As shown in the previous chapter (see Fig. 7.4), a drug is nearly in constant motion from the instant it is introduced into the body until the time it leaves. Thus, the therapeutic target essentially responds to a running stream of drug of varying concentration. Chapter 9 discusses how this is relevant to the therapeutic response in vivo; this present chapter relates to the factors controlling the characteristics of that motion, what drug properties affect it and how they can be measured and quantified.

The process of permeation and absorption controls the rate of entry of a drug into the central compartment; once there, immediate factors begin the process of drug clearance from the body and/or other processes that make the drug inaccessible to the therapeutic target. One of those, namely plasma protein binding, has been discussed briefly in Chapter 7. This process sequesters drug away from metabolic and renal processes of removal; it will be seen later in this chapter that plasma protein binding keeps the drug in the central compartment and does not allow it to be sequestered into other tissues. This has the effect of reducing the volume of distribution of the drug (vide infra). While plasma protein binding reduces free drug concentration, generally it is not a problem that needs to be addressed through medicinal chemical alteration of the molecule (see Box 8.1). This is because dosing is usually adjusted to accommodate it and limitations in free drug concentration are somewhat offset by a reduction in clearance afforded by plasma protein binding. For example, the antimuscarinic antagonists Zamifenacin and Darifenacin are of comparable potency (between two- to four-fold differences in IC₅₀) but differ by a factor of 300 in their plasma protein binding (Darifenacin is 94% protein bound while Zamifenacin is 98.98% protein bound). In spite of this radical difference in plasma protein binding, the equieffective clinical doses of Zamifenacin and Darifenacin differ by only a factor of two. In addition, the physico-chemical changes needed to change plasma protein binding are usually extensive and probably would interfere with primary activity or other ADME properties. The one realm where plasma protein is important is when clinical dose is compared to observed response and the true potency (and safety margin) of drugs needs to be calculated. This will be considered further in the next chapter (Chapter 9) on the measurement of pharmacologic effect in vivo.

In addition to these factors, there are three forces moving drugs out of the central compartment (see Fig. 7.4), these are: (1) distribution to other compartments in the body; (2) renal excretion and (3) hepatic metabolism. Of these, hepatic metabolism is usually the most important and this will be considered first.

The body is a non-equilibrium system where drugs enter at a certain rate and are removed at a certain rate; the removal of a drug from the body is referred to as drug clearance. Drugs can be cleared through numerous organs in the body (i.e., liver, kidney, brain, lungs, sweat glands, etc.) and these are all treated as processes connected in parallel, except for the lungs which are considered a series process. Drugs introduced via the oral route undergo first pass metabolism (absorption from the gastrointestinal tract and then immediate shunting via the portal vein into the liver) while drugs introduced into the central compartment by other routes of administration are mainly cleared by the hepatic or renal system. The central compartment is cleansed of drug by cyclic filtering through either the liver or kidney (or both) until the drug is eliminated (see Fig. 8.1). In practical terms for non-polar drugs, the main organ of clearance is the liver. The efficiency of the liver as a removal organ can be quantified by an extraction ratio (E_H) given by:

Thus, if a concentration of 1mg/L enters the liver and 0.3mg/L emerges, this would be an extraction ratio of 1 − (0.3/1)=0.7, i.e., 70% of all drug that enters the liver is metabolized. Clearance is the rate of complete cleansing of a given volume of body water per unit time. Thus, if the liver receives 20mL/min•kg of blood (this is the Q_H of the liver blood flow for a healthy adult) and a removal process extracts 70% of this, then the hepatic clearance (CL_H) is given by Q_H×E_H=20mL/minkg×0.7=14mL/minkg. For a 70kg male this equals 980mL/min. It is useful to denote levels of clearance in general terms as a fraction of liver blood flow. For a healthy male, liver blood flow is 1450mL/min. Thus, a clearance value of 0 to 40% of liver blood flow is considered low (<580mL/min), 40–70% medium (580 to 1015mL/min) and >70% (>1015mL/min) high clearance.

Clearance is extremely important in pharmacokinetics as it determines the dose rate for clinical infusions to achieve therapeutic steady-state concentrations and it determines the dosing schedule for repeat administration in chronic treatment. It is the single most important determinant of whether a drug is a once a day, twice a day, etc., treatment. It can be measured in vivo by comparing the exposure to drug (expressed as the area under the concentration–time curve) and the dosage; it should be noted when in vivo clearance is measured in this way there is no restriction as to mechanism, i.e., it may be a mixture of removal mechanisms including hepatic and renal. Thus, Clearance_invivo is given by CL=Dosage_iv/AUC_iv (see Fig 8.2).

One additional mechanism of drug clearance related to hepatic function is secretion into the enterohepatic circulation. The liver secretes from 0.25 to 1L of bile each day containing anions, cations and low molecular weight (<300) non-ionized molecules. The lower molecular weight compounds are reabsorbed before being excreted into the bile duct, but molecules of high molecular weight (approximately 500 or greater) can be secreted into the bile duct and continue on to be deposited into the gastrointestinal tract. The glucuronide conjugates of small polar structures can attain these sizes and glucuronides are known to take part in enterohepatic excretion. A practical aspect of this for clinical trials (and therapy) is the observation that some drugs that take part in this process (i.e., chloramphenicol; see Box 8.2) can demonstrate large secondary oral absorption curves after a meal as the bile is secreted into the GI tract in response to food.

