Human pharmacokinetics of ginkgo terpene lactones and impact of carboxylation in blood on their platelet-activating factor antagonistic activity.

Terpene lactones are a class of bioactive constituents of standardized preparations of Ginkgo biloba leaf extract, extensively used as add-on therapies in patients with ischemic cardiovascular and cerebrovascular diseases. This investigation evaluated human pharmacokinetics of ginkgo terpene lactones and impact of their carboxylation in blood. Human subjects received oral YinXing-TongZhi tablet or intravenous ShuXueNing, two standardized ginkgo preparations. Their plasma protein-binding and platelet-activating factor antagonistic activity were assessed in vitro. Their carboxylation was assessed in phosphate-buffered saline (pH 7.4) and in human plasma. After dosing YinXing-TongZhi tablet, ginkgolides A and B and bilobalide exhibited significantly higher systemic exposure levels than ginkgolides C and J; after dosing ShuXueNing, ginkgolides A, B, C, and J exhibited high exposure levels. The compounds' unbound fractions in plasma were 45-92%. Apparent oral bioavailability of ginkgolides A and B was mostly >100%, while that of ginkgolides C and J was 6-15%. Bilobalide's bioavailability was probably high but lower than that of ginkgolides A/B. Terminal half-lives of ginkgolides A, B, and C (4-7 h) after dosing ShuXueNing were shorter than their respective values (6-13 h) after dosing YinXing-TongZhi tablet. Half-life of bilobalide after dosing the tablet was around 5 h. Terpene lactones were roughly evenly distributed in various body fluids and tissues; glomerular-filtration-based renal excretion was the predominant elimination route for the ginkgolides and a major route for bilobalide. Terpene lactones circulated as trilactones and monocarboxylates. Carboxylation reduced platelet-activating factor antagonistic activity of ginkgolides A, B, and C. Ginkgolide J, bilobalide, and ginkgo flavonoids exhibited no such bioactivity. Collectively, differences in terpene lactones' exposure between the two preparations and influence of their carboxylation in blood should be considered in investigating the relative contributions of terpene lactones to ginkgo preparations' therapeutic effects. The results here will inform rational clinical use of ginkgo preparations.

Daclatasvir: A Review of Preclinical and Clinical Pharmacokinetics.

Daclatasvir is a first-in-class, highly selective, hepatitis C virus, non-structural protein 5a polymerase replication complex inhibitor with picomolar potency and broad genotypic coverage in vitro. Daclatasvir undergoes rapid absorption, with a time to reach maximum plasma concentration of 1-2h and an elimination half-life of~10 to 14h observed in single-ascending dose studies. Steady state was achieved by day 4 in multiple-ascending dose studies. Daclatasvir can be administered without regard to food or pH modifiers. Daclatasvir exposure is similar between healthy subjects and subjects infected with hepatitis C virus. Intrinsic factors such as age, race, or sex do not impact daclatasvir exposure. No dose adjustment is necessary for patients with any degree of hepatic or renal impairment. Daclatasvir has low-to-moderate clearance with the predominant route of elimination via cytochrome P450 3A4-mediated metabolism and P-glycoprotein excretion and intestinal secretion. Renal clearance is a minor route of elimination for daclatasvir. As a result, the dose of daclatasvir should be reduced from 60 to 30mg once daily when co-administered with strong inhibitors of cytochrome P450 3A4. No dose adjustment is required when daclatasvir is co-administered with moderate inhibitors of cytochrome P450 3A4. The dose of daclatasvir should be increased from 60 to 90mg once daily when co-administered with moderate inducers of cytochrome P450 3A4. Co-administration of daclatasvir with strong inducers of cytochrome P450 3A4 is contraindicated. Concurrent medications with inhibitory effects on P-glycoprotein without concurrent inhibition of cytochrome P450 3A4 are unlikely to cause marked changes in daclatasvir exposure, as the clearance of daclatasvir is through both cytochrome P450 3A4 and P-glycoprotein. The potential for daclatasvir to affect the pharmacokinetics of concomitantly administered drugs that are substrates of the cytochrome P450 enzyme system is low. In vitro, daclatasvir is a weak-to-moderate inhibitor of transporters including organic cation transporter 1, P-glycoprotein, organic transporting polypeptide 1B1, organic transporting polypeptide 1B3, and breast cancer resistance protein, although in clinical studies, daclatasvir has not altered the pharmacokinetics of concomitantly administered drugs that are substrates of these transporters to an appreciable degree, except for rosuvastatin. In summary, daclatasvir is a hepatitis C virus, non-structural protein 5a-selective inhibitor with a well-characterized pharmacokinetic profile that forms part of potent and well-tolerated all-oral treatment regimens for chronic hepatitis C virus infection.

