scholarly journals Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

2014 ◽  
Vol 16 (5) ◽  
pp. 1085-1096 ◽  
Author(s):  
Chelsea M. Hosey ◽  
Fabio Broccatelli ◽  
Leslie Z. Benet
Keyword(s):  
Biliary Excretion ◽  
Parent Drug ◽  
Major Route

The pharmacokinetics (PK) and pharmacodynamics (PD) of ABT-751 in children with recurrent neuroblastoma or other solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9557-9557
Author(s):  
E. Fox ◽  
B. C. Widemann ◽  
J. M. Maris ◽  
S. L. Cohn ◽  
H. Xiong ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Parent Drug ◽  
Molar Ratio ◽  
Primary Metabolite ◽  
Drug Concentrations ◽  
Apparent Clearance ◽  
Major Route ◽  
Microtubule Formation ◽  
Sulfate Conjugate

9557 Background: ABT-751 is an orally administered agent that binds to the colchicine site on β-tubulin and blocks microtubule formation. We studied the PK and PD of ABT-751 and its sulfate and glucuronide conjugates in children enrolled on a phase 1 trial in solid tumors and a pilot study in neuroblastoma. Methods: Seventy-two children (2–18 yrs) received ABT-751 on a once, daily × 7d or daily × 21d schedule. Sixty had PK plasma sampling (53 sets analyzed), and 41 had a 24h urine collection after the first dose. Drug concentrations were quantified with a LC/MS/MS assay. Results: Median (range) plasma PK parameters are shown in the table . ABT-751 was rapidly absorbed (Tmax , 2h), and the Cmax and AUC0-8 increased in proportion to dose. The median molar ratio of the sulfate plasma AUC0-8 to glucuronide plasma AUC0-8 was 1.5. The median (range) percent of the administered dose excreted in urine as ABT-751, glucuronide, or sulfate conjugates was 0.09 (0–0.4)%, 10.2 (1.0–38.5)%, and 12.6 (2.3–50.9)%, respectively. The median ABT-751 AUC0-8 was higher in patients with dose-limiting toxicity (DLT) compared to those without DLT on the 7d (118 vs. 74.5 μg·h/mL; P=0.014) and 21d (73.8 vs 49.3 μg·h/mL; P=0.049) schedules. In 28 patients with neuroblastoma, the AUC0-8 did not correlate with time to progression. Apparent clearance (CL/F) did not correlate with age or gender. Conclusions: PK samples were obtained from 83% (60/72) of children enrolled. The ABT-751 AUC0-8 was dose proportional; inter- and intra-patient variability was low. Patients who experienced DLT had higher ABT-751 AUC0-8. The mean CL/F of ABT-751 was similar to that observed in adults (40 mL/min/m2) but did not correlate with age or gender. The sulfate conjugate was the primary metabolite in plasma and urine. Urinary excretion was not a major route of elimination of the parent drug. [Table: see text] No significant financial relationships to disclose.

scholarly journals Metabolism, Excretion, and Mass Balance of [ 14 C]-Rezafungin in Animals and Humans

2021 ◽  
Author(s):  
Voon Ong ◽  
Sarah Wills ◽  
Deborah Watson ◽  
Taylor Sandison ◽  
Shawn Flanagan
Keyword(s):  
Mass Balance ◽  
Parent Drug ◽  
Invasive Fungal Disease ◽  
Total Radioactivity ◽  
Fecal Excretion ◽  
Total Recovery ◽  
Clinical Pharmacokinetics ◽  
Blood And Marrow Transplantation ◽  
Clinical Observations ◽  
Major Route

