Custom Search

Tuesday, October 5, 2010

DRUG METABOLISM/DRUG INTERACTION STUDIES DRUG DEVELOPMENT PROCESS STUDIES INVITRO

TECHNIQUES AND APPROACHES FOR STUDIES IN VITRO OF DRUG METABOLISM AND DRUG INTERACTIONS


DRUG METABOLISM/DRUG INTERACTION STUDIES IN THE DRUG DEVELOPMENT PROCESS: STUDIES IN VITRO

After entering the body, a drug is eliminated either by excretion or by metabolism to one or more active or inactive metabolites. When elimination occurs primarily by metabolism, the routes of metabolism can significantly affect the drug’s safety and efficacy and the directions for use. When elimination occurs via a single metabolic pathway, individual differences in metabolic rates can lead to large differences in drug and metabolite concentrations in the blood and tissue. In some instances, differences exhibit a bimodal distribution indicative of a genetic polymorphism (e.g., CYP450 2D6, CYP450 2C19, N-acetyl transferase). When a genetic polymorphism affects an important metabolic route of elimination, large dosing adjustments may be necessary to achieve the safe and effective use of the drug. Pharmacogenetics already has influenced therapeutics. For a drug that is primarily metabolized by CYP450 2D6, approximately 7 percent of Caucasians will not be able to metabolize the drug, but the percentage for other racial populations is generally far lower. Similar information is known for other pathways, prominently, CYP450 2C19 and N-acetyl-transferase. Equally important, if not more so, many enzymatic metabolic routes of elimination, including most of those occurring via the CYP450 enzymes, can be inhibited or induced by concomitant drug treatment. As a result, abrupt changes can occur with a co-administered agent in a single
individual. Such interactions can lead to a substantial decrease or increase in the blood and tissue concentrations of a drug or metabolite or cause the accumulation of a toxic substance (e.g., certain antihistamine-antifungal interactions). These types of changes can alter a new drug’s safety and efficacy profile in important ways, particularly a drug with a narrow therapeutic range.

An understanding of metabolic pathways and potential interactions sometimes allows the use of a drug that would produce an unacceptable level of toxicity if blood levels were not predictable. For these reasons, it is important to learn at an early stage of development whether a drug is eliminated primarily by excretion of unchanged drug or by one or more routes of metabolism. If elimination is primarily by metabolism, the principal metabolizing route(s) should be understood. This information will help identify the implications of metabolic differences between and within individuals and the importance of certain drug-drug and other interactions. Having such information also will aid in determining whether the pharmacologic properties of certain metabolites should be explored further.

OBSERVATIONS AND CONCLUSIONS
The following general observations and conclusions underlie the suggestions found here:

*The concentrations of the parent drug and/or its active metabolite(s) circulating in the body are the effectors of desirable and/or adverse drug actions.

*A principal regulator of drug concentration in the body is clearance. Metabolism can be a major determinant of clearance.

*Even for drugs that are not substantially metabolized, the potential effect of that drug on the metabolism of concomitant drugs could be important.

*Large differences in blood levels can occur because of individual differences in metabolism. Some drugs, such as tricyclic antidepressants, exhibit order of magnitude differences in blood concentrations depending on the enzyme status of patients. Drug drug interactions can have similarly large effects when one drug inhibits the metabolism of another. For example, ketoconazole greatly increases concentrations of parent terfenadine, leading to QT prolongation and torsades de pointes.

*Major advances have been made recently in the availability and use of human tissue and recombinant enzymes for studies in vitro of drug metabolism and drug-drug interactions.

*The development of sensitive and specific assays for a drug and its metabolites is critical to the study of drug metabolism and interactions. Development of such assay methods has long been a high priority for drug development programs, and such assays are increasingly available early in development. Once reliable assays are available, the techniques are available for readily assessing drug metabolism and drug-drug interactions in vitro and interpreting the results.

The studies in vitro described here are one set of approaches to developing
information about drug metabolism and drug-drug interactions. Mechanistic and empirical clinical study approaches are available as well to provide further information. As always, a carefully designed mix of approaches is likely to yield optimal results in the shortest time and at the least cost. Metabolic effects and drug-drug interactions should be considered as early as possible as well as later in the drug development process. Appropriately designed pharmacokinetic/phase 1 studies could provide important information about drug metabolism, relevant metabolites, and actual or potential drug interactions. Blood level data obtained during phase 2 and 3 clinical trials, for example, via a pharmacokinetic screen, also could reveal interactions or marked inter-individual differences. Because clinical trial protocols sometimes limit concomitant drug use, some later studies may not be optimally informative about possible drug interactions. Decreasing exclusions of concomitant drug treatment and
measurement of blood levels before and after treatment with a test drug (interaction screen), as well as testing drug blood levels more frequently, could make later phase clinical studies more useful. All of these studies could be more informative if significant metabolites and prodrugs could be identified and their pharmacological properties described.

Identifying metabolic differences in patient groups based on genetic polymorphisms, or on other readily identifiable factors such as age, race, and gender, could help guide the design of dosimetry studies for such populations groups. This kind of information also will provide improved dosing recommendations in product labeling, facilitating the safe and effective use of a drug by allowing prescribers to anticipate necessary dose adjustments. Indeed, in some cases, understanding how to adjust dose to avoid toxicity may allow the marketing of a drug that would have an unacceptable level of toxicity were its toxicity unpredictable and unpreventable.