A Study of 11-[³H]-Tetrodotoxin Absorption, Distribution, Metabolism and Excretion (ADME) in Adult Sprague-Dawley Rats.

Tetrodotoxin (TTX) is a powerful sodium channel blocker that in low doses can safely relieve severe pain. Studying the absorption, distribution, metabolism and excretion (ADME) of TTX is challenging given the extremely low lethal dose. We conducted radiolabeled ADME studies in Sprague-Dawley rats. After a single dose of 6 μg/(16 μCi/kg) 11-[3H]TTX, pharmacokinetics of plasma total radioactivity were similar in male and female rats. Maximum radioactivity (5.56 ng Eq./mL) was reached in 10 min. [3H]TTX was below detection in plasma after 24 h. The area under the curve from 0 to 8 h was 5.89 h·ng Eq./mL; mean residence time was 1.62 h and t½ was 2.31 h. Bile secretion accounted for 0.43% and approximately 51% of the dose was recovered in the urine, the predominant route of elimination. Approximately 69% was recovered, suggesting that hydrogen tritium exchange in rats produced tritiated water excreted in breath and saliva. Average total radioactivity in the stomach, lungs, kidney and intestines was higher than plasma concentrations. Metabolite analysis of plasma, urine and feces samples demonstrated oxidized TTX, the only identified metabolite. In conclusion, TTX was rapidly absorbed and excreted in rats, a standard preclinical model used to guide the design of clinical trials.

Pharmacokinetics of the Novel Echinocandin CD101 in Multiple Animal Species.

ABSTRACTCD101 is a novel semisynthetic echinocandin with antifungal activity against Candida and Aspergillus spp. The pharmacokinetics (PK) of CD101 administered intravenously to mice, rats, dogs, cynomolgus monkeys, and chimpanzees are presented. CD101 consistently exhibited very low clearance, a modest volume of distribution at steady state (Vss), and a long half-life (t1/2) across all species tested. In mouse, rat, dog, cynomolgus monkey, and chimpanzee, CD101 clearance was 0.10, 0.47, 0.30, 0.41, and 0.06 ml/min/kg, respectively; Vss was 206, 1,390, not determined, 597, and 400 ml/kg, respectively; and t1/2 was 25, 39, 53, 40, and 81 h, respectively. CD101 demonstrated a lower clearance and correspondingly longer half-life than those of anidulafungin, with more pronounced differences in higher species (anidulafungin t1/2, 8 h in cynomolgus monkey and 30 h in chimpanzee). In the rat, tissue/plasma area under the concentration-time curve (AUC) ratios, in descending order, were 4.62 (kidney), 4.33 (lung), 4.14 (liver), 3.87 (spleen), 1.09 (heart), and 0.609 (brain), indicating that CD101 exposure relative to plasma levels was comparable for major organs (approximately 4-fold higher in tissue than in plasma), with the exception of the heart and brain. Biliary elimination of intact CD101 was the predominant route of excretion; the mean cumulative amount of CD101 excreted into the bile and feces over the course of 5 days accounted for 22.6% and 27.7% of the total dose administered, respectively. There were no sex differences in the pharmacokinetics of CD101. Given its low clearance, long half-life, and wide tissue distribution, CD101 once weekly is expected to provide appropriate systemic levels for treatment and prevention of invasive fungal infections.

Mass balance, pharmacokinetics, and metabolism of linsitinib in cancer patients.

