Kasutaja:Ehitaja/Ravimi seotus vereplasma valkudega

Ravimi seotus vereplasma valkudega on faktor, mis võib mõjutada olulisel määral ravimi efektiivsust. Mida vähemal määral ravim vereplasmas valkude ehk proteiinidega seondub, seda tõhusamalt võib see läbida rakumembraane või veres hajuda. Tüüpiliselt seovad ravimimolekule sellised verevalgud nagu albumiinid, lipoproteiinid, glükoproteiinid ning α-, β- ja γ-globuliinid.

Sidumine

Veres eksisteerivad ravimid kahel kujul: seotult ja sidumata. Sõltuvalt konkreetse ravimi afiinsusest vereplasma proteiinide suhtes (kalduvusest nendega seotusele) võib osa ravimist siduda end plasmavalkudega ning ülejäänu jääda sidumata. Kui seotus valguga on pöörduv, toimib seotud ja sidumata vormide vahel keemiline tasakaal:

Valk + ravim⇌ Valgu-ravimi kompleks

Väärib tähelepanu, et farmakoloogilist mõju avaldab just ravimi sidumata osa. See on ka see osa, mida keha saab seedida või väljutada. Nii näiteks on antikoagulant varfariini seotud vormi osakaal 97%. See tähendab, et tervest veres sisalduvast varfariini kogusest on 97% seotud vereplasma valkudega. Aktiivne on vaid ülejäänud 3% (sidumata osa)m mis võidakse väljutada. (See ei tähenda aga, et 97% verevalkudest oleks seotud ravimiga.)

Seotus valguga võib mõjutada ravimi bioloogilist poolestusaega. Seotud osa võib toimida tagavarana, millest ravim vabaneb aeglaselt sidumata kujule. Kuna ravimi sidumata vormi hulka kahaneb, kui keha seda seedib või väljutab, vabaneb seotud osa vähehaaval, hoides alal tasakaalu.

Since albumin is alkalotic, acidic and neutral drugs will primarily bind to albumin. If albumin becomes saturated, then these drugs will bind to lipoprotein. Basic drugs will bind to the acidic alpha-1 acid glycoprotein. This is significant because various medical conditions may affect the levels of albumin, alpha-1 acid glycoprotein, and lipoproteins.

Impact of the altered protein binding

Only the unbound fraction of the drug undergoes metabolism in the liver and other tissues. As the drug dissociates from the protein, more and more drug undergoes metabolism. Changes in the levels of free drug change the volume of distribution because free drug may distribute into the tissues leading to a decrease in plasma concentration profile. For the drugs which rapidly undergo metabolism, clearance is dependent on the hepatic blood flow. For drugs which slowly undergo metabolism, changes in the unbound fraction of the drug directly change the clearance of the drug.

Note: The most commonly used methods for measuring drug concentration levels in the plasma measure bound as well as unbound fractions of the drug.

The fraction unbound can be altered by a number of variables, such as the concentration of drug in the body, the amount and quality of plasma protein, and other drugs that bind to plasma proteins. Higher drug concentrations would lead to a higher fraction unbound, because the plasma protein would be saturated with drug and any excess drug would be unbound. If the amount of plasma protein is decreased (such as in catabolism, malnutrition, liver disease, renal disease), there would also be a higher fraction unbound. Additionally, the quality of the plasma protein may affect how many drug-binding sites there are on the protein.

Drug interactions

Using 2 drugs at the same time can sometimes affect each other's fraction unbound. For example, assume that Drug A and Drug B are both protein-bound drugs. If Drug A is given, it will bind to the plasma proteins in the blood. If Drug B is also given, it can displace Drug A from the protein, thereby increasing Drug A's fraction unbound. This may increase the effects of Drug A, since only the unbound fraction may exhibit activity.

	Before Displacement	After Displacement	% increase in unbound fraction
Drug A
% bound	95	90
% unbound	5	10	+100
Drug B
% bound	50	45
% unbound	50	55	+10

Note that for Drug A, the % increase in unbound fraction is 100% – hence, Drug A's pharmacological effect can potentially double (depending on whether the free molecules get to their target before they are eliminated by metabolism or excretion). This change in pharmacologic effect could have adverse consequences.

However, this effect is really only noticeable in closed systems where the pool of available proteins could potentially be exceeded by the number of drug molecules. Biological systems, such as humans and animals, are open systems where molecules can be gained, lost or redistributed and where the protein pool capacity is almost never exceeded by the number of drug molecules. A drug that is 99% bound means that 99% of the drug molecules are bound to blood proteins not that 99% of the blood proteins are bound with drug. When two, highly protein-bound drugs (A and B) are added into the same biological system it will lead to an initial small increase in the concentration of free drug A (as drug B ejects some of the drug A from its proteins). However, this free drug A is now more available for redistribution into the body tissues and/or for excretion. This means the total amount of drug in the system will decrease quite rapidly, keeping the free drug fraction (the concentration of free drug divided by the total drug concentration) constant and yielding almost no change in clinical effect .

The effects of drugs displacing each other and changing the clinical effect (though important in some examples) is vastly overestimated usually and a common example incorrectly used to display the importance of this effect is the anticoagulant Warfarin. Warfarin is highly protein-bound (>95%) and has a low therapeutic index. Since a low therapeutic index indicates that there is a high risk of toxicity when using the drug, any potential increases in warfarin concentration could be very dangerous and lead to hemorrhage. In horses, it is very true that if warfarin and phenylbutazone are administered concurrently, the horse can develop bleeding issues which can be fatal. This is often explained as being due to the effect of phenylbutazone ejecting warfarin from its plasma protein, thus increasing the concentration of free warfarin and increasing its anticoagulant effect. However, the real problem is that phenylbutazone interferes with the liver's ability to metabolize warfarin so free warfarin cannot be metabolized properly or excreted. This leads to an increase in free warfarin and the resulting bleeding issues.

Plasma protein binding prediction software

• Quantum Plasma Protein Binding
• S+ Plasma Protein Binding
• Albumin binding prediction

Kirjandus

• Shargel, Leon (2005). Applied Biopharmaceutics & Pharmacokinetics. New York: McGraw-Hill, Medical Pub. Division. ISBN 0-07-137550-3.

Välislingid

• Plasma Protein Binding Assay
• Dennis A. Smith, Li Di & Edward H. Kerns The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery Nature Reviews Drug Discovery, 2010, Volume 9, pp. 929–939
• Nicole A. Kratochwil, Walter Huber, Francis Müller, Manfred Kansy, Paul R. Gerber Predicting plasma protein binding of drugs: a new approach Biochemical Pharmacology, Volume 64, Issue 9, 1 November 2002, pp. 1355-1374
• Leslie Z. Benet, Betty-ann Hoener Changes in plasma protein binding have little clinical relevance Clinical Pharmacology & Therapeutics (March 2002) Vol. 71, pp. 115–121
• P. E. Rolan Plasma protein binding displacement interactions—why are they still regarded as clinically important? British Journal of Clinical Pharmacology, Volume 37, Issue 2, February 1994, pp. 125–128
• Kenneth M. Piafsky, Olof Borga Plasma protein binding of basic drugs Clinical Pharmacology & Therapeutics (November 1977) Volume 22, Issue 5 part 1, pp. 545–549

Kategooria:Farmakoloogia Kategooria:Biokeemia