Pharmacokinetic Processes

To elicit an effect on its target, a drug must be absorbed and then distributed to its binding site before being metabolized and excreted.9-11 These pharmacokinetic processes affect the amount of free drug that ultimately will reach its binding site on a receptor. At all times, free drug in the systemic circulation is in equilibrium with its protein-, tissue reservoir-, and receptor-bound fractions (Figure 5). Only the receptor-bound fraction will have a pharmacologic effect.

Figure 5.
To elicit an effect on its target, a drug must be absorbed and then distributed to its binding site before being metabolized and excreted
To elicit an effect on its target, a drug must be absorbed and then distributed to its binding site before being metabolized and excreted.

All human cells have a lipid bilayer cytoplasmic membrane consisting mainly of phospholipids, sterols, and glycolipids. The membrane’s semipermeable lipid bilayer presents the major barrier to drugs. Nonetheless, most small, nonpolar, lipophilic molecules are able to diffuse through lipid bilayer membranes along the concentration gradient by passive diffusion until equilibrium is reached. However, passive diffusion is ineffective for the transport of large, polar molecules.

Since only the nonpolar faction of a drug can diffuse across biological membranes, net diffusion of acidic and basic drugs is affected by a charge-based phenomenon known as pH trapping, which depends on a drug’s acid dissociation constant (pKa) and the pH of the biological environment (Figure 6). The pKa of a drug is defined as that pH of a biological medium at which 50% of the drug is protonated (i.e., electrically neutral) and 50% is deprotonated (i.e., electrically negative).

Figure 6.
Chart showing the relationship between the pKa of an acidic and a base drug
The relationship between the pKa of an acidic (AH) and a basic (B) drug and the pH of the biological medium. Note that at low pH the predominant fraction of a basic drug is ionized; conversely, the predominant fraction of an acidic is nonionized.

This charge-based phenomenon can be illustrated with the use of lidocaine (pKa 7.8). When administered into a healthy extracellular environment, which is more acidic (pH 7.4) in relation to lidocaine’s pKa of 7.8, the protonated, electrically neutral form of lidocaine, which can diffuse into a neuron, represents about 28% of the dose administered. When lidocaine is administered into an inflamed/infected area (pH <7.4), its neutral fraction is further reduced and anesthesia fails.

Lipid bilayer plasma membranes also contain transmembrane proteins of the human solute carrier (SLC) superfamily, which can transport some polar drugs across biological membranes. Protein channels or carrier proteins may facilitate the transport of some drugs down their concentration gradient by energy-independent facilitated transport. The transport of drugs against their concentration gradient may be accomplished by energy-dependent active transport.

Unlike other anatomic regions, the central nervous system (CNS) presents a special challenge to pharmacotherapy. The blood-brain barrier is characterized by specialized tight junctions to prevent passive diffusion of most drugs from the systemic to the cerebral circulation. Drugs designed to act on the CNS must either be sufficiently small and lipophilic to cross the blood-brain barrier or use existing transport proteins in the blood-brain barrier to penetrate the CNS.

Since most drugs reach their sites of action directly from the systemic circulation, drug absorption can limit the drug’s bioavailability, i.e., the fraction of administered drug that reaches the systemic circulation. Drug formulations and routes of administration such as enteral (oral), parenteral (subcutaneous, intramuscular, intravenous, intrathecal), mucous membrane, and transdermal, are chosen to take advantage of transport and other mechanisms that permit the drug to enter the body.

The enteral route is the most common, convenient, economical, and painless method of drug administration. It is also the least predictable. A drug administered orally must be stable until absorbed from the gastric environment. Furthermore, a drug’s rate of absorption is greatly influenced by such factors as the pH of the gastrointestinal tract, gastric motility, splanchnic blood flow, the presence of food in the stomach, and patients’ adherence to the prescribed drug regimen.

Another important determinant of bioavailability, unique to the oral administration of a drug, is first-pass metabolism, a process by which liver enzymes inactivate a fraction of the drug. A drug given enterically that is subject to significant first-pass metabolism must be administered in a quantity sufficient to ensure that an effective concentration of the active drug is reached in the systemic circulation. Drugs administered non-enterically are not subject to first-pass metabolism.

The subcutaneous (SC) route allows for the administration of small volumes of oil-based drugs and provides for a slow rate of drug absorption to maintain steady-state concentrations. Local tissue irritation such as sloughing, necrosis, and severe pain may occur. The intramuscular (IM) route allows for rapid absorption of aqueous solutions, while oil-based formulations provide for slow, constant absorption. This route may be painful and cause intramuscular hemorrhage.

The intravenous (IV) route provides for rapid onset of action and allows for controlled drug delivery into the systemic circulation. The dose can be adjusted to patient response. Administering drugs by the IV route too rapidly or in incorrect doses can result in increased toxicity. Local irritation and thromboembolic complications may occur with some drugs. Drugs administered by the intrathecal (IT) route bypass the blood-brain barrier and reach their target the fastest.