This study characterized the pharmacokinetics, mass balance, routes and extent of elimination, metabolites, and safety of a single oral dose of (14)C-linsitinib, an IGF-1R/IR inhibitor, in patients with advanced solid tumors. The tolerability of linsitinib after multiple-dose administration was assessed in those patients who wished to continue treatment beyond the single (14)C-linsitinib dose. Five patients received a single oral dose of 150mg (14)C-linsitinib, followed by collection of blood, plasma, urine, and feces for 10days. The collected material was analyzed for total radioactivity, linsitinib, and metabolites. The safety of 150mg of unlabeled linsitinib administered twice daily until disease progression was also assessed. The median time to reach the maximum plasma concentration of linsitinib was 3.0h, median maximum plasma concentration was 1789ng/mL, median terminal half-life was 2.4h, and median apparent oral clearance was 12.45L/h. After a single dose of (14)C-linsitinib, 5.44 and 76.4% of mean total radioactivity administered were recovered in urine and feces, respectively. Eighteen linsitinib metabolites (M1-M18) were detected in plasma, urine, and feces samples, and their structures were elucidated. The main metabolic reactions of linsitinib in humans were oxidation and sulfate conjugation. Linsitinib was well tolerated after a single dose of (14)C-linsitinib, and fatigue was the most frequent adverse event following multiple doses of unlabeled linsitinib. (14)C-linsitinib is rapidly absorbed and extensively metabolized. Linsitinib excretion via bile into feces is the predominant elimination route from plasma with minor renal elimination.

Biodistribution of the multidentate hydroxypyridinonate ligand [(14) C]-3,4,3-LI(1,2-HOPO), a potent actinide decorporation agent.

The pharmacokinetics and biodistribution of the (14) C-labeled actinide decorporation agent 3,4,3-LI(1,2-HOPO) were investigated in young adult Swiss Webster mice and Sprague Dawley rats, after intravenous, intraperitoneal, and oral dose administration. In all routes investigated, the radiolabeled compound was rapidly distributed to various tissues and organs of the body. In mice, the 24 h fecal elimination profiles suggested that the biliary route is the predominant route of elimination. In contrast, lower fecal excretion levels were observed in rats. Tissue uptake and retention of the compound did not differ significantly between sexes although some differences were observed in the excretion patterns over time. The male mice eliminated a greater percentage of (14) C through the renal pathway than the female mice after receiving an intravenous or intraperitoneal dose, while the opposite trend was seen in rats that received an intravenous dose. Metabolite profiling performed on selected rat samples demonstrated that a putative major metabolite of [(14) C]-3,4,3-LI(1,2-HOPO) is formed, accounting for approximately 10% of an administered oral dose. Finally, to improve its oral bioavailability, 3,4,3-LI(1,2-HOPO) was coformulated with a proprietary permeability enhancer, leading to a notable increase in oral bioavailability of the compound.

A single-dose mass balance and metabolite-profiling study of vemurafenib in patients with metastatic melanoma.

Vemurafenib, a selective inhibitor of oncogenic BRAF kinase carrying the V600 mutation, is approved for treatment of advanced BRAF mutation–positive melanoma. This study characterized mass balance, metabolism, rates/routes of elimination, and disposition of 14C-labeled vemurafenib in patients with metastatic melanoma. Seven patients with metastatic BRAF-mutated melanoma received unlabeled vemurafenib 960 mg twice daily for 14 days. On the morning of day 15, patients received 14C-labeled vemurafenib 960 mg (maximum 2.56 MBq [69.2 μCi]). Thereafter, patients resumed unlabeled vemurafenib (960 mg twice daily). Blood, urine, and feces were collected for metabolism, pharmacokinetic, and dose recovery analysis. Within 18 days after dose, ∼95% of 14C-vemurafenib–related material was recovered from feces (94.1%) and urine (<1%). The parent compound was the predominant component (95%) in plasma. The mean plasma elimination half-life of 14C-vemurafenib–related material was 71.1 h. Each metabolite accounted for <0.5% and ≤6% of the total administered dose in urine and feces, respectively (0–96 h postdose). No new metabolites were detected. Vemurafenib was well-tolerated. Excretion of vemurafenib via bile into feces is considered the predominant elimination route from plasma with minor renal elimination (<1%).

Absorption and metabolism of triclosan after application to the skin of B6C3F1 mice

Triclosan is used as an antimicrobial agent in personal care products, household items, medical devices, and clinical settings. Humans can receive lifelong exposures to triclosan; however, data on the toxicity and carcinogenicity after topical application are lacking. This study determined the absorption, distribution, metabolism, and excretion of triclosan after application to the skin of B6C3F1 mice. [(14)C(U)]triclosan (10 or 100 mg triclosan/kg body weight) was administered topically to mice in two separate experiments: a vehicle selection experiment using propylene glycol, ethanol, and a generic cosmetic cream, and a toxicokinetic experiment. Mice were killed up to 72 h after triclosan administration, and excreta and tissues were analyzed for radioactivity. Ethanol had the best properties of the vehicles evaluated. Maximum absorption was obtained at approximately 12 h after dosing. Radioactivity appeared in the excreta and in all tissues examined, with the highest levels in the gall bladder and the lowest levels in the brain. Triclosan was metabolized to triclosan sulfate, triclosan glucuronide, 2,4-dichlorophenol, and hydroxytriclosan. The metabolite profile was tissue-dependent and the predominant route of excretion was fecal. The AUC(0-∞) and the Cmax of plasma and liver in females were greater than those in males. Slightly lower absorption was observed in mice with Elizabethan collars.

