Drug Metabolism and Disposition

Drug Metabolism and Disposition
Title	Drug Metabolism and Disposition
Abbreviation	Drug Metab. Dispos.
Discipline	Pharmacology, Toxicology
Language	English
Editor	John O. Miners
Publisher	American Society for Pharmacology and Experimental Therapeutics
Country	United States
History	1973–present
Frequency	Monthly
Openaccess	Hybrid
Impact	4.4
Impact-year	2022
ISSN	0090-9556
EISSN	1521-009X
CODEN	DMDSAE
Website	http://dmd.aspetjournals.org/
LCCN	73646238
OCLC	01799907

Drug Metabolism and Disposition. It is a peer-reviewed scientific journal published monthly by the American Society for Pharmacology and Experimental Therapeutics. The journal focuses on the biochemical and molecular mechanisms of drug disposition, including biotransformation and transport, and their impact on pharmacology and toxicology. Its editorial board includes prominent researchers like John O. Miners and it is considered a leading publication in the fields of pharmacokinetics and xenobiotic metabolism.

Overview of Drug Metabolism and Disposition

The study of these processes is fundamental to understanding the therapeutic index and potential adverse drug reactions of pharmaceutical agents. Research published in the journal often explores the fate of compounds from absorption to excretion, a concept central to ADME (Absorption, Distribution, Metabolism, and Excretion). Investigations frequently involve both in vitro systems, such as human liver microsomes, and in vivo studies in models like the Sprague-Dawley rat. The work is critical for regulatory submissions to agencies like the Food and Drug Administration and the European Medicines Agency.

Phases of Drug Metabolism

Drug metabolism is classically divided into Phase I and Phase II reactions. Phase I reactions, mediated primarily by enzymes like the cytochrome P450 superfamily, introduce or unmask functional groups through oxidation, reduction, or hydrolysis. Phase II reactions, involving transferases like UDP-glucuronosyltransferase and sulfotransferase, conjugate these metabolites with endogenous substrates such as glucuronic acid, increasing their water solubility for excretion. A notable example is the metabolism of acetaminophen, which involves both CYP2E1-mediated oxidation and subsequent glutathione conjugation.

Factors Influencing Drug Disposition

Numerous intrinsic and extrinsic factors can alter the processes of metabolism and disposition. Genetic polymorphisms in enzymes like CYP2D6 and CYP2C19 can create subpopulations of poor or ultrarapid metabolizers, affecting drugs like warfarin and clopidogrel. Disease states, particularly those affecting the liver or kidneys, such as cirrhosis or chronic kidney disease, can significantly impair clearance. Environmental factors, including concomitant administration of St. John's wort or grapefruit juice, can induce or inhibit metabolic pathways, leading to drug-drug interactions.

Enzymatic Systems in Drug Metabolism

The cytochrome P450 system, particularly isoforms like CYP3A4, CYP2D6, and CYP2C9, is responsible for metabolizing a vast array of drugs. Other important Phase I enzymes include flavin-containing monooxygenase and epoxide hydrolase. Key Phase II systems are the aforementioned UDP-glucuronosyltransferase family and enzymes like N-acetyltransferase and glutathione S-transferase. Transport proteins, such as P-glycoprotein (encoded by the ABCB1 gene) and members of the solute carrier family, are also crucial for the disposition of drugs across membranes in tissues like the intestine and blood-brain barrier.

Clinical Significance and Applications

Understanding these processes is vital for personalized medicine and avoiding therapeutic failure or toxicity. Pharmacogenomic testing for variants in genes like CYP2C9 and VKORC1 is used to guide warfarin dosing. The concept of the therapeutic window is directly influenced by interindividual variability in metabolism. Research in this area also drives the development of prodrugs, which are inactive until metabolized, and informs the design of clinical trials monitored by bodies like the Institutional Review Board.

Methods for Studying Drug Metabolism

Modern research employs a wide array of techniques. In vitro approaches use recombinant enzymes, human hepatocytes, and subcellular fractions like microsomes from liver preparations. Analytical methods rely heavily on liquid chromatography–mass spectrometry for identifying and quantifying metabolites. In vivo, studies may use animal models, including knockout mouse models for specific enzymes, or human mass balance studies using radiolabeled compounds. Computational modeling and physiologically based pharmacokinetic modeling are increasingly important for prediction.

Category:Pharmacology journals Category:American Society for Pharmacology and Experimental Therapeutics publications Category:Monthly journals