Pharmacokinetics

Drug Elimination

Drugs are eliminated from the body through metabolism in the liver, excretion from the kidneys, or a combination of both (usually metabolism followed by excretion). The classic drug that is largely metabolized is alcohol, and its elimination past a certain level is entirely metabolic and thus conforms to what is known as zero-order kinetics, in which the absolute amount of drug that is removed from the body over time is constant and conforms to the capacity of the liver to break down the drug. Thus, zero-order kinetics result from the liver’s metabolism of drugs. For alcohol in a nontolerant social drinker, the average metabolism for a 70 kg male is approximately 0.01 gram percent (g%) per hour (for more information, see, Alcohol).

Figure 2.5 Absorption of drugs through different routes of administration. Drugs entering the body through the gastrointestinal tract (oral administration), skin (transdermal administration), or lungs (inhalation) must first cross the epithelial barrier before they can enter the interstitium (or interstitial fluid; the fluid that surrounds cells). Drugs administered subcutaneously or intramuscularly bypass the epithelial barrier and enter the interstitium directly and then must cross the capillary wall. Drugs administered intravenously further bypass the capillary wall and enter the blood stream directly. [Modified with permission from Levine RR. Pharmacology: Drug Actions and Reactions, 2nd edition. Little, Brown and Company, Boston, 1978.]

The excretion of a drug or drug metabolite follows first-order kinetics, in which a constant percentage of the drug in the blood stream is excreted over time. Such a concept reflects the drug’s half-life. Half-life is defined as the time it takes to remove 50% of the drug from the blood stream. As an example, morphine administered intramuscularly at a dose of 10 mg in a 70 kg male produces a blood level of approximately 70 ng/ml. The half-life of morphine is approximately 2.5 h, so, as shown in (Table 2.3), at the 7.5 h time point, the amount of morphine in the blood is reduced to 8.75 ng/ml. The half-life of some drugs can be changed by adjusting the pH of urine. For example, alkaloids, which constitute all major drugs of abuse with the exception of marijuana (see above), can have their half-life significantly shortened by acidifying the urine using ascorbic acid (vitamin C). This is used by physicians in an emergency room, who will intravenously administer ascorbic acid to a patient who presents with amphetamine-induced psychosis. The process by which this works is called ion trapping, in which there is a build-up of a high concentration of a drug across a cell membrane because of a difference in pH across the membrane. Therefore, a basic drug (one with a high pH) will accumulate in the acid (or low-pH) compartment (for example, acidic urine for amphetamine). In an acidic medium, the drug becomes more ionized (more polar/charged and less lipophilic) and thus is less likely to cross a lipid barrier or membrane.

TABLE 2.3

Drug Elimination

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