Pharmacokinetics: Absorption, Distribution, Metabolism, and Elimination

Transport of Drugs Across Membranes

Drugs administered orally, intramuscularly, or subcutaneously must cross membranes to be absorbed and enter the systemic circulation. Not all agents need to enter the systemic circulation such as drugs given orally to treat gastrointestinal (GI) tract infections, stomach acidity, and other diseases within the GI tract; however, these agents often cross membranes and are absorbed into the general circulation. Drugs administered by intravenous injection must also cross capillary membranes to leave the systemic circulation and reach extracellular and intracellular sites of action. Even materials directed against platelets or other blood-borne elements must cross membranes. Renal elimination also requires the drugs or metabolites to traverse membranes.

Membranes are composed of a lipid bilayer and are strongly hydrophobic. However, most drugs must have

some affinity for H₂O (i.e., hydrophilicity), or they cannot dissolve and be transported to their sites of action by the blood and other body fluids.

Drugs that are uncharged, nonpolar, and have low molecular weight and high lipid solubility are easily transported across membranes. Compounds that are ionized or in which the electronic distribution is distorted so that there is a separation of positive and negative charge imparting polarity are not compatible with the uncharged nonpolar lipid environment. Also, the ordered lipid membrane does not allow for the existence of aqueous pores large enough (>0.4 nm diameter) to allow passage of most drugs (generally >1 nm diameter); thus only low molecular weight molecules can normally pass through membranes. Large molecular weight proteins cannot pass through many membranes, and often, active transport using carrier molecules is required to accomplish transmembrane transport. Most high molecular weight polypeptides and proteins cannot be administered orally because there are no mechanisms for their absorption from the GI tract, even if they could survive the high acidity of or the proteolytic enzymes in the stomach.

Generally, drugs that have high lipid solubility cross membranes better than those with low lipid solubility. This is exemplified in Figure 2-2 for three different barbiturates. The oil/water equilibrium partition coefficient is a measure of lipid solubility, or hydrophobicity. Drug is added to a mixture of equal volumes of oil and H₂O, and the mixture is agitated to promote solubilization of the compound in each phase. When equilibrium is attained, the phases are separated and undergo assay for drug. The ratio of the concentration in the two phases is the partition coefficient. Therefore the larger the partition coefficient is, the greater the lipid solubility is. Figure 2-2 shows that absorption across the stomach wall is greater for the barbiturate with the largest lipid solubility.

FIGURE 2–2 Increased lipid solubility influences the amount of drug absorbed from the stomach for three different barbiturates. The number above each column is the oil/water equilibrium partition coefficient. The compounds have roughly equivalent pK_a values, so the degree of ionization is similar for all three drugs.

Many drugs are weak acids or bases and take up or release a hydrogen ion. Within some ranges of pH, these drugs will be ionized; in other pH ranges the compounds will be uncharged. The uncharged form of a drug is lipid soluble and crosses biological membranes easily. In the barbiturate example, the compounds were selected so that the pK_a of each drug was similar. Otherwise, the differences in absorption could have been caused by varying degrees of ionization of the three compounds. As discussed in the following text, study of the pH influence helps to predict the distribution of a drug between body compartments that differ in pH.

Influence of pH on Drug Absorption and Distribution

Passive diffusion of a drug that is a weak electrolyte is generally a function of the pK_a of the drug and the pH of the two compartments, because only the uncharged form of the drug can diffuse across membranes. The pH values of the major body fluids, which range from 1 to 8, are shown in Table 2-1. To predict how a drug will be distributed between gastric juice (pH 1.0) on one side of the membrane and blood (pH 7.4) on the other side, the degree of dissociation of the drug at each pH value is determined.

TABLE 2–1 pH of Selected Body Fluids

An acid is defined as a compound that can dissociate and release a hydrogen ion, whereas a base can take up a hydrogen ion. By this definition, RCOOH and RNH₃⁺ are acids and RCOO^–and RNH₂ are bases. The equilibrium dissociation expression and the equilibrium dissociation constant (K_a) can be described for an acid HA or BH⁺ and a base A^– or B, as shown below. The convention for K_a requires that the acid appear on the left and the base appear on the right of the dissociation equation as:

(2-1)

(2-2)

Taking the negative log of both sides yields:

(2-3)

(2-4)

By definition the negative log of [H⁺] is pH and the negative log of K_a is pK_a. Therefore, equations 2-3 and 2-4 can be simplified and rearranged to give:

(2-5)

(2-6)

Equations 2-5 and 2-6 are the acid and base forms, respectively, of the Henderson-Hasselbach equation, and they can be used to calculate the pH of the solution when the pK_a and the ratios of [A^–]/[HA] or [B]/[BH⁺] are known. In pharmacology it is often of interest to calculate the ratios of [A^–]/[HA] or [B]/[BH⁺] when the pH and the pK_a are known. For this calculation, equations 2-5 and 2-6 are rearranged to equations 2-7 and 2-8 as follows:

(2-7)

(2-8)

The results are plotted in Figure 2-3 to show the fraction of the nonionized (HA or B) forms. The pK_a is the pH when the drug is 50% dissociated. Applying equations 2-7 and 2-8 to an acidic drug with a pK_a of 6.0 enables one to calculate the degree of ionization for this drug in the stomach or blood (assuming the blood pH is 7.0 for ease of calculation), as follows:

FIGURE 2–3 Degree of acidic or basic drug in nonionized (uncharged) form (HA, acid; B, base) at different pH values, with pH expressed relative to the drug pK_a.

