BASIC PHARMACOKINETIC PARAMETERS

2005-04-09T07:17:00.000-07:00

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Bioavailability and Absorption Rate Constant
The extent of drug absorption into the general circulation is expressed by the bioavailability, the fraction of a dose reaching the plasma site of measurement. The speed of absorption is often expressed by the absorption rate constant. Changes in these 2 parameters influence the maximum (or peak) concentration, the time at which the maximum concentration occurs, and the area under the concentration-time curve after a single oral dose. In chronic drug therapy, bioavailability is the more important measurement because it relates to the average level obtained, whereas the degree of fluctuation is related to the absorption rate constant.

Volume of Distribution and Unbound Fraction
The apparent volume of distribution and the fraction unbound in plasma are the 2 most widely used parameters for drug distribution. The volume of distribution is useful because it allows estimation of the dose required to achieve a given concentration and, conversely, the concentration achieved on administering a given dose. The unbound fraction is useful because it relates the measured total concentration to the unbound concentration, which is presumably more closely associated with drug effects. It is a particularly useful parameter when plasma protein binding is altered, eg, in hypoalbuminemia (a low albumin level), renal disease, hepatic disease, and displacement interactions.

Clearance, Renal Clearance, and Fraction Excreted Unchanged
The rate at which a drug is eliminated from the body is proportional to the plasma concentration. The parameters relating rates of renal excretion and metabolism to the plasma concentration are renal clearance, and metabolic clearance. Because the rate of elimination is the sum of the rates of renal excretion and extrarenal elimination, it follows that

Total clearance = Renal clearance + Extrarenal (metabolic) clearance

The ratio of the rate of renal excretion to the rate of total elimination, also the ratio of renal clearance to (total) clearance, is the fraction excreted unchanged. This parameter is useful in assessing the potential effect of renal and hepatic diseases on drug elimination.

Elimination Rate Constant and Half-life
The elimination rate constant relates the rate of elimination to the amount of drug in the body. As the rate of elimination equals clearance times plasma drug concentration and the amount of drug in the body equals volume of distribution times plasma drug concentration, it follows that

Clearance
Elimination rate constant = __________________
Volume of distribution

Expressed in these terms, the elimination rate constant is a function of how a drug is cleared from the blood by the eliminating organs and how the drug distributes throughout the body.
Half-life (elimination) is the time required for the plasma drug concentration or the amount in the body to decrease by 50%. For most drugs, the half-life remains constant regardless of how much drug is in the body. It is related to the elimination rate constant (0.693) by

0.693
Half-life = ___________________
Elimination rate constant (r)

VARIABILITY IN PARAMETER VALUES
Many of the variables affecting pharmacokinetic parameters have been recognized and can be taken into account
Age and Weight
For some drugs, changes in pharmacokinetics with age and weight are well established. In children and young people, renal function appears to correlate well with body surface area. Thus, for drugs primarily eliminated unchanged by renal excretion, clearance varies with age according to the change in surface area. In persons over age 20, renal function decreases about 1%/yr. For neonates and young infants, both renal and hepatic functions are not fully developed and no generalization, except for the occurrence of rapid change, can be made.
Disease
Renal function impairment: The renal clearance of most drugs appears to vary directly with creatinine clearance, regardless of the renal disease present. The change in (total) clearance depends upon the contribution of the kidneys to total elimination. Thus, (total) clearance is expected to be proportional to renal function (creatinine clearance) for drugs solely excreted unchanged and not to be affected for drugs eliminated by metabolism.
Hepatic disease produces changes in metabolic clearance, but good correlates or predictors of the changes are unavailable. Dramatically reduced drug metabolism has been associated with hepatic cirrhosis. Reduced plasma protein binding is often observed in this disease because of lowered plasma albumin. Acute hepatitis, with elevated serum enzymes, is usually not associated with altered drug metabolism. Heart failure, pneumonia, hyperthyroidism, and many other diseases also alter the pharmacokinetics of drugs.
Drug Interactions
Drug interactions can cause changes in pharmacokinetic parameter values and, therefore, in drug response. Most of these interactions are graded, and the extent of the interaction depends upon the concentrations of both of the interacting drugs.
Dose and Time Dependence
In some instances, the values of the pharmacokinetic parameters change with dose administered, concentration in plasma, or time; eg, a decreased bioavailability of griseofulvin as the dose is increased, a disproportionate increase in the steady-state plasma phenytoin concentration on increasing its dosing rate, and a decrease in plasma carbamazepine concentration during its chronic administration. The decreased bioavailability of griseofulvin is due to the drug's low solubility in the GI tract. Phenytoin shows a concentration (dose) dependency because the metabolizing enzymes have a limited capacity to eliminate the drug, and the usual rate of administration approaches the maximum rate of metabolism. Carbamazepine shows time dependence because it induces its own metabolism.

MONITORING DRUG TREATMENT
Once a therapeutic objective is defined and a drug and dosage regimen are chosen for a patient, drug therapy is conventionally managed by monitoring the incidence and intensity of both therapeutic and undesirable effects.

MONITORING DRUG IN PLASMA
Plasma drug concentration monitoring is a procedure that can provide a facile and rapid estimation of dosage requirements. For some drugs it is routinely useful; for others it can be helpful in certain situations.

INDICATIONS FOR MONITORING
Criteria Related to the Drug
1. The intensity and probability of therapeutic or toxic effects must correlate quantitatively with the plasma level.
2. The objective of the regimen must be to attain and maintain a therapeutic effect.
3. When assessed therapeutic end points are lacking, plasma concentration monitoring becomes particularly attractive; e.g., in antiepileptic therapy, for which the therapeutic end point is the absence of seizures.
4. The probability of a therapeutic problem is greater for a drug with a low margin of safety or a low therapeutic index.
5. Prior knowledge of the therapeutic concentrations and the pharmacokinetic parameters of a drug is essential for plasma concentration monitoring to be effective.
6. Inter-individual differences and, in certain conditions, intra-individual differences in the pharmacokinetics of drugs are principal reasons for monitoring plasma concentrations.

Criteria Related to the Situation
For a patient with GI disease or with a gastric resection, an orally administered drug known to have poor bioavailability may be a candidate for monitoring. Similarly, the presence of renal, hepatic, thyroid, or cardiovascular disease may also suggest monitoring. For drugs that are primarily excreted unchanged, the presence of renal disease requires special attention.

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KINETIC PRINCIPLES OF DRUG ADMINISTRATION

BASIC PHARMACOKINETIC PARAMETERS