In vitro-in vivo correlation (IVIVC) of intrinsic clearance in preclinical species of rat and dog was established using the hepatocyte relay method to support high-confidence prediction of human pharmacokinetics for low-clearance compounds. Good IVIVC of intrinsic clearance was observed for most of the compounds, with predicted values within 2-fold of the observed values. The exceptions involved transporter-mediated uptake clearance or metabolizing enzymes with extensive extrahepatic contribution. This is the first assay available to address low clearance challenges in preclinical species for IVIVC in drug discovery. It extends the utility of the hepatocyte relay method in addressing low clearance issues.

https://dmd.aspetjournals.org/content/dmd/early/2013/07/15/dmd.113.053322.full.pdf

In Vitro–In Vivo Correlation for Low-Clearance Compounds Using Hepatocyte Relay Method

1. The excretion and metabolism of [2-(14)C]cimetidine (500 mg orally) was studied in five male volunteers. 2. Over 70% of the 14C was excreted in the urine after 24 h by all individuals with 5% in the faeces; 97% being recovered in total after three days. 3. Unchanged cimetidine was the largest urinary component (63%), followed by a polar conjugate tentatively identified as cimetidine N'-glucuronide (24%). Smaller amounts of the oxidized metabolites, cimetidine sulphoxide and 5-hydroxymethylcimetidine, together with the hydrolysis products, cimetidine guanylurea and cimetidine guanidine, were also observed. 4. Cimetidine and its sulphoxide were identified in faecal samples. Anaerobic incubations of cimetidine or cimetidine sulphoxide with faecal homogenates showed that reduction was the predominant reaction under these conditions. 5. Studies in one individual over a wide dose range (0.5 mg to 1.5 g orally) showed little variation in excretory profile or metabolic spectrum.

The metabolism of [14C]cimetidine in man

In vitro–in vivo correlation (IVIVC) of intrinsic clearance in preclinical species of rat and dog was established using the hepatocyte relay method to support high-confidence prediction of human pharmacokinetics for low-clearance compounds. Good IVIVC of intrinsic clearance was observed for most of the compounds, with predicted values within 2-fold of the observed values. The exceptions involved transporter-mediated uptake clearance or metabolizing enzymes with extensive extrahepatic contribution. This is the first assay available to address low clearance challenges in preclinical species for IVIVC in drug discovery. It extends the utility of the hepatocyte relay method in addressing low clearance issues.

Special Section on Prediction of Human Pharmacokinetic Parameters from In Vitro Systems In Vitro-In Vivo Correlation for Low-Clearance Compounds Using Hepatocyte Relay Method

Discontinuous absorption property of cimetidine

Pharmacologically Active Compounds and other Thiophene Derivatives

In rats, the bile is not a major route of excretion of cimetidine or its metabolites, since only 10% of the14C associated with an oral dose of labelled cimetidine was excreted in the bile during 8 h after dosing.

Biliary excretion and metabolism of14C cimetidine following oral administration to male and female rats

A series of nitrothiophene compounds, with activity against Schistosoma mansoni in mice, is described and shown to be more effective than the corresponding nitrofurans.

Nitrothiophenes with schistosomicidal activity.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

R. M. Lee

Author Tools

Chat about Author

Papers

Biliary excretion and metabolism of14C cimetidine following oral administration to male and female rats

Nitrothiophenes with schistosomicidal activity.