alt="equation"/>
where C0 = the initial apparent plasma concentration. By taking logarithms, the exponential curve can be transformed into a more convenient straight line (right, bottom graph) from which C0 and t1/2 can readily be determined.
Volume of distribution (VD) This is the apparent volume into which the drug is distributed. Following is an intravenous injection:
A value of VD < 5 L implies that the drug is retained within the vascular compartment. A value of <15 L suggests that the drug is restricted to the extracellular fluid, whereas large volumes of distribution (VD > 15 L) indicate distribution throughout the total body water or concentration in certain tissues. The volume of distribution can be used to calculate the clearance of the drug.
Clearance This is an important concept in pharmacokinetics. It is the volume of blood or plasma cleared of drug in unit time. Plasma clearance (Clp) is given by the relationship:
The rate of elimination = Clp × Cp. Clearance is the sum of individual clearance values. Thus, Clp = Clm (metabolic clearance) + Clr (renal excretion). Clearance, but not t1/2, provides an indication of the ability of the liver and kidney to dispose of drugs.
Drug dosage Clearance values can be used to plan dosage regimens. Ideally, in drug treatment, a steady‐state plasma concentration (Cpss) is required within a known therapeutic range. A steady state will be achieved when the rate of drug entering the systemic circulation (dosage rate) equals the rate of elimination. Thus, the dosing rate = Cl × Cpss. This equation could be applied to an intravenous infusion because the entire dose enters the circulation at a known rate. For oral administration, the equation becomes:
where F = bioavailability of the drug. The t1/2 value of a drug is useful in choosing a dosing interval that does not produce excessively high peaks (toxic levels) and low troughs (ineffective levels) in drug concentration.
Bioavailability This is a term used to describe the proportion of administered drug reaching the systemic circulation. Bioavailability is 100% following an intravenous injection (F = 1), but drugs are usually given orally, and the proportion of the dose reaching the systemic circulation varies with different drugs and also from patient to patient. Drugs subject to a high degree of first‐pass metabolism may be almost inactive orally (e.g. glyceryl trinitrate, lidocaine).
Excretion
Renal excretion This is ultimately responsible for the elimination of most drugs. Drugs appear in the glomerular filtrate, but if they are lipid soluble, they are readily reabsorbed in the renal tubules by passive diffusion. Metabolism of a drug often results in a less lipid‐soluble compound, aiding renal excretion (see Chapter 4).
The ionization of weak acids and bases depends on the pH of the tubular fluid. Manipulation of the urine pH is sometimes useful in increasing renal excretion. For example, bicarbonate administration makes the urine alkaline; this ionizes aspirin, making it less lipid soluble and increasing its rate of excretion.
Weak acids and weak bases are actively secreted in the proximal tubule, e.g. penicillins, thiazide diuretics, morphine.
Biliary excretion Some drugs (e.g. diethylstilbestrol) are concentrated in the bile and excreted into the intestine where they may be reabsorbed. This enterohepatic circulation increases the persistence of a drug in the body.
4 Drug metabolism
Drug metabolism has two important effects.
1 The drug is made more hydrophilic – this hastens its excretion by the kidneys (right, ) because the less lipid‐soluble metabolite is not readily reabsorbed in the renal tubules.
2 The metabolites are usually less active than the parent drug. However, this is not always so, and sometimes the metabolites are as active as (or more active than) the original drug. For example, diazepam (a drug used to treat anxiety) is metabolized to nordiazepam and oxazepam, both of which are active. Prodrugs are inactive until they are metabolized in the body to the active drug. For example, levodopa, an antiparkinsonian drug (Chapter 26), is metabolized to dopamine, whereas the hypotensive drug methyldopa (Chapter 15) is metabolized to α‐methylnorepinephrine.
The liver is the main organ of drug metabolism and is involved in two general types of reaction.
Phase I reactions
These involve the biotransformation of a drug to a more polar metabolite (left of the figure) by introducing or unmasking a functional group (e.g. –OH, –NH2, –SH).
Oxidations are the most common reactions and these are catalysed by an important class of enzymes called the mixed function oxidases (cytochrome P450s). The substrate specificity of this enzyme complex is very low and many different drugs can be oxidized (examples, top left). Other phase I reactions are reductions (middle left) and hydrolysis (bottom left).
Phase II reactions
Drugs or phase I metabolites that are not sufficiently polar to be excreted rapidly by the kidneys are made more hydrophilic by conjugation with endogenous compounds in the liver (centre of the figure).
Repeated administration of some drugs (top) increases the synthesis of cytochrome P450 (enzyme induction). This increases the rate of metabolism of the inducing drug and also of other drugs metabolized by the same enzyme (top right). In contrast, drugs sometimes inhibit microsomal enzyme activity (top,
In addition to these drug–drug interactions, the metabolism of drugs may be influenced by genetic factors (pharmacogenetics), age and some diseases, especially those affecting the liver.
Drugs
Most drugs are highly lipophilic and are often bound to plasma proteins. As the protein‐bound drug is not filtered at the renal glomerulus and the free drug readily diffuses back from the tubule into the blood, such drugs would have a very prolonged action if their removal relied on renal excretion alone. In general, drugs are metabolized to more polar compounds, which are more easily excreted by the kidneys. A few drugs are highly polar because they are fully ionized at physiological pH values.