The interactions of lenalidomide with human uptake and efflux transporters and UDP-glucuronosyltransferase 1A1: lack of potential for drug–drug interactions

Lenalidomide is an immunomodulatory agent used for the treatment of myelodysplastic syndromes and multiple myeloma. Renal clearance of lenalidomide is the predominant elimination route and is approximately twofold greater than the glomerular filtration rate (GFR), suggesting the potential contribution of an active secretory mechanism. In vitro studies were conducted to examine whether lenalidomide is a substrate of drug transporters, namely P-glycoprotein (P-gp), human breast cancer resistance protein (BCRP), multidrug resistance proteins (MRP1, MRP2, MRP3), organic anion transporters (OAT1, OAT3), organic cation transporters (OCT1 and OCT2), human organic cation transporter novel 1 and 2 (OCTN1 and OCTN2), multidrug and toxin extrusion (MATE1) and organic anion transporting polypeptide (OATP1B1). Lenalidomide was also evaluated as an inhibitor of P-gp, BCRP, MRP2, OCT2, OAT1, OAT3, OATP1B1, OATP1B3 and bile salt export pump (BSEP). In addition, inhibition of UDP-glucuronosyltransferase 1A1 (UGT1A1) variants by lenalidomide was also assessed. Cells or vesicles expressing each of the human transporters were used for uptake and inhibition studies, with appropriate probe substrates and known inhibitors. Results of these studies indicate that the lenalidomide is not a substrate for the transporters examined, except that it is weak substrate of P-gp. None of the transporters studied were inhibited by lenalidomide. Lenalidomide is not an inhibitor of UGT1A1*1/*1 or its polymorphic variants UGT1A1*1/*28 and UGT1A1*28/*28. Drug interactions are unlikely to occur when lenalidomide is co-administered with substrates or inhibitors of these transporters. In addition, lenalidomide is unlikely to cause interactions when co-administered with substrates of UGT1A1.

Nonclinical pharmacokinetics and metabolism of EPZ‐5676, a novel DOT1L histone methyltransferase inhibitor

(2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol (EPZ-5676) is a novel DOT1L histone methyltransferase inhibitor currently in clinical development for the treatment of MLL-rearranged leukemias. This report describes the preclinical pharmacokinetics and metabolism of EPZ-5676, an aminonucleoside analog with exquisite target potency and selectivity that has shown robust and durable tumor growth inhibition in preclinical models. The in vivo pharmacokinetics in mouse, rat and dog were characterized following i.v. and p.o. administration; EPZ-5676 had moderate to high clearance, low oral bioavailability with a steady-state volume of distribution 2-3 fold higher than total body water. EPZ-5676 showed biexponential kinetics following i.v. administration, giving rise to a terminal elimination half-life (t1/2 ) of 1.1, 3.7 and 13.6 h in mouse, rat and dog, respectively. The corresponding in vitro ADME parameters were also studied and utilized for in vitro-in vivo extrapolation purposes. There was good agreement between the microsomal clearance and the in vivo clearance implicating hepatic oxidative metabolism as the predominant elimination route in preclinical species. Furthermore, low renal clearance was observed in mouse, approximating to fu -corrected glomerular filtration rate (GFR) and thus passive glomerular filtration. The metabolic pathways across species were studied in liver microsomes in which EPZ-5676 was metabolized to three monohydroxylated metabolites (M1, M3 and M5), one N-dealkylated product (M4) as well as an N-oxide (M6).

Abstract B216: Mass balance, routes of excretion and pharmacokinetics of investigational oral [14C]alisertib (MLN8237) in patients with advanced solid tumors or lymphoma.

