Mass Spectrometry in Drug Metabolism and Pharmacokinetics

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Identifying the CYP enzymes involved in the metabolism of lead compounds is important for predicting potential drug-drug interactions. PK profiles are used for dose translation in pre-clinical disease animal models. Healthy animals are employed to generate time-dependent concentration profiles for calculating clearance and volume of distribution of compounds. Understanding oral bioavailability can help guide the selection of lead compounds for further development. We can identify drug distribution and concentration in 15 different target organs in rodent models.

This information helps to understand drug distribution in the body as well as accumulation in a specific tissue of interest. Drug metabolism and pharmacokinetics DMPK are essential for the process of validation and optimization of compounds prior to licensure by pharmaceutical interests. Both depend on drug metabolism. Drug metabolism has become an integral part of the lead optimization phase in drug discovery. Also, identifying the major metabolic enzymes that act on a drug can predict likely drug-drug interactions that should be evaluated in the process of drug development.

Pharmacokinetics PK is the study of the time course of drug absorption, distribution, metabolism, and excretion in the body. PK and tissue distribution also play important roles in drug development. The liver is the major site of drug metabolism. Human liver microsomes HLM are an important in vitro experimental model for the evaluation of drug metabolism. HLM are subcellular fractions derived from the endoplasmic reticulum of hepatic cells and are prepared by homogenization of liver.

In addition, microsomes are pooled from multiple donors, which minimize the effect of variability between individuals. These subcellular fractions are a rich source of many drug-metabolizing enzymes like cytochrome Ps CYPs , flavin monooxygenases, carboxyl esterases, epoxide hydrolases, and UDP glucuronyl transferases. Therefore, they are widely used as an in vitro model system to investigate the metabolic fate of xenobiotics, their stability, and metabolite identification.

Additionally, recombinant Ps E. Nedderman , Gordon J. Dear , Stephanie E. Nanotracing and cavity-ring down spectroscopy: A new ultrasensitive approach in large molecule drug disposition studies Nicole A. Kratochwil , Stephen R. Approaches to intravenous clinical pharmacokinetics: Recent developments with isotopic microtracers.

Abdul Mutlib, Ph.D.

Graham Lappin. Assessment of the absorption profile of ascorbic acid as a biomarker for moringa oleifera lam absorption after a bolus oral dose Isaac Chipako. Tonika Bohnert , Aarti J. Absolute oral bioavailability and pharmacokinetics of canagliflozin: A microdose study in healthy participants. Disposition and metabolic profiling of [ 14 C]cerlapirdine using accelerator mass spectrometry. References Publications referenced by this paper.

The use of isotopes in the determination of absolute bioavailability of drugs in humans. The models used in non-linear pharmacokinetics are largely based on Michaelis—Menten kinetics. A reaction's factors of non-linearity include the following:. It can therefore be seen that non-linearity can occur because of reasons that affect the entire pharmacokinetic sequence: absorption, distribution, metabolism and elimination. Variable volume pharmacokinetic models can be drug centered models that imply a volume of drug distribution to be that volume in which the drug is distributed at that elapsed time following drug administration.

At a practical level, a drug's bioavailability can be defined as the proportion of the drug that reaches its site of action. Once a drug's bioavailability has been established it is possible to calculate the changes that need to be made to its dosage in order to reach the required blood plasma levels.

Bioavailability is therefore a mathematical factor for each individual drug that influences the administered dose. Therefore, if a drug has a bioavailability of 0. This concept depends on a series of factors inherent to each drug, such as: [13]. These concepts, which are discussed in detail in their respective titled articles, can be mathematically quantified and integrated to obtain an overall mathematical equation:.

When two drugs have the same bioavailability, they are said to be biological equivalents or bioequivalents. This concept of bioequivalence is important because it is currently used as a yardstick in the authorization of generic drugs in many countries. A number of phases occur once the drug enters into contact with the organism, these are described using the acronym LADME:.

Recent Drug Metabolism and Pharmacokinetics Articles - Elsevier

Some textbooks combine the first two phases as the drug is often administered in an active form, which means that there is no liberation phase. Others include a phase that combines distribution, metabolism and excretion into a disposition phase.

Each of the phases is subject to physico-chemical interactions between a drug and an organism, which can be expressed mathematically. Pharmacokinetics is therefore based on mathematical equations that allow the prediction of a drug's behavior and which place great emphasis on the relationships between drug plasma concentrations and the time elapsed since the drug's administration.

Bioanalytical methods are necessary to construct a concentration-time profile. Chemical techniques are employed to measure the concentration of drugs in biological matrix , most often plasma. Proper bioanalytical methods should be selective and sensitive. Pharmacokinetics is often studied using mass spectrometry because of the complex nature of the matrix often plasma or urine and the need for high sensitivity to observe concentrations after a low dose and a long time period.

The most common instrumentation used in this application is LC-MS with a triple quadrupole mass spectrometer. Tandem mass spectrometry is usually employed for added specificity. Standard curves and internal standards are used for quantitation of usually a single pharmaceutical in the samples. The samples represent different time points as a pharmaceutical is administered and then metabolized or cleared from the body. Blank samples taken before administration are important in determining background and ensuring data integrity with such complex sample matrices.

Much attention is paid to the linearity of the standard curve; however it is common to use curve fitting with more complex functions such as quadratics since the response of most mass spectrometers is not linear across large concentration ranges. There is currently considerable interest in the use of very high sensitivity mass spectrometry for microdosing studies, which are seen as a promising alternative to animal experimentation.

Population pharmacokinetics is the study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a drug of interest. For example, steady-state concentrations of drugs eliminated mostly by the kidney are usually greater in patients suffering from renal failure than they are in patients with normal renal function receiving the same drug dosage. Population pharmacokinetics seeks to identify the measurable pathophysiologic factors and explain sources of variability that cause changes in the dose-concentration relationship and the extent of these changes so that, if such changes are associated with clinically relevant and significant shifts in exposures that impact the therapeutic index, dosage can be appropriately modified.

An advantage of population pharmacokinetic modelling is its ability to analyse sparse data sets sometimes only one concentration measurement per patient is available. Clinical pharmacokinetics arising from the clinical use of population pharmacokinetics is the direct application to a therapeutic situation of knowledge regarding a drug's pharmacokinetics and the characteristics of a population that a patient belongs to or can be ascribed to. An example is the relaunch of the use of ciclosporin as an immunosuppressor to facilitate organ transplant. The drug's therapeutic properties were initially demonstrated, but it was almost never used after it was found to cause nephrotoxicity in a number of patients.

This practice has allowed this drug to be used again and has facilitated a great number of organ transplants.


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Clinical monitoring is usually carried out by determination of plasma concentrations as this data is usually the easiest to obtain and the most reliable. The main reasons for determining a drug's plasma concentration include: [24]. Ecotoxicology is the branch of science that deals with the nature, effects, and interactions of substances that are harmful to the environment. From Wikipedia, the free encyclopedia.


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Innovative Tools and Strategies for Lead Optimization and Early Dosing

Please help by editing the article to make improvements to the overall structure. April Learn how and when to remove this template message. Main article: Bioavailability. Main article: ADME. This section needs expansion. You can help by adding to it. April Pure and Applied Chemistry. Pharmacology for Health Professionals. Amsterdam: Elsevier.

Synopsis der Biopharmazie und Pharmakokinetik in German. Journal of Pharmaceutical Sciences. Retrieved Bibcode : PLoSO.. Hemodialysis International.