Rezafungin is a novel echinocandin being developed for treatment of candidemia and invasive candidiasis and for prevention of invasive fungal disease caused by Candida , Aspergillus , and Pneumocystis spp. in recipients of blood and marrow transplantation. Studies using [ 14 C]-radiolabeled rezafungin were conducted in rats, monkeys, and humans to characterize the mass balance, excretion, and pharmacokinetics of [ 14 C]-rezafungin and to evaluate relative amounts of rezafungin metabolites compared with parent drug. Fecal excretion was the main route of elimination in rats, monkeys, and humans. Radioactivity was primarily excreted as unchanged drug, with ≥95% average total recovery in rats (through 336 hours) and monkeys (through 720 hours). In humans, cumulative recovery of radioactivity through the first 17 days was 52% (38% in feces, 14% in urine) with estimated mean overall recovery through Day 60 of 88.3% (73% in feces, 27% in urine). The clinical pharmacokinetics of rezafungin following a single 400-mg intravenous infusion (200 μCi of [ 14 C]-rezafungin) were similar in plasma, plasma total radioactivity, and whole blood total radioactivity. Unchanged rezafungin represented the majority of total radioactivity in plasma, and the partitioning of total radioactivity into red blood cells was negligible. Across species, rezafungin was primarily metabolized by hydroxylation of the terphenyl, pentyl ether side chain. In these excretion/mass balance, metabolism, and PK studies, clinical observations were consistent with findings in the rat and monkey demonstrating the minimal metabolism and slow elimination of rezafungin after intravenous administration, with fecal excretion as the major route of elimination.

Hepatobiliary Kinetics of 113mIn-Phenolphthalexon

1981 ◽  
Vol 20 (02) ◽  
pp. 90-93
Author(s):  
P.B. Parab ◽  
U.R. Raikar ◽  
R.D. Ganatra ◽  
M. C. Patel
Keyword(s):  
Biliary Excretion ◽  
Iminodiacetic Acid ◽  
Organ Distribution ◽  
Liver Uptake ◽  
On Line ◽  
Rapid Clearance ◽  
Chemical Purity ◽  
Kinetics Of ◽  
High Liver

Phenolphthalexon, a compound with iminodiacetic acid as a functional group, has been labelled with 113mIn to high chemical purity and its usefulness in studies of biliary excretion patency has been studied. Organ distribution of 113mIn-phenolphthalexon in mice was characterized by high liver uptake (50.8% of the administered dose after 5 min) and rapid clearance through the gall bladder. An animal model for studying obstruction of biliary excretion has been developed. Data on the kinetics of the radiopharmaceutical were obtained by collecting in-vivo data through an on-line computer.

The effects of contaminated sediments of the Blesbok Spruit near Witbank on water quality and the toxicity thereof to Daphnia pulex

1999 ◽  
Vol 39 (10-11) ◽  
pp. 173-176 ◽  
Author(s):  
Liesl Hill ◽  
Sebastian Jooste
Keyword(s):  
Surface Water ◽  
Mine Drainage ◽  
Interstitial Water ◽  
Stream Water ◽  
Daphnia Pulex ◽  
Contaminated Sediments ◽  
Toxicity Tests ◽  
Major Route ◽  
Acute Toxicity Tests ◽  
Route Of Exposure

With the increasing focus on environmental issues, the objective of this study is to evaluate the potential impact of contaminated sediments of the Blesbok Spruit near Witbank - which receives acid mine drainage (AMD) inter alia - on biota. Direct transfer of chemicals from sediments to organisms is considered to be a major route of exposure for many species, and therefore focusing attention on sediment contamination and highlighting the fact that sediments are an important resource. Acute toxicity tests were performed on Daphnia pulex using both extracted sediment interstitial water and surface water. Chemical analyses were also performed on the sediment, interstitial water and surface water samples. The toxicity results suggest that metal toxicity adds significantly to the toxicity of the stream water which is enhanced by the effect of pH. The pH of the stream and interstitial water was consistently below 4.5.

The design, synthesis, pharmacokinetic and pharmacodynamic evaluation of acyloxyalkyl-substituted T705 prodrugs

2019 ◽  
Vol 15 ◽  
Author(s):  
Xingzhou Li ◽  
Tianhong Zhang ◽  
Wu Zhong
Keyword(s):  
Plasma Concentration ◽  
Development Strategy ◽  
Parent Compound ◽  
Systemic Exposure ◽  
Parent Drug ◽  
New Drugs ◽  
Structure Modification ◽  
Design Synthesis ◽  
Pharmacokinetic Properties

