2.2.3.1 Most drug biotransformation occurs in the liver.

However, drugs can undergo biotransformation reaction other sites ( e.g., the gut wall, skin, adrenal glands and bloodstream). There are for main type of chemical reaction which may be involved in drugs biotransformation: (i) oxidation, (ii) reduction, (iii) hydrolysis, (iv) conjugation. The usual effect of drugs biotransformation is to convert drugs into more polar molecules which are less pharmacologically active and more readily excreted than the parent drugs molecules. Most drug oxidation occurs in the liver in the so-called microsomal mixed oxidase system. This group of enzymes appears to have the physiological function of oxidizing endogenous steroids. Such drug oxidation can lead to (i) formation of hydroxy derivatives from acyclic carbon compounds. And particularly formation of phenols from the benzene rings which so often occur in drug molecules, (ii) formation of oxides at nitrogen and sulphur atoms in drug molecules and/or (iii) cleavage of groups from molecules ( often oxidative dealkylation or deamination). Apart from these non-specific enzymatic oxidations. Certain drugs may undergo oxidation by specific enzymes in the liver and other sites (e.g., by monoamine oxidase, alcohol dehydrogenase, aldehyde dehydrogenase). Certain chemical groups in drugs molecules -- e.g. nitro group (-NO2)may be reduced enzymatically, forming amines. Esters (RE-O-R) and to some extent amides (R-CONH2) may undergo enzymatic hydrolytic cleavage. Parent drug molecules, or their first-stage biotransformation products e.g those containing hydroxyl (-OH) groups may undergo conjungtion reaction, mainly in the liver. Most drug conjugation involves linkage to glucoronic acid, producing various types of glucorinade. However, sulphate, glycine, methyl and acetyl conjugatres may also be formed from certain drugs. Because these various biotransformation reaction are enzymatically mediated they are ratelimited and follow Michaelis-Menten kinetics. Despite this, at drug concentrations tolerated in humans the bodys biotransformation capacity for must drugs is far from saturated. Hence the biotransformation process for most drug under therapeutic c conditions can be described mathematically with reasonable accuracy in terms of first-other kinetics. However, at therapeutic concentrations a few drugs (e.g., phenytoin, salicylate) are eliminated by process which clearly follow Michaelis-Menten kinetics. The more simple first-other kinetics may not adequately describe what happens to these drugs in human body. 2.2.3.2 Excretion Drugs and drug biotransformation products may be excreted from the body in urine, feaces. Sweat, saliva, milk, tears and expired air. Except in the case of gaseous anaaesthetics, most drug excretion occurs in urine. 2.2.3.2.1 excretion in urine The renal glomerular capillary endothelium is more permeable to small molecules (MW<69 000) than is capillary endothelium elsewhere in the body. All drug molecules free in plasma water (i.e., not

bound to plasma proteins). Irrespective of ionization, may be filtered from plasma water into glomerular fluid. As glomelural filtrate passed down the renal tubules there is resorption of water and resorption and secretion of ions, with consequent pH changes. As water is resorbed from tubular urine, lipidsoluble (non-ionized) drug molecules are likely to be resorbed passively into extracellular fluid so that their intraluminal concentration does not rise. Drug molecules in ionized form are generally too polar to be resorbed across the renal tubular epithelium and tend to remain behind in the tubular lumen. Here their concentration becomes higher than in extracellular water. Tubular fluid pH is adjusted, particularly in the distal tubules, so that is usually is lower than the pH at which drug molecules are filtered in to glomerular fluid. As tubular fluid pH changes, there maybe concomitant alterations in the proportion of drug molecules in the tubular lumen that are ionized. This is ** alters the extent of drug resorption from distal tubular fluid. The extent to which many drugs are excreted in urine depends on urine pH. Acid urine increase ionization of basic drugs, diminishes their resorption and therefore facilitates their excretion. Conversely, alkaline urine favours the excretion of acid drug. As well as being resorbed from renal tubular fluid does may be actively secreted in to the renal tubular lumen. This occurs particularly in the proximal renal tubules. Here there specific enzymatic mechanisms for secreting acid or basic molecules and glucoronide conjugates. Molecules secreted into the proximal tubular lumen. This occurs particularly in the proximal renal tubules. Here there are enzymatic mechanism for secreting acidic or basic molecules and glucorinade conjugates. Molecules secreted into the proximal tubular lumen may still undergo passive resorption further along the renal tubular system, depending on the various factors discussed above. 2.2.3.2.2. excretion in bile