Also see :

TECHNIQUES AND APPROACHES FOR STUDIES IN VITRO OF DRUG METABOLISM AND DRUG INTERACTIONS



A. Cytochrome P-450, Microsomes, and Related Tools

B. Other Hepatic Enzymes

C. Gastrointestinal Drug Metabolism

D. Interspecies Metabolic Comparisons and Other Uses of Animal Data

For Reading Above Topics refer http://whoguideline.blogspot.com/2010/10/drug-metabolismdrug-interaction-studies.html


Also see :
CORRELATION BETWEEN STUDIES IN VITRO AND IN VIVO


TIMING OF METABOLISM STUDIES, LABELING, RELATED APPLICATIONS AND CONSIDERATIONS

=====================================================================================================
Do you know now this website has become a most popular and most referred website in pharmaceutical industry and pharmaceutical companies and pharmaceutical manufacturers from all over the world ,for almost all topics related to Pharmaceutical Manufacturing , Pharmaceutical Regulatory Affairs and Good Manufacturing Practice for Pharmaceutical Manufacturing (c GMP guidelines ) and latest news and new drugs developments.

=====================================================================================================
You may also like following articles

Whar is Referance Listed Drug  ? ( RLD )

What is Pharmaceutical Equivalents

What is Pharmaceutical Alternatives

What is Therapeutic Equivalents


Do Physical properties contribute to drug activity.

What is drug receptor , How a drug resistance occurs

Mechanism of drug resistance

What is drug interaction

Drug interaction, and its examples

What is first pass metabolism of a drug

What is What is 510(k) Clearances ?

What is 510(k) Clearances,

Premarket Notification for medical devices - PMN or 510(k)

What is a drug interaction

Examples of drug interactions


Antibiotic Definition and classification


Antibiotic resitance and Antibiotic resistance mechanism

Antioxidants food suppliments

Vitamin D Details on FDA cautions on accurate dosage of Vitamin D


What is an antibody? what is monoclonal and polyclonal antibodies?

Terminologies In vaccine Production

Multi stage testing of Virus vaccine production

Testing of vaccines at different stages of production

TESTING FOR ADVENTITIOUS AGENTS CELL PROPERTIES IN VIRAL VACCINE PRODUCTION

Enzyme linked immunosorbent assay ELISA

Raido Immuno assay

http://whoguideline.blogspot.com/2010/04/terminalogy-and-their-explanations.html

Pharmaceutical Aseptic Manufacturing Process Terms , Terminology and Definitions.

http://whoguideline.blogspot.com/2010/02/pharmaceutical-aseptic-manufacturing.html

Here are some articles which will be useful for you in further understanding of aspects of sterile dosage form manufacturing and regulatory affairs and good manufacturing practice in

pharmaceutical industry

Pharmaceutical Validation

Types of validations in pharmaceutical manufacturing


Requirements of documents for validation of sterilisation process

How to investigate OOS out of specification results

Determination of Phenol coefficient of a disinfectant

Sterility testing

Cleen Room Classification

Time limitations in sterile pharmaceuticals processing

Aspects of validation of manufacturing process in sterile pharmaceuticals

Clinical Trials

Controlling Pyrogens in injectable dosage forms

Media fill run process simulation aspects Validation of Aseptic Process and Sterilisation

New Drug Application (NDA) how to make a New Drug Application (NDA) to US FDA

Abbreviated New Drug Application (ANDA) What is ANDA , detaied information about ANDA preparation and submission to US FDA

How to make Investigational New Drug (IND) Application to US FDA

Drug applications submission to us fda Over the counter Drugs OTC drugs

BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS

Electronic record in pharmaceutical manufacturing industry

Good manufacturing practice in pharmaceutical industry

Pharmaceutical industry pharmaceutical companies and FDA latest updates

Here is an interesting article on world wide pharmaceutical industry and making a carrier in one of pharmaceutical companies article on Pharmaceutical Industry pharmaceutical industry

Find a Job in Pharmaceutical Company
To Find Pharmaceutical jobs and make a Pharmaceutical careers see here pharmaceutical companies
Here are some interesting articles on Quality assurance systems for pharmaceutical company

1.Quality assurance in pharma industry

2.Quality by designe concept for pharmaceutical industry

3.Quality by designe concept in pharmaceutical industryan explanation

No comments:

Posted by: Martin

How to sucessfuly activate and receive our articles on pharmaceuticals by E-Mail

Dear readers if you wish to receive our articles on pharmaceutical automatically into your email Inbox , as and when we write a new article over this website, then follow these 3 simple steps.


1.You should write your Email ID in the box provided and push the subscribe butten


2.Enter the text code that we show you in a small new browser window after you enter your email ID.

3.Log in to your email and Cheke our verification email sent by "FEEDBURNER" , there you should verify the link we send you by email.




Enter your email address get our articles by email whenever this website is updated





Delivered by FeedBurner



Join the list of our readers from Universities ,Research and Development centers Pharmaceutical Companies from all over the world.











Pharma Research Regulatory Guidelines Website
Texas Dallas, TX 75211 US
Email: editor@pharmacistspharmajournal.org Website: http://pharmacistspharmajournal.org/
Copyright © 2008-2015 all rights reserve www.pharmacistspharmajournal.org