Background: The pharmacokinetic properties of T705 are not optimal for the development of new drugs. Objective: To improve the pharmacokinetic properties of T-705, structure modification of T-705 was conducted using a prodrug strategy. Method: The acidic amide H atom (N4-H) of T705 was attempted to be replaced with acyloxyalkyl groups following the prodrugs development strategy for carboxylic acids, and the resulting compounds were investigated whether could work as prodrugs and contribute to improving the pharmacokinetic properties of the parent compound T705 in vivo. Results: 4-acyloxyalkyl-T705 (4a–e), did act as prodrugs in vivo. 4-iso-butyryloxymethyl-T705 (4a) and 4-acetoxymethyl-T705 (4b) could significantly improve the plasma concentration and systemic exposure for T705, compound 4a displayed non inferior anti-influenza activities, compared with its parent drug T705. Conclusion: Our prodrugs development strategy for T705 is feasible, which may serves as a reference to prodrugs development of similar heterocyclic amides compounds.

Simultaneous Determination of Imatinib and N-Desmethyl Imatinib in Rat Plasma and Tissues Using LC-MS/MS

2019 ◽  
Vol 15 (2) ◽  
pp. 121-129
Author(s):  
Zhi Rao ◽  
Bo-xia Li ◽  
Yong-Wen Jin ◽  
Wen-Kou ◽  
Yan-rong Ma ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Oral Administration ◽  
Parent Drug ◽  
Gradient Elution ◽  
Biological Tissues ◽  
Rat Plasma ◽  
Running Water ◽  
Liver And Kidney ◽  
The Brain

Background: Imatinib (IM) is a chemotherapy medication metabolized by CYP3A4 to Ndesmethyl imatinib (NDI), which shows similar pharmacologic activity to the parent drug. Although methods for determination of IM and/or NDI have been developed extensively, only few observations have been addressed to simultaneously determine IM and NDI in biological tissues such as liver, kidney, heart, brain and bone marrow. Methods: A validated LC-MS/MS method was developed for the quantitative determination of imatinib (IM) and N-desmethyl imatinib (NDI) from rat plasma, bone marrow, brain, heart, liver and kidney. The plasma samples were prepared by protein precipitation, and then the separation of the analytes was achieved using an Agilent Zorbax Eclipse Plus C18 column (4.6 × 100 mm, 3.5 µm) with gradient elution running water (A) and methanol (B). Mass spectrometric detection was achieved by a triplequadrupole mass spectrometer equipped with an electrospray source interface in positive ionization mode. Results: This method was used to investigate the pharmacokinetics and the tissue distributions in rats following oral administration of 25 mg/kg of IM. The pharmacokinetic profiles suggested that IM and NDI are disappeared faster in rats than human, and the tissue distribution results showed that IM and NDI had good tissue penetration and distribution, except for the brain. This is the first report about the large penetrations of IM and NDI in rat bone marrow. Conclusion: The method demonstrated good sensitivity, accuracy, precision and recovery in assays of IM and NDI in rats. The described assay was successfully applied for the evaluation of pharmacokinetics and distribution in the brain, heart, liver, kidney and bone marrow of IM and NDI after a single oral administration of IM to rats.

A Phase I Study of OMN54 (Aneustat™) in Patients with Advanced Malignancies

2020 ◽  
Vol 7 (2) ◽  
pp. 125-132
Author(s):  
Karen A. Gelmon ◽  
Christian Kollmannsberger ◽  
Stephen Chia ◽  
Anna V. Tinker ◽  
Teresa Mitchell ◽  
...  
Keyword(s):  
Phase I ◽  
Salvia Miltiorrhiza ◽  
Performance Status ◽  
Parent Drug ◽  
Maximum Tolerated Dose ◽  
Ecog Performance Status ◽  
Advanced Malignancies ◽  
Gi Toxicity ◽  
Adequate Organ Function ◽  
Recommended Phase Ii Dose

