Excretion

The kidneys and the liver are the main organs that clear drugs from the body, and the only ones that elicit active excretion processes provided the compounds are ionized. Rates of excretion are always faster for hydrophilic than for lipophilic compounds, however, metabolites cannot be excreted more rapidly than the parent drug, as their excretion is limited by their formation from the parent drug.

5.02.3.5.1 Renal excretion

Three separate processes are involved in renal excretion, namely, glomerular filtration, active tubular excretion, and passive tubular reabsorption.

Glomerular filtration is a simple filtration of plasma through the pores of the glomeruli, whose size allows only the plasmatic free drug and metabolites to be cleared. The amount of compound eliminated is restricted by the glomerular filtration rate and as a result by the renal blood flow. Thus, it may be modified by comedications that increase the rate of elimination of other drugs (e.g., diuretics), and obviously by various pathophysiological conditions.

Active tubular excretion is the process by which tubules excrete ionized compounds, a process requiring energy supply and specific transporters. P-glycoprotein and multidrug resistance-associated proteins (type 2) transfer amphiphilic anions and most of the conjugates. Other transporters transfer organic cations. Most of the renal transporters work from plasma to urine and to a lesser extent back from urine to plasma. The fact that this process involves only ionized compounds underlines the prominent role of plasma pH as a factor influencing the degree of ionization.

Passive tubular reabsorption takes place at proximal and distal tubules. Following filtration, nonionized compounds may return to capillaries provided that a favorable gradient exists. This process involves mostly the more lipophilic parent compounds. It is directed by the pH of elementary urine as a determinant of percentage of the reabsorbed nonionized form.

The total elimination of a parent compound and metabolites requires the integrity of these three separate processes, which themselves depend on plasma pH, urine pH, and renal blood flow. All active processes may be restricted by the amount of available transporters and energy supply, which may lead to competitive drug-drug interactions.

5.02.3.5.2 Hepatic elimination

Three main processes may be involved in the hepatic elimination of a drug and its metabolites, namely uptake, metabolism, and biliary secretion. These processes can be minor or even lacking depending on the physicochemical properties of the drug (e.g., its hydrophilicity). As in the kidney, hepatocytes excrete unchanged drugs and metabolites by active processes involving transporters. As a result, competition for biotransformation and excretion may also take place in the liver. Following bile secretion, the excreted compounds reach the duodenum where they may be either excreted from the body via the feces, partly reabsorbed in enterohepatic recycling, or partly metabolized by the intestinal flora (as an example, conjugated morphine is partly deconjugated). Metabolites may also be excreted in plasma from which they are cleared by kidneys.

In conclusion, prescribing of drugs in a rational way requires a knowledge of what causes pharmacological activity to stop, namely:

• by which processes (biotransformation to inactive metabolites, biliary secretion without reabsorption, or urinary excretion); and

• at which rates (clearance and half-life).

An alteration in any of these processes may necessitate a dosage adjustment or even a drug change.

5.02.3.5.3 Other routes of excretion

Fecal excretion of drugs can result from incomplete intestinal absorption following oral administration, biliary elimination, or direct excretion by enterocytes. Pulmonary excretion is found for volatile agents, even lipophilic ones, but in situ transformation may also occur. Excretion in saliva, sweat, and tears results from passive diffusion processes. Assaying concentrations in saliva may be useful to monitor some drugs or toxins as they reflect free plasma concentrations.

Special attention should be given to the secretion of drugs in breast milk, which, being more acidic than blood plasma, can concentrate basic compounds. Milk also contains a high proportion of lipids, a factor favoring the secretion of lipophilic drugs. The amount of drug transferred by this route from mother to baby is usually low, but it can be sufficient to induce side effects in the newborn, especially in the CNS since the blood-brain barrier is lacking at birth.

Drug disposition in hair has no pharmacokinetic relevance but may indicate drug intake.

5.02.4 Pharmacokinetic Parameters

5.02.4.1 Introduction

Pharmacokinetic parameters are assessed by monitoring variations in concentration of the drug and/or its metabolites in physiological fluids that are easy to access (i.e., plasma and urine). Plasma concentrations are usually checked, and in addition biopsies can be taken from animals and sometimes from humans. Pharmacokinetic parameters give an overall indication of the behavior of the drug in the body; the basic parameters are listed in Table 1.11-13 (Figures 3 and 4) Since the kinetics of absorption, distribution, metabolism, and excretion of a drug are usually linear, a poly-exponential function may be adjusted to the plasma concentrations allowing the calculation of pharmacokinetic parameters. However, adjustment is not always feasible and is not mandatory. It is sufficient to consider the terminal part of the concentrations-versus-time curve, assuming that absorption and distribution, being almost complete, would have no significant influence on both metabolism and excretion. A monoexponential function can then be fitted, according to eqn [8]:

The logarithmic transformation gives eqn [9]:

which is the equation of a straight line. C and l1 can be calculated by linear regression, C being the concentration at time t, C0 the concentration extrapolated to the origin, and l1 the apparent elimination constant.

5.02.4.2 Calculation of Individual Parameters

The lag time (tj) is the time between administration and the first measurable concentration. In the case of oral administration, for instance, it is not nil but corresponds to the time needed for the tablet to disintegrate in the gastrointestinal tract, the drug to dissolve, and absorption to occur. Cmax is deduced from the observation of time-related plasma concentrations. After intravascular bolus administration, Cmax is obviously the first concentration measured, however rapidly the first sampling was taken. After an infusion, Cmax is the concentration measured at the end of the infusion. The time that corresponds to Cmax is tmax.

Table 1 Basic pharmacokinetic parameters

Parameters obtained from plasma concentrations After an intravascular administration (Figure 3)

AUC — area under the curve of a plasma concentration versus time profile CL — total plasma clearance Vd — volume of distribution ti/2 — elimination half-life After an extravascular administration (Figure 4) tl — lag time

Cmax — maximum concentration tmax — time to reach Cmax

AUC — area under the curve of a plasma concentration versus time profile ti/2 — elimination half-life

Parameters obtained from urine concentrations (whatever the route of administration) MU — amount excreted in urine

CLr — renal clearance when plasma concentrations are known

LIN/LIN

LIN/LOG

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