Stomach: 1.0 – 6.0 = log Y; log Y = –5, or Y = 10^–5; Y =[A^–]/[HA] = 0.00001; if [HA] is 1.0, then [A^–] is 0.00001 and the compound is ionized very little.

Blood: 7.0 – 6.0 = log Y; log Y = +1, or Y =10⁺¹; Y = [A^–]/[HA] = 10.0; if [HA] is 1.0, then [A^–] is 10.0 and the compound is ionized considerably.

Thus the drug is ionized little in stomach but appreciably in blood and should cross easily in the stomach-to-plasma direction but hardly at all in the reverse direction.

Another example is shown in Figure 2-4 for a basic drug. This approach is particularly useful for predicting whether drugs can be absorbed in the stomach, the upper intestine, or not at all. Figure 2-5 provides a summary of the effects of pH on drug absorption in the GI tract for several acidic and basic drugs. It also assists in predicting which drugs will undergo tubular reabsorption, which is discussed later.

FIGURE 2–4 Equilibrium distribution of drug when pH is 4 on one side and 7 on the other side of membrane for an acid drug with a pK_a of 8.0. Nonionized form, HA, of the drug can readily cross the membrane. Thus HA has the same concentration on both sides of the membrane. The concentration of nonionized drug is arbitrarily set at 10 mg/mL, and the expressions are solved to determine the concentration of ionized species at equilibrium.

FIGURE 2–5 Summary of pH effect on degree of ionization of several acidic and basic drugs. Statements refer to compounds with extremes of pK_a values and allow prediction of where drugs with various pK_as will be absorbed.

Most drugs are transported across membranes by simple passive diffusion. The concentration gradient across the membrane is the driving force that establishes the rate of diffusion from high to low concentrations. Other mechanisms, including active transport, facilitated diffusion, or pinocytosis, also exist. Active transport involves specific carrier molecules in the membrane that bind to and carry the drug across the lipid bilayer. Because there are a finite number of carrier molecules, they exhibit classical saturation kinetics. Drugs may also compete with a specific carrier molecule for transport, which can lead to drug-drug interactions that modify the time and intensity of action of a given drug. An active transport system may concentrate a drug on one side of a membrane, because cellular energy is used to drive transport, with no dependence on a concentration gradient. The primary active drug transport systems are present in renal tubule cells, biliary tract, blood-brain barrier, and the GI tract.

Distribution to Special Organs and Tissues

The rate of blood flow determines the maximum amount of drug that can be delivered per minute to specific organs and tissues at a given plasma concentration. Tissues that are well perfused can receive a large quantity of drug, provided the drug can cross the membranes or other barriers present. Similarly, tissues such as fat that are poorly perfused receive drug at a slower rate, so the concentration of drug in fat may still be increasing long after the concentration in plasma has started to decrease.

Two compartments of special importance are the brain and the fetus. Many drugs do not readily enter brain. Capillaries in brain differ structurally from those in other tissues, with the result that a barrier exists between blood within brain capillaries and the extracellular fluid in brain tissue. This blood-brain barrier hinders transport of drugs and other materials from blood into brain tissue. The blood-brain barrier is found throughout brain and spinal cord at all regions central to the arachnoid membrane, except for the floor of the hypothalamus and the area postrema. Structural differences between brain and non-brain capillaries, and how these differences influence blood-brain transport of solutes, are shown schematically in Figure 2-6. Non-brain capillaries have fenestrations (openings) between the endothelial cells through which solutes move readily by passive diffusion, with compounds having molecular weights greater than approximately 25,000 daltons (Da) undergoing transport by pinocytosis. In brain capillaries, tight junctions are present because there are no fenestrations, and pinocytosis is greatly reduced. Special transport systems are available at brain capillaries for glucose, amino acids, amines, purines, nucleosides, and organic acids; all other materials must cross two endothelial membranes plus the endothelial cytoplasm to move from capillary blood to tissue extracellular fluid. Thus the main route of drug entry into central nervous system (CNS) tissue is by passive diffusion across membranes, restricting the available compounds used to treat brain disorders. At the same time, the potential deleterious effects of many compounds on the CNS are not realized, because the blood-brain barrier acts as a safety buffer. Generally, only highly lipid-soluble drugs cross the blood-brain barrier, and thus for these drugs no blood-brain barrier exists. In infants and the elderly, the blood-brain barrier may be compromised, and drugs may diffuse into brain.

FIGURE 2–6

Buy Membership for Basic Science Category to continue reading. Learn more here