Drugs and drug metabolites may enter bile from liver cells by passive diffusion along concentration gradients. There are also enzymatic mechanism for active secretion of certain acidic and basic molecules into bile. After bile reaches the small intestine some of drug or drug metabolite that has been excreted into the bile masy be absorbed into the bloodstream across the extensive mucosal surface of the intestine. Thus drug and metabolite molecules may undergo an enterohepatic circulation. Glucoronide conjugates of the drug that are present in bile may undergo hydrolytic cleavage in the small intestine. Owing to the activity of enzyme beta-g;ucoronidase in the intestinal lining, and in intestinal bacteria. This hydrolysis provides drug or drug metabolite molecules which are lesspolar than the glucoronade conjugates. These projects of hydrolysis are therefore more likely to be resorbed across the intestinal mucosa than are the unhydrolysed glucoronide. 2.2.3.2.3 excretion in feces

Drugs which have not been absorbed after oral administration, and also drugs and drug metabolite which have been excreted into bile after initial absorption, but not reabsorbed after their enterohepatic circuit, amy be lost the body in the feces. 2.2.3.2.4. other routes of excretion

Volatile drug (for practical purposes gaseous anaesthetics) are eliminated chiefly by being in expired air, and small quantities of drug maybe lost from the body in sweat, saliva, tears, etc. appreciable drug loss in milk mayoccur in lactating women. In general drugs enter all these various fluid by passive diffusion, and drug concentrations in these fluids tend to similar to drug concentrations in plasma water. However, if drugs bind to proteins, druf concentrations in the fluid with appreciable protein content (e.g. whole milk) may be concentrated in the lipid deposits of milk. Although the excretion of some drugs involves an element of active, enzyme mediated secretion, for thr most part drug excretion is a passive process which follows first-order kinetics. Overall then, drug elimination may involve. (i) Mechaelis-Manten kinetically determined biotransformation, which often occurs at such low substrate concentration in man that simple first-order kinetics usually describes process adequately. Excretion, largely a passive process, which can be described adequately in terms of firstorder kinetics.

(ii)

Therefore, in many instances, the whole process of drug elimination can be accounted for by the use of first-order kinetics. 2.2.4 therapeutic Ranges For some drugs, certain ranges of plasma drug concentration have been determined which give the best chance of controlling the disorder for which the drug is prescribed without producing an undue incidence of unwanted effects. These ranges are termed the therapeutic ranges for the drugs in question. Plasma levels the incidence and/or the severity of unwanted effects in most patients is likely to become unacceptable in relation to the benefit. However, toxicity, particularly idiosyncratic, toxicity, can occur with therapeutic or even subtherapeutic plasma drug levels. It should be realized that the therapeutic ranges have often not been determined by rigorous statistical analysis, but rather loosely derived from clinicians impression. 2.2.5 interactions When two drugs are taken simultaneously by a patient, they may interact. If drug A alters the absorption, distribution, or elimination of drug B (already taken by the patient) the amount of drug B in the plasma water will be changed; its pharmacological effect correspondingly will increase or decrease. Interactions which occur during drug during drug absorption, distribution, or elimination are termed pharmacokinetic interactions. They alter plasma drug concentration. An interaction may also occur when drug A acts at recepotors of drug B to increase or decrease the effect of previously administered drug B. Such pharmacokinetic interactions (e.g. drug egonism, antagonism) do not alter the plasma concentrations of the interacting drugs.