A main pathway for drug excretion from the body is through the kidney; this is the primary method of clearance for polar water-soluble chemicals. The kidney receives about 173 liters of water a day and returns approximately 171 liters back to the body. It filters water at a rate of 110 to 130mLmin⁻¹ through a system of approximately one million nephrons (tubules) that have distinct properties (Fig. 8.3A shows one such tubule). Filtration begins at the glomerulus, an area of vasculature that has uniquely large pores that allow all but protein bound drug (> m.w. 30,000) to pass. The blood passes through the glomerulus at a rate of 1200mLmin⁻¹ and 10^% is filtered through as plasma water. The clearance by glomerular filtration is CL_GF=f_u×GFR where f_u refers to the free fraction of drug (non-protein bound) and GFR is the filtration rate (approximated at 120mLmin⁻¹). The filtrate then progresses to the proximal tubule which has secretory pumps capable of actively transporting drugs from the circulation into the tubule. There are two main secretory processes; one for negatively charged molecules (weak acids) and one for positively charged molecules (weak bases). This process is saturable and designated CL_S (see Fig. 8.3). Finally, in the loop of Henle, all but 1 or 2mL of the 120mL, filtered at the glomerulus, is reabsorbed. It is here that non-ionized membrane-soluble drugs are also reabsorbed according to a concentration gradient. This process is controlled by urine volume (high volume=low gradient=low reabsorption). Since only non-ionized drug is reabsorbed, pH and pK_a may become factors in how much drug is reabsorbed. In cases where urine pH is subject to change (i.e., pH is lowered in conditions of chronic obstructive pulmonary disease, diabetic ketoacidosis, etc.), renal clearance may change for some drugs with disease state.

Referring to Fig. 7.4, it can be seen that another major process that a molecule undergoes, when introduced into the body, is redistribution. The body is comprised of numerous compartments, and drugs, owing to their particular physico-chemical properties, may sequester in some of these but not others. Knowledge of where drugs go in the body can be useful to determine the therapeutic potential of drugs; a tool to make these estimates is the volume of distribution (V_d). The volume of distribution of a drug is a virtual quantity of water into which a given drug would appear to be dissolved when the concentration is measured from the central compartment. Because the body is like a container with a hole in it, drug concentration changes with time. Therefore, to gauge the volume of distribution, the concentration at the instant the drug enters the body is required. This can be measured by estimating the clearance of a single intravenous dose of molecule. Figure 8.4A shows the decay in concentration with time of an intravenous dose of 20mg of an experimental drug. This exponential decay curve can be linearized by plotting the natural logarithm of the concentration with time, as shown in Fig. 8.4B, allowing the extrapolation of the decay curve to time zero. This is the theoretical concentration of drug in the central compartment the instant the drug is injected. From this concentration value and knowledge of the amount of drug injected, the apparent volume of distribution of the drug can be calculated. In this case it is 20mg÷0.5mg/mL=40L. This is approximately the amount of water in a 70kg male, suggesting that the drug is evenly distributed in the body water. This procedure can be used to detect drug sequestration. For example, when 300mg of the antimalarial drug chloroquine is given in a single intravenous dose, the concentration at time zero by extrapolation is 40ng/mL (0.04mg/L). [1] This leads to an estimation of V_d of 300mg÷0.04mg/L=7500L, a volume approximately 180 times the volume of water in a human. This inordinately large V_d value indicates that chloroquine distributes to other tissues and is not present in the central compartment (see Fig. 8.4C). When drugs leave the central compartment and concentrate in other tissues (i.e., adipose tissue, muscle), the central compartment concentration will be exceedingly low and this, in turn, leads to an extremely high apparent volume of distribution. Therefore, high values for V_d are indicative of drug sequestration out of the central compartment. The factors that can cause drugs to be sequestered in special areas of the body (away from the central compartment) are entry into separated compartments such as the blood–brain barrier, mammary circulation, placenta, intracellular tissue binding, high lipid solubility and trapping due to pK_a/pH combinations. Binding of drugs to plasma proteins actually decreases the volume of distribution since it prevents free drug from diffusing elsewhere into the body.

There is a temporal aspect of the distribution of drugs within the body that leads to multi-compartment pharmacokinetics. The body is made up of many compartments of varying size, accessibility and blood flow, and access to these compartments varies with time. Upon injection, drugs rapidly distribute to highly perfused organs such as the liver, brain, kidney and lungs, over a time-scale of minutes. Over a period of hours thereafter, drugs then equilibrate according to their physico-chemical properties throughout the body viscera (muscle, skin, fat). This leads to clearance curves that are more complex than those describing a single compartment. Figure 8.5 shows clearance from a three compartment system where the first two compartments are rapidly cleared to give a steep initial component to the curve; this profile represents redistribution of the drug within the body. The final phase of the curve represents true clearance where the drug leaves the body.