Abstract Background: Alisertib (MLN8237) is an investigational, orally administered, selective oral Aurora A kinase inhibitor under clinical development for treatment of solid tumors and hematologic malignancies. We herein report the mass balance, routes of excretion and pharmacokinetics (PK) of alisertib following oral administration of radiolabeled [14C]alisertib in cancer patients. Material and methods: This was a two-part, open-label, single oral dose (Part A) followed by multiple-dose (Part B) study in patients with advanced malignancies. Eligible patients were aged ≥ 18 years with histologic or cytologic diagnosis of advanced solid tumors or lymphoma, ECOG PS 0-1. In Part A, patients received a single 35 mg dose of 14C-labeled alisertib (approximately 80 μCi) administered as oral solution. Serial blood samples were collected over a 10-day period for analysis of plasma and whole blood PK of alisertib and total radioactivity (drug-related material). Complete urinary and fecal outputs were collected until at least 80% of the administered radioactivity was recovered or excretion of radioactivity fell below 1% per day for assessment of drug-related material recovery in excreta and products of alisertib biotransformation. In Part B, patients received 50 mg of nonradiolabeled alisertib twice daily administered as enteric-coated tablets for 7 days in 21-day cycles until disease progression or unacceptable toxicity. Results: Three patients with ovarian cancer, bladder cancer and mesothelioma, respectively, completed Part A of the study. Demographic features of patients enrolled in the study were: 2 males and 1 female, median age 66 years, mean body weight 79 kg. Following single dose of [14C]alisertib oral solution, the median time to first reach maximal plasma concentration of alisertib and drug-related material was 1 hr. The mean terminal half-life for alisertib and drug-related material were 22 and 39 hrs, respectively. The mean plasma exposure (AUC0-inf) ratio of alisertib versus total drug-related material was 0.46, indicating the presence of alisertib metabolites in circulation. The apparent oral clearance of alisertib was 3.9 L/hr and renal clearance of the parent drug was negligible. Following a single oral dose of [14C]alisertib, 87% and 2.7% of administered radioactivity were recovered in feces and urine, respectively, by 2 weeks post-dose. Grade 1 fatigue was the most frequent adverse event (2/3) during the study. One patient experienced grade 3 neutropenia. Conclusions: The predominant route of elimination for drug-related material was fecal, consistent with hepatic metabolism and biliary excretion of alisertib. Renal clearance of unchanged alisertib was negligible. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B216. Citation Format: Xiaofei Zhou, Sandeepraj Pusalkar, Swapan Chowdhury, Shawn Searle, Yuexian Li, Jaime Mertz, Bin Zhang, Yong Ben, Karthik Venkatakrishnan. Mass balance, routes of excretion and pharmacokinetics of investigational oral [14C]alisertib (MLN8237) in patients with advanced solid tumors or lymphoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B216.

Absorption, distribution, metabolism and excretion of the novel SARM GTx-024 [(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide] in rats

1. GTx-024, a novel selective androgen receptor modulator, is currently being investigated as an oral treatment for muscle wasting disorders associated with cancer and other chronic conditions.2. Absorption of GTx-024 was rapid and complete, with high oral bioavailability. A wide tissue distribution of [14C]GTx-024 derived radioactivity was observed. [14C]GTx-024-derived radioactivity had a moderate plasma clearance (117.7 and 74.5 mL/h/kg) and mean elimination half-life of 0.6 h and 16.4 h in male and female rats, respectively.3. Fecal excretion was the predominant route of elimination, with ∼70% of total radioactivity recovered in feces and 21–25% in urine within 48 h. Feces of intact rats contained primarily unchanged [14C]GTx-024 (49.3–64.6%). Metabolites were identified in urine and feces resulting from oxidation of the cyanophenol ring (M8, 17.6%), hydrolysis and/or further conjugation of the amide moiety (M3, 8–12%) and the cyanophenol ring (M4, 1.3–1.5%), and glucuronidation of [14C]GTx-024 at the tertiary alcohol (M6, 3.5–3.7%). There was no quantifiable metabolite in plasma.4. In summary, in the rat GTx-024 is completely absorbed, widely distributed, biotransformed through several metabolic pathways, and eliminated in feces primarily as an unchanged drug.

