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Half of the concentration at the beginning of any period is eliminated during the period. Thus, each successive half-life removes less drug, but the concentration at the beginning of the period is reduced by 50% during the period. "Micrograms per milliliter.

Half of the concentration at the beginning of any period is eliminated during the period. Thus, each successive half-life removes less drug, but the concentration at the beginning of the period is reduced by 50% during the period. "Micrograms per milliliter.

the intravenous formulation (F = 1). The absolute bioavailability of a drug can be calculated as:

where the route of administration is other than intravenous (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 products 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 formulation (e.g., another tablet). Thus, bioavailability is not routinely calculated in an individual patient but reserved for product development by a drug manufacturer. However, it is important to have an idea of how formulations or routes of administration differ with respect to bioavailability so as to allow proper dosage adjustment when changing formulations or routes of administration.

Clearance

Clearance is a pharmacokinetic parameter used to describe 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 example, 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, uptake 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 equations given below:

Dose AUC

where Vd is the volume of distribution (see below) and the remainder of the parameters are as defined previously. One must give the drug intravenously to assure 100% bioavailability, because lack of 100% bioavail-

ability can change the dose numerator, which is required to calculate total clearance. Frequently, however, one wishes to calculate drug clearance but intravenous administration is not feasible. In this situation, the apparent clearance (also called oral clearance) can be estimated by the following equation:

and can be rearranged to give

Cla app F

Dose AUC

The term apparent clearance is used because the bioavailability of the compound is unknown. Thus, estimations of apparent clearance will always be higher than the true systemic clearance because of this unknown bioavailability.

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

Ae AUC

where Ae is the total amount of drug excreted unchanged 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 distribution and the elimination rate, it adjusts for differences in distribution characteristics and elimination rates among people, thus permitting more accurate comparisons 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 intravenous administration, yet this parameter can be profoundly 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 indication 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 distributed throughout extracellular fluid but is unable to penetrate 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 considerably in excess of the entire fluid volume of the body. Thus, because of their physicochemical characteristics, 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 person. 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" volume 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 a1-acid glycoprotein (AGP) to some degree. This becomes clinically important as it is assumed that only unbound (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 pharmacological action and metabolism. If the presence of renal disease 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 results in only a transient increase in free drug concentration, 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.

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