Background/Objective: With the increasing interest in natural products, a phase I openlabel study of OMN54 (Aneustat™) in patients with advanced malignancies was initiated to determine toxicity, maximum tolerated dose (MTD), dose limiting toxicities (DLT), and pharmacokinetics (PK). OMN54 is a multitargeted agent, combining three Chinese botanicals; Ganoderma lucidium, Salvia miltiorrhiza and Scutellaria barbata. Methods: Eligible patients (pts) were >18 years of age with advanced solid tumors, able to swallow oral capsules, ECOG performance status < 2, measurable disease as defined by RECIST 1.1 and adequate organ function. Results: Twenty-two patients were enrolled in 6 dose levels, 2 with daily dosing and 4 with twicedaily dosing ranging from 1 to 5 grams daily. All were evaluated for toxicity and 20 for response. No treatment-related dose-limiting toxicities (DLTs) were reported and the recommended phase II dose (RP2D) was determined to be 2.5 g twice daily. Seven adverse events in 5 patients were reported as possibly drug-related; 6 were GI toxicity and 1 was a skin disorder. All were grade 1 except one grade 2 vomiting. No RECIST responses were seen. Six pts were treated with > 2 cycles; one for 8 cycles. Four patients had reductions in TGF –β and EGF, exploratory biomarkers possibly suggestive of a drug effect. Plasma half-lives of 1 -2 hours were noted for all parent drug chemical markers with no accumulation over time. Conclusion: OMN54 was well tolerated, with no DLTs observed. Further studies at the RP2D will assess the biological activity.

scholarly journals Urinary Excretion and Bactericidal Activities of Gemifloxacin and Ofloxacin after a Single Oral Dose in Healthy Volunteers

2001 ◽  
Vol 45 (12) ◽  
pp. 3524-3530 ◽  
Author(s):  
Christoph K. Naber ◽  
Michaela Hammer ◽  
Martina Kinzig-Schippers ◽  
Christian Sauber ◽  
Fritz Sörgel ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Urinary Tract ◽  
Urinary Excretion ◽  
Enterococcus Faecalis ◽  
Urinary Tract Infections ◽  
Parent Drug ◽  
Oral Dosage ◽  
Tract Infections ◽  
Cumulative Excretion

ABSTRACT In a randomized crossover study, 16 volunteers (8 men, 8 women) received single oral doses of 320 mg of gemifloxacin and 400 mg of ofloxacin on two separate occasions in the fasting state to assess the urinary excretion and urinary bactericidal titers (UBTs) at intervals for up to 144 h. Ofloxacin showed higher concentrations in urine compared with those of gemifloxacin. The median (range) cumulative excretion of gemifloxacin was 29.7% (8.4 to 48.7%) of the parent drug administered, and median (range) cumulative excretion of ofloxacin was 84.3% (46.5 to 95.2%) of the parent drug administered. The UBTs, i.e., the highest twofold dilutions (with antibiotic-free urine as the diluent) of urine that were still bactericidal, were determined for a reference strain and nine uropathogens for which the MICs of gemifloxacin and ofloxacin were as follows:Escherichia coli ATCC 25922, 0.016 and 0.06 μg/ml, respectively; Klebsiella pneumoniae, 0.03 and 0.06 μg/ml, respectively; Proteus mirabilis, 0.125 and 0.125 μg/ml, respectively; Escherichia coli, 0.06 and 0.5 μg/ml, respectively; Pseudomonas aeruginosa, 1 and 4 μg/ml, respectively; Staphylococcus aureus, 0.008 and 0.25 μg/ml, respectively; Enterococcus faecalis, 0.06 and 2 μg/ml, respectively;Staphylococcus aureus, 0.25 and 4 μg/ml, respectively;Enterococcus faecalis, 0.5 and 32 μg/ml, respectively; and Staphylococcus aureus, 2 and 32 μg/ml, respectively. Generally, the UBTs for gram-positive uropathogens were higher for gemifloxacin than for ofloxacin and the UBTs for gram-negative uropathogens were higher for ofloxacin than for gemifloxacin. According to the UBTs, ofloxacin-resistant uropathogens (MICs, ≥4 mg/liter) should also be considered gemifloxacin resistant. Although clinical trials have shown that gemifloxacin is effective for the treatment of uncomplicated urinary tract infections, whether an oral dosage of 320 mg of gemifloxacin once daily is also adequate for the treatment of complicated urinary tract infections has yet to be confirmed.

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