Mucous membrane routes such as sublingual, ocular, pulmonary, nasal, and rectal, because of the highly vascular nature of these tissues, allow for rapid absorption of drugs by passive diffusion as a function of concentration, molecular size, lipid solubility, and pKa of the drug. The transdermal route allows for slow absorption of lipophilic drugs across skin and subcutaneous tissues into the systemic circulation and is ideal for drugs that require prolonged administration.

Once a drug has been absorbed into the systemic circulation (vascular compartment), it is then capable of reaching any target organ by the process of distribution. The volume of distribution (Vd) reflects the extent to which a drug is partitioned between plasma and various other tissue compartments. Thus, the Vd is low for drugs that are retained within the vascular compartment and high for drugs that are highly distributed to adipose tissue and various other tissue compartment.

As an illustration, consider the effect of two drugs of equal potency administered to a patient. The drug that is more highly distributed among the various body tissues requires a higher initial dose to establish a therapeutic plasma concentration than does a drug that is less highly distributed. The capacity of tissues to absorb drugs increases the tendency of drugs to diffuse from the vascular compartment. This tendency, however, is counteracted by the plasma protein binding of drugs.

Albumin is responsible for most drug-plasma protein binding. Plasma protein binding reduces the availability of free drug for diffusion or transport into other tissues because, in general, only the free or unbound fraction of a drug is capable of crossing biological membranes. The administration of two drugs that bind to plasma proteins result in a higher than expected plasma concentration of the free fraction of either or both drugs as they compete for the same plasma protein binding site.

Most drugs are xenobiotics, substances that are not naturally found in the body. Some of these are inherently active drugs used to modulate bodily functions for therapeutic ends. Others are inherently inactive prodrugs that must be converted to active drugs. Active drugs may be further converted to active, inactive or toxic metabolites. Finally, unexcretable drugs and unexcretable active, inactive or toxic metabolites of drugs must be converted to excretable metabolites.

These processes are called drug metabolism or drug biotransformation and are classified as oxidation/reduction reactions and conjugation/hydrolysis reactions. The most common pathway of oxidation/reduction reactions that modify the structure of drugs involve the hepatic microsomal cytochrome P450 enzyme system. Oxidation/reduction reactions can convert a prodrug to its active form; they can also transform drugs to more polar, excretable metabolites.

Conjugation/hydrolysis reactions can also result in the metabolic activation of prodrugs. More commonly, these reactions convert drugs to large, polar molecules in order to inactivate them and to enhance their clearance. The conjugation/hydrolysis enzymes are located in both the cytosol and the endoplasmic reticulum of hepatocytes. Many drugs induce or inhibit enzymes associated with biotransformation, a phenomenon important in understanding drug-drug interactions.

Oxidation/reduction and conjugation/hydrolysis reactions enhance the water solubility of drugs, which facilitates their eliminated from the body. A small number of drugs are excreted in the bile, or through the respiratory and dermal routes. Most drugs are eliminated through renal excretion. Drugs may be filtered at the renal glomerulus, secreted into the proximal tubule, reabsorbed from the tubular lumen and transported back into the blood, and excreted into the urine.

The rate of drug metabolism and excretion by an organ is limited by the rate of blood flow to that organ. Most drugs demonstrate first-order kinetics, i.e., the amount of drug that is metabolized and excreted in a given unit of time is directly proportional to the concentration of the free drug in plasma at that time. A small number of drugs demonstrate saturation or zero-order kinetics, i.e., metabolic and clearance rates fail to increase with increasing plasma drug concentrations.

The distribution half-life of a drug is the time required to distribute 50% of a drug from plasma to tissue reservoirs. The amount of time over which a drug’s concentration in plasma decreases to one-half of its original value because of metabolism and excretion kinetics is known as the elimination half-life (t1/2) of the drug. Knowing a drug’s t1/2 allows the clinician to establish the frequency of dosing required to maintain a drug’s plasma concentration within therapeutic range.

Therapeutic dosing seeks to maintain the trough (lowest) drug concentration above the minimally effective dose and the peak (highest) plasma drug concentration below the toxic concentration. It takes four t1/2 for tissue distribution and plasma concentration of a drug to reach steady-state (Figure 7). A loading dose, i.e., a much higher initial dose than would be required if the drug were retained in plasma, may be used to achieve therapeutic levels with only one or two doses of drug.

Figure 7.
Chart showing at optimal dosing, steady-state plasma concentration remains within the therapeutic range
At optimal dosing, steady-state plasma concentration remains within the therapeutic range.

However, continued excessive drug dosing may saturate the body’s capacity to eliminate the drug, e.g., overwhelm the hepatic cytochrome P450 enzyme system. When the elimination rate of the drug does not increase with increasing plasma drug concentrations, it may reach toxic levels. Once steady-state concentration of a drug is achieved, subsequent doses, i.e., maintenance doses need to replace only the amount of drug that is lost through metabolism and excretion.