Pharmacokinetics: Absorption, Distribution, Metabolism, and Elimination

Chapter 2 Pharmacokinetics: Absorption, Distribution, Metabolism, and Elimination

Abbreviations
CL_h	Hepatic clearance
CL_r	Renal clearance
CNS	Central nervous system
CSF	Cerebrospinal fluid
GI	Gastrointestinal
Km	Michaelis constant
NAD(P)	Nicotinamide adenine dinucleotide (phosphate)
pH	Logarithm of the reciprocal of the hydrogen ion concentration
pK_a	Logarithm of the reciprocal of the dissociation constant
UDP	Uridine diphosphate
V_max	Maximum rate of reaction

WHAT HAPPENS TO DRUGS IN THE BODY?

In nearly all cases drugs must traverse membranes to reach their site of action. The ease by which a compound crosses membranes is key to assessing the rates and extent of absorption and distribution throughout multiple compartments of the body. This chapter considers factors for assessing how specific drugs cross membranes and what variables are most important.

Drugs are transported throughout the circulatory system, and except for a few targeting techniques, end up at tissues and organs where their presence is beneficial and in some areas where their presence may be detrimental. Because of the potential importance of this problem, special mention is made in this chapter about drug distribution to the brain.

The principal routes by which drugs disappear from the body are by elimination of the unchanged drug or by metabolism to other active or inactive compounds, which are subject to further elimination or metabolism.

Numerous factors influence the rate of delivery, distribution, and disappearance of drug to and from its site of action. All these processes and variables, depicted in Figure 2-1, are described in this chapter.

FIGURE 2–1 Factors influencing drug concentration at its site of action and at different times after administration. The circulatory system is the major pathway for drug delivery to its site of action. Possible entry routes and distribution and disposition sites are also shown.

ABSORPTION AND DISTRIBUTION

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

Fluids	pH
Gastric juice	1.0-3.0
Small intestine: duodenum	5.0-6.0
Small intestine: ileum	8
Large intestine	8
Plasma	7.4
Cerebrospinal fluid	7.3
Urine	4.0-8.0

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.