2.2.6 Quantitative Aspect of pharmacokinetics The various kinetics process involved in drug absorption, distribution, and elimination have already been mentioned. While the pharmacokinetic of drugs can usefully be described purely in qualitative term, expression of pharmacokinetic data in numerical terms are appearing increasingly often in the literature. The clinicians need some acquaintance with the quantitative implication of pharmacokinetic parameters so that he may make use of the considerable amount of data already available. Here it is proposed to discuss pharmacokinetic only in very simple way, with emphasis on the clinical implications of the various pharmacokinetic parameters that are commonly described and for which values will be quoted, where possible, when specific drug are discussed later in this book. 2.2.6.1 Time course of Plasma Drugs Levels

When a drug is swallowed, after an interval (the lag time) it begins to appear in plasma in measurable quantities as absorption proceeds. After a time (Tmax) the plasma level reaches its peak; thereafter it declines as elimination exceeds absorption. If the logarithms of plasma drug concentration are plotted against time, both the phase of rising plasma levels (the absorption phase) and the phase of decline levels (the elimination phase) often appear as straight lines, connected by a curved line corresponding to the time of the peak level (figure 2.5)

This is so because, as indicated earlier, in most instances both absorption and and elimination are firstorder processes. To some extent the Tmax is an indication of the speed of drug absorption. However, it is really a measure of the time when elimination begins to excedd absorption. Therefore Tmax depends on both absorption rate and elimination rate. Clinically it is useful to have an indication of when maximum drug action is likely to occur after each dose, and the Tmax may provide such an indication. The slope of the elimination phase line determines the elimination rate constant i.e. the fraction of drug dose eliminated in unit time. The elimination rate constant (k) is often converted into the half-life (T ) , another measure of elimination rate. This quantity is perhaps more easily appreciated by clinicians than is the elimination rate constant itself. The half-life is the time in which plasma drug level falls by half. The half-life is related to the elimination rate constant as follows :

the values on the absorption phase of the plasma level curve may be be subtracted from the values at the corresponding times on elimination phase back extrapolated to the axis of the plasma level-time plot. The differences can provide a plot against ime of the amount of drug still to be absorbed at each

time. From this plot an absorption rate constant, and an absorption half-time (analogous to the elimination parameters discussed above) can be calculated. In some circumstances (e.g. after intravenous administration, ang for certain drugs given orally) the plot of logarithm of plasma levels (the alpha and beta phases). This occurs because the drug is first distributed through a relatively small portion of the body (the central compartment ) and then more slowly distributed through a second peripheral compartment. For many drugs given orally the -phase is not seen, since it occurs while drug absorption is going on and is concealed by this. In the twocompartment situation the slope of the -phases defines the half-line. The area under the plasma level curve (expressed in milligrams per litre hours, or other concentration time units) is proportional to the amount of drug absorbed. If it is assumed there is 100% absorption, as there is after intravenous administration, the dose, divided by the area under the plasma level curve (the AUC), defines the volume of the body cleared of drug each unit of time. That is,

Clearance is a measure of the amount of drug eliminated in unit time. The clearance, divided by elimintastion rate constant (k), defines the apparent volume of the body (the VD) through which the drug is distributed. Hence

Should the full dose of drug not be absorbed when the drug not be absorbed when the drug is given by mouth, the AUC after the drug is given intravenously to the same subject. The ratio

Define the bioavailability of drug, or the extent to which the drug entery to the systematic circulation after oral administration. Impired bioavailability may be due to orally administrated drug disintegrating, dissolving and/or absorbing slowly, so that the full dose not have time to absorbed before the drug is lost from the alimentary tract. However, the appearance of impaired bioavailability can occur if a drug fully absorbed but is very rapidly metabilzed on its first passage through the intestinal wall and/or the liver after it enters portal circulation. Because of this first-pass effect (pre-systematic elimination), the full dose of drug does not reach the systematic circulation unmetabolized. Significant fisrt-pass metabolism may be suspected if bioavailability is incomplete yet a drug is absorbed rapidly, and if its clearance of the drug may approximate the expected value of total portal blood flow i.e. 96 L/hr (L/kg per hour). Pharmacokinetics analysis can be very much more complex than the description above, particularly if the elimination phase follows mixed Michaelis-Menten (biotransformation) and first-order (excretion) processes. However, the simple parameters discussed here are the most generally useful ones. From them the clinician can draw very useful inferences.