Additional Pharmacokinetic Parameters

ADDITIONAL PHARMACOKINETIC PARAMETERS

Bioavailability

Bioavailability (designated as F) is defined as the frac-tion of the administered drug reaching the systemic cir-culation as intact drug. Bioavailability is highly depend-ent on both the route of administration and the drug formulation. For example, drugs that are given intra-venously exhibit a bioavailability of 1, since the entire dose reaches the systemic circulation as intact drug. However, for other routes of administration, this is not necessarily the case.

Subcutaneous, intramuscular, oral, rectal, and other extravascular routes of administration require that the drug be absorbed first, which can reduce bioavailability. The drug also may be subject to metabolism prior to reaching the systemic circulation, again potentially re-ducing bioavailability. For example, when the β-blocking agent propranolol is given intravenously, F= 1, but when it is given orally, F= ~0.2, suggesting that only ap-proximately 20% of the administered dose reaches the systemic circulation as intact drug.

With respect to the effect of drug formulation on bioavailability, the drug digoxin provides a good exam-ple. Given orally as a solution, the bioavailability of digoxin approaches F= 1, suggesting essentially com-plete bioavailability and one that approaches that of the intravenous formulation. Digoxin liquid capsules also exhibit F =~1 when given orally and thus are also com-pletely available. However, for digoxin tablets, F =~0.7, suggesting incomplete bioavailability, probably because of lack of absorption.

Two types of bioavailability can be calculated, de-pending on the formulations available and the informa-tion required. The gold standard is a calculation of the absolute bioavailability of a given product compared to the intravenous formulation (F =1). The absolute bioavailability of a drug can be calculated as:

where the route of administration is other than intra-venous (e.g., oral, rectal). For calculation of absolute bioavailability, complete concentration-time profiles are needed for both the intravenous and other routes of administration.

The other computation is that of relative bioavail-ability. This calculation is determined when two prod-ucts are compared to each other, not to an intravenous standard. This is commonly calculated in the generic drug industry to determine that the generic formulation (e.g., a tablet) is bioequivalent to the original formula-tion (e.g., another tablet). Thus, bioavailability is not routinely calculated in an individual patient but re-served for product development by a drug manufac-turer. However, it is important to have an idea of how formulations or routes of administration differ with re-spect to bioavailability so as to allow proper dosage ad-justment when changing formulations or routes of ad-ministration.

Clearance

Clearance is a pharmacokinetic parameter used to de-scribe the efficiency of irreversible elimination of drug from the body. More specifically, clearance is defined as the volume of blood from which drug can be completely removed per unit of time (e.g., 100 mL/minute). Clearance can involve both metabolism of drug to a metabolite and excretion of drug from the body. For ex-ample, a molecule that has undergone glucuronidation is described as having been cleared, even though the molecule itself may not have left the body. Clearance of drug can be accomplished by excretion of drug into the urine, gut contents, expired air, sweat, and saliva as well as metabolic conversion to another form. However, up-take of drug into tissues does not constitute clearance.

In the broadest sense, total (systemic) clearance is the clearance of drug by all routes. Total (systemic) clearance (Cl) can be calculated by either of the equa-tions given below:

where Vd is the volume of distribution  and the remainder of the parameters are as defined previ-ously. One must give the drug intravenously to assure 100% bioavailability, because lack of 100% bioavail- ability can change the dose numerator, which is re-quired to calculate total clearance. Frequently, however, one wishes to calculate drug clearance but intravenous administration is not feasible. In this situation, the ap-parent clearance (also called oral clearance) can be es-timated by the following equation:

The term apparent clearance is used because the bioavailability of the compound is unknown. Thus, esti-mations of apparent clearance will always be higher than the true systemic clearance because of this un-known bioavailability.

The final clearance value that is frequently calcu-lated is that of renal clearance, or that portion of clear-ance that is due to renal elimination. Renal clearance is calculated as:

where Ae is the total amount of drug excreted un-changed into the urine. Calculation of renal clearance is especially useful for drugs that are eliminated primarily by the kidney.

Because clearance estimates the efficiency of the body in eliminating drug, the calculation of clearance can be especially useful in optimizing dosing of patients. Since this parameter includes both the volume of distri-bution and the elimination rate, it adjusts for differences in distribution characteristics and elimination rates among people, thus permitting more accurate compar-isons among individuals. However, as stated earlier, by far the easiest clearance parameter to estimate is that of apparent (oral) clearance, since it does not require in-travenous administration, yet this parameter can be pro-foundly affected by bioavailability of the drug.

Volume of Distribution

Vd relates a concentration of drug measured in the blood to the total amount of drug in the body. This mathematically determined value gives a rough indica-tion of the overall distribution of a drug in the body. For example, a drug with a Vd of approximately 12 L (i.e., interstitial fluid plus plasma water) is probably distrib-uted throughout extracellular fluid but is unable to pen-etrate cells. In general, the greater the Vd, the greater the diffusibility of the drug.

The volume of distribution is not an actual volume, since its estimation may result in a volume greater than the volume available in the body (~40 L in a 70-kg adult). Such a value will result if the compound is bound or sequestered at some extravascular site. For example, a highly lipid-soluble drug, such as thiopental, that can be extensively stored in fat depots may have a Vd con-siderably in excess of the entire fluid volume of the body. Thus, because of their physicochemical character-istics, different drugs can have quite different volumes of distribution in the same person.

The antiinflammatory drug ibuprofen, for example, typically exhibits a volume of distribution of 0.14 L/kg such that for a 70-kg person, the Vd would be 10.8 L. This volume (10.8 L) is approximately equal to the plasma volume of a person that size, suggesting that this drug does not distribute widely into tissues (though it does reach tissues to some degree to exert its action). In contrast, the antiarrhythmic amiodarone has a Vd of 60 L/kg, giving a total Vd of 4200 L for this same 70-kg per-son. This large Vd suggests that amiodarone distributes widely throughout the body; in fact, it does distribute to various tissues, such as the liver, lungs, eyes, and adipose tissue. Since the total volume of the body does not equal 4200 L, it can clearly be seen that this is not a “real” vol-ume but one that relates the blood concentration to the amount of drug in the body.

Protein Binding

Most drugs bind to plasma proteins such as albumin and ₁-acid glycoprotein (AGP) to some degree. This be-comes clinically important as it is assumed that only un-bound (free) drug is available for binding to receptors, being metabolized by enzymes, and eliminated from the body. Thus, the free fraction of drug is important. For example, phenytoin is approximately 90% bound to plasma proteins, leaving 10% of the concentration in the blood as free drug and available for pharmacologi-cal action and metabolism. If the presence of renal dis-ease or a drug interaction were to alter the degree of protein binding to only 80%, this change could have substantial clinical consequences. Even though the total percent bound changes relatively little, the net result is to double the amount of free drug. In fact, for pheny-toin, this can have clinical consequences. However, for most drugs, displacement from protein binding sites re-sults in only a transient increase in free drug concentra-tion, since the drug is rapidly redistributed into other body water compartments. Thus, interactions or changes in protein binding in most cases have little clinical effect despite these theoretical considerations.