Therapeutic Equivalence of Ursodeoxycholic Acid Tablets and Ursodeoxycholic Acid Capsules for the Treatment of Primary Biliary Cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic cholestatic, progressive inflammatory liver disease with a suspected autoimmunological pathogenesis. The disease is typically diagnosed in women at an age between 30 and 65 years and has a prevalence of up to 1 in 1000 women over the age of 40. The only approved medical therapy for PBC is ursodeoxycholic acid (UDCA) in a recommended dose of 13–15mg/kg/day. UDCA is a hydrophilic dihydroxy bile acid (3a,7bdihydroxy-5b-cholanoic acid). In humans, UDCA accounts for up to 4% of the bile acid pool. Following oral administration, approximately 30–60% of UDCA is absorbed in the gut. After intestinal absorption, UDCA enters the portal circulation and is then taken up by the hepatocytes via specific bile acid transporters. Within the hepatocyte, UDCA is conjugated to glycine or taurine and is subsequently transported into the bile ducts by the bile salt export pump (BSEP). In bile, UDCA concentration peaks 1 3 h following oral administration. In humans, the biological half-life of UDCA is 3.5–5.8 days and the predominant route of elimination is by feces. UDCA exerts its beneficial effects at the level of hepatocytes and cholangiocytes. It stimulates hepatocyte secretion by mostly post-transcriptional mechanisms, including insertion of transporters like BSEP and the anion exchanger AE2. In addition, UDCA exerts antiapoptotic effects in hepatocytes and protects cholangiocytes against endogenous toxic bile acids by modifying micelle formation. UDCA consistently improves the biochemical parameters of cholestasis, delays the histological progression and the time to liver transplantation in patients suffering from PBC. Both, UDCA 250mg capsules and UDCA 500mg tablets (“Ursofalk1”), are registered in Germany and other European countries for the treatment of PBC. UDCA 500mg tablets were developed to facilitate medication intake compared to the standard UDCA 250mg capsule preparations. Tablets are considerably smaller, but contain twice as much active pharmaceutical ingredient compared to the capsule preparation, which might improve the compliance of patients and thereby increase its therapeutic efficacy. Ursofalk tablets were registered in Germany on the basis of bioequivalence studies comparing tmax, Cmax, and AUC values of UDCA between capsules and tablets. Cmax values of UDCA in plasma are probably of only limited clinical relevance for the efficacy and safety of UDCA. Aim of this trial was to assess if the therapeutic efficacy of UDCA 500mg tablets is equivalent to that of UDCA 250mg capsules (both at 14 2mg/kg BW/day once daily) in patients with PBC. Therapeutic efficacy was measured by comparing the liver enzyme parameters alkaline phosphatase (AP), g-glutamyl transferase (gGT), and alanine aminotransferase (ALT) under both treatments. The secondary objectives were to assess the safety Clinical Pharmacology in Drug Development XX(XX) 1–6 © The Author(s) 2013 DOI: 10.1002/cpdd.24

Elucidation of the Metabolic Pathways and the Resulting Multiple Metabolites of Almorexant, a Dual Orexin Receptor Antagonist, in Humans

Almorexant [(2R)-2-{(1S)-6, 7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-N-methyl-2-phenyl-acetamide], a tetrahydroisoquinoline derivative, is a dual orexin receptor antagonist with sleep-promoting properties in both animals and humans. This study investigated the disposition, metabolism, and elimination of almorexant in humans. After oral administration of a 200-mg dose of ¹⁴C-almorexant, almorexant was rapidly absorbed (Tmax = 0.8 hour), and the apparent terminal half-life (t(1/2)) was 17.8 hours. The radioactive dose was almost completely recovered with 78.0% of the administered radioactive dose found in feces and 13.5% in urine. Unchanged almorexant was not found in urine and represented 10% of the administered dose in feces. In total, 47 metabolites were identified of which 21 were shown to be present in plasma. There are four primary metabolites, the isomeric phenols M3 and M8, formed by demethylation, the aromatic isoquinolinium ion M5, formed by dehydrogenation, and M6, formed by oxidative dealkylation with loss of the phenylglycine moiety. Most of the subsequent products are formed by permutations of these primary metabolic reactions followed by conjugation of the intermediate phenols with glucuronic or sulfonic acid. The percentage of dose excreted in urine or feces for any of the metabolites did not exceed 10% of the administered radioactive dose, nor did any of the metabolites represent more than 10% of the total drug-related exposure. In conclusion, after rapid absorption, almorexant is extensively metabolized, and excretion of metabolites in feces is the predominant route of elimination in humans.

