Pharmacokinetics

Pharmacokinetics (in Greek: “pharmacon” meaning drug and “kinetikos” meaning putting in motion, the study of time dependency; sometimes abbreviated as “PK”) is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism. In practice, this discipline is applied mainly to drug substances, though in principle it concerns itself with all manner of compounds ingested or otherwise delivered externally to an organism, such as nutrients, metabolites, hormones, toxins, etc.

Pharmacokinetics is often studied in conjunction with pharmacodynamics. Pharmacodynamics explores what a drug does to the body, whereas pharmacokinetics explores what the body does to the drug. Pharmacodynamics studies the actions of drugs within the body. This includes the routes and mechanisms of absorption and excretion, the rate at which a drug action begins and the duration of the effect, the biotransformation of the substance in the body and the effects and routes of excretion of the metabolites of the drugs. [cite book |author=Elliot, Michelle A.; Anderson, Douglas R.; Keith, Jeff; Novak, Patricia D. |title=Mosby's medical, nursing, & allied health dictionary |publisher=Mosby |location=St. Louis |year=2002 |pages= |isbn=0-323-01430-5 |edition=6th ed. |oclc= |doi= |accessdate=]

ADME

Pharmacokinetics is divided into several areas which includes the extent and rate of Absorption, Distribution, Metabolism and Excretion. This commonly referred to as the ADME scheme.

*Absorption is the process of a substance entering the body.
*Distribution is the dispersion or dissemination of substances throughout the fluids and tissues of the body.
*Metabolism is the irreversible transformation of parent compounds into daughter metabolites.
*Excretion is the elimination of the substances from the body. In rare cases, some drugs irreversibly accumulate in a tissue in the body.

Pharmacokinetics describes how the body affects a specific drug after administration. Pharmacokinetic properties of drugs may be affected by elements such as the site of administration and the concentration in which the drug is administered. These may affect the absorption rate. [cite book |author=Kathleen Knights; Bronwen Bryant |title=Pharmacology for Health Professionals |publisher=Elsevier |location=Amsterdam |year=2002 |pages= |isbn=0-7295-3664-5 |oclc= |doi= |accessdate=]

Analysis

Pharmacokinetic analysis is performed by noncompartmental (model independent) or compartmental methods. Noncompartmental methods estimate the exposure to a drug by estimating the area under the curve of a concentration-time graph. Compartmental methods estimate the concentration-time graph using kinetic models.

Noncompartmental analysis

Noncompartmental PK analysis is highly dependent on estimation of total drug exposure. Total drug exposure is most often estimated by Area Under the Curve methods, with the trapezoidal rule (numerical differential equations) the most common area estimation method. Due to the dependence of the length of 'x' in the trapezoidal rule, the area estimation is highly dependent on the blood/plasma sampling schedule. That is, the closer your time points are, the closer the trapezoids are to the actual shape of the concentration-time curve.

Compartmental analysis

Compartmental PK analysis uses kinetic models to describe and predict the concentration-time curve. PK compartmental models are often similar to kinetic models used in other scientific disciplines such as chemical kinetics and thermodynamics. The advantage of compartmental to noncompartmental analysis is the ability to predict the concentration at any time. The disadvantage is the difficulty in developing and validating the proper model. The simplest PK compartmental model is the one-compartmental PK model with IV bolus administration and first-order elimination. The most complex PK models (called PBPK models) rely on the use of physiological information to ease development and validation.

Bioanalytical methods

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.

Mass spectrometry

Pharmacokinetics is often studied using mass spectrometry because of the complex nature of the matrix (often blood or urine) and the need for high sensitivity to observe low dose and long time point data. 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 or t=0 samples taken before administration are important in determining background and insuring data integrity with such complex sample matrices. Much attention is paid to the linearity of the standard curve; however it is not uncommon to use curve fitting with more complex functions such as quadratics since the response of most mass spectrometers is less than linear across large concentration ranges. [cite journal |author=Hsieh Y, Korfmacher WA |title=Increasing speed and throughput when using HPLC-MS/MS systems for drug metabolism and pharmacokinetic screening |journal=Current Drug Metabolism |volume=7 |issue=5 |pages=479–89 |year=2006 |month=Jun |pmid=16787157 |doi= |url=http://www.bentham-direct.org/pages/content.php?CDM/2006/00000007/00000005/0004F.SGM] [cite journal |author=Covey TR, Lee ED, Henion JD |year=1986 |title=High-speed liquid chromatography/tandem mass spectrometry for the determination of drugs in biological samples |journal=Anal. Chem. |volume=58 |pages=2453–60 |month=Oct |pmid=3789400 |doi=10.1021/ac00125a022] [cite journal | title = Thermospray liquid chromatography/mass spectrometry determination of drugs and their metabolites in biological fluids | author = Covey TR, JB Crowther, EA Dewey, JD Henion | journal = Anal. Chem. |month=Feb | year = 1985 | volume = 57 | issue = 2 | pages = 474–81 |pmid=3977076 | doi = 10.1021/ac50001a036]

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.cite web|url=http://www.emea.europa.eu/pdfs/human/swp/259902en.pdf|title=Position Paper on Non-Clinical Studies to Support Clinical Trials with a Single Microdose|last=Committee for Medicinal Products for Human Use (CHMP)|date=2004-06-23|work=CPMP/SWP/2599/02 Rev 1|publisher=European Medicines Agency, Evaluation of Medicines for Human Use|language=en|accessdate=2008-06-09]

Population pharmacokinetics

"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. [cite journal|last=Sheiner|first=L.B.|coauthors=Rosenberg, B., Marathe, V.V.|date=1977|title=Estimation of Population Characteristics of Pharmacokinetic Parameters from Routine Clinical Data|journal=J. Pharmacokin. Biopharm.|volume=5|pages=445–79 |doi=10.1007/BF01061728] [cite journal|last=Sheiner|first=L.B.|coauthors=Beal, S.L., Rosenberg, B. Marathe, V.V.|date=1979|title=Forecasting Individual Pharmacokinetics|journal=Clin. Pharmacol. Ther. |volume=26|pages=294–305 | pmid = 466923] Certain patient demographic, pathophysiological, and therapeutical features, such as body weight, excretory and metabolic functions, and the presence of other therapies, can regularly alter dose-concentration relationships. 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 that cause changes in the dose-concentration relationship and the extent of these changes so that, if such changes are associated with clinically significant shifts in the therapeutic index, dosage can be appropriately modified. The industry standard software for population pharmacokinetics analysis is NONMEM. [cite journal|last=Beal|first=S.|coauthors=Sheiner L.B.|date=1980|title=The NONMEM System|journal=The American Statistician|volume=34|pages=118–9|doi=10.2307/2684123] . An alternative is MCSim, originally developed for PBPK models.

See also

* blood alcohol concentration
* Biological half-life
* bioavailability
* toxicokinetics
* Patlak plot

References

External links

* [http://pri-home.net/services.html Pharmacokinetic analysis service]
* [http://www.boomer.org/pkin/soft.html Pharmacokinetic software]
* [http://www.biokinetica.pl/Biokinetica%2031.pdf Biokinetica Program]
* [http://www.boomer.org General Pharmacokinetic Info]
* [http://pharmacyinfo.110mb.com/Pharmacokinetics/ Aditional Pharmacokinetic Info]