Metabolite Profiles of Degarelix, a New Gonadotropin-Releasing Hormone Receptor Antagonist, in Rat, Dog, and Monkey

Degarelix is a novel competitive gonadotropin-releasing hormone receptor blocker (antagonist). In this study, the nonclinical metabolism and excretion of degarelix was investigated in Sprague-Dawley rat, beagle dog, and cynomolgus monkey. Degarelix was found to be stable when incubated in microsomes and cryopreserved hepatocytes from animal liver tissue. Absorption, distribution, metabolism, and excretion studies in male rat, dog, and monkey showed that after a subcutaneous dose of tritium-labeled degarelix, the peptide was rapidly absorbed with C(max) in plasma of 1 to 2 h. The predominant route of excretion was via the kidneys and the bile. In rat and dog, most of the degarelix dose was eliminated within 48 h via urine and feces in equal amounts (40-50% in each matrix), whereas in monkey the major route of excretion was fecal (50%) and renal (22%). In plasma and urine samples from all three species, mainly intact degarelix was detected. In bile and feces samples from rats and dogs, the same truncated peptides of the parent decapeptide were detected. The major metabolites identified represented the N-terminal tetrapeptide, the pentapeptide, and the heptapeptide. From the animal studies, it could be concluded that degarelix is subject to common peptidic degradation in the liver and bile and is fully excreted via metabolic and biliary (as metabolites and parent compound) and urinary (mainly as parent compound) pathways. Systemic exposure to metabolic products seems to be low.

Metabolism and Disposition of Eltrombopag, an Oral, Nonpeptide Thrombopoietin Receptor Agonist, in Healthy Human Subjects

The metabolism and disposition of eltrombopag, the first-in-class small molecule human thrombopoietin receptor agonist, were studied in six healthy men after a single oral administration of a solution dose of [(14)C]eltrombopag (75 mg, 100 μCi). Eltrombopag was well tolerated. The drug was quickly absorbed and was the predominant circulating component in plasma (accounting for 63% of the total plasma radioactivity). A mono-oxygenation metabolite (M1) and acyl glucuronides (M2) of eltrombopag were minor circulating components. The predominant route of elimination of radioactivity was fecal (58.9%). Feces contained approximately 20% of dose as glutathione-related conjugates (M5, M6, and M7) and another 20% as unchanged eltrombopag. The glutathione conjugates were probably detoxification products of a p-imine methide intermediate formed by metabolism of M1, which arises through cytochrome P450-dependent processes. Low levels of covalently bound drug-related intermediates to plasma proteins, which could result from the reaction of the imine methide or acyl glucuronide conjugates with proteins, were detected. The bound material contributes to the longer plasma elimination half-life of radioactivity. Renal elimination of conjugates of hydrazine cleavage metabolites (mostly as M3 and M4) accounted for 31% of the radiodose, with no unchanged eltrombopag detected in urine.

Metabolism of [2-14C]p-hydroxyphenyl acetic acid in rat, monkey and human hepatocytes and in bile-duct cannulated rats

We determined the metabolism of [2-14C]p-hydroxyphenyl acetic acid (p-HPA) in rat (male, Sprague–Dawley), monkey (male, Cynomolgus), and human (male, Caucasian) hepatocytes, and in bile-duct cannulated (BDC) rats (male, Sprague–Dawley). Unchanged p-HPA ranged from 87.0 to 92.6% of the total radioactivity (TRA) in the extracts of rat, monkey, and human hepatocytes. Metabolites M1 (a glucuronide conjugate of p-HPA) and M2 (a glycine conjugate of p-HPA) were detected, accounting for 1–4% of TRA.After an oral dose of [2-14C]p-HPA to BDC rats, p-HPA-related components was predominantly excreted in urine, accounting for 83% of the dose. Bile excretion was limited, accounting for only 1.5% of the dose. Unchanged p-HPA was the predominant radioactivity in plasma (84.6% of the TRA in 1-h pooled plasma) and urine (69.6% of the dose). Metabolites M1, M2, and M3 (a glucuronide of p-HPA) were all detected in plasma, urine, and bile as minor components.In summary, p-HPA was not metabolized extensively in rat, monkey, and human hepatocytes. In rats, absorption and elimination of p-HPA were nearly complete with urinary excretion of the unchanged p-HPA as the predominant route of elimination after oral dosing. No oxidative metabolites were detected, suggesting a minimal role for P450 enzymes in its overall metabolic clearance. Therefore, p-HPA has a low potential for drug–drug interactions mediated by the concomitant inhibitors and inducers of P450 enzymes.