Metabolism of a drug sometimes terminates its action, but other effects of drug metabolism are also important. Some drugs, when given orally, are metabolized before reaching the systemic circulation first pass metabolism ( low bioavailability).
Drug metabolism for termination of drug action – the action of many drugs is terminated before they are excreted, since they are metabolized to biologically inactive derivatives (e.g. phenothiazines
Drug metabolism for activating a drug – pro-drugs are inactive when administered and must be metabolized in the body to become active. Many drugs are active when administered and have active metabolites (e.g. levodopa, methyldopa).
Drug elimination without metabolism – some drugs are not modified by the body. They continue to act until they are excreted (e.g. lithium).
Kinetics of metabolism
First order kinetics – the metabolic transformation of a drug is catalyzed by enzymes and most reactions obey the Michaelis-Menten kinetics:
V = rate of drug metabolism = Vmax[C] / (Km + [C])
In most clinical situations the conc. of the drug, [C], is much lower than the Michaelis constant, Km, therefore the equation is:
V = Vmax[C] / Km
That is, the rate of drug metabolism is directly proportional to the conc. of the drug and 1st order kinetics are observed. This means that a constant fraction of drug is metabolized per unit time.
Zero order kinetics – with a few drugs the doses are very large, so the [C] is much greater than Km, and velocity equation becomes:
V = Vmax[C] / [C] = Vmax
A constant amount of drug is metabolized per unit time.
Biotransformation – all higher organisms require mechanisms for ridding themselves of active foreign molecules that are absorbed from the environment as well as for excreting undesirable substances produced within the body. Biotransformation of drugs is one such mechanism.
It is an important mechanism by which the body terminates the action of some drugs.
Most drugs are relatively lipid soluble, which ensures good absorption. This will also result in very slow removal from the body, because the molecule would also be readily reabsorbed from the renal tubules. The body helps excretion by transforming the drug to a less lipid soluble, less rapidly reabsorbed form.
Types of metabolic reactions
Phase-I reactions – include oxidation (esp. by CP450), reduction, deamination, or hydrolysis.
Phase-II reactions – are synthetic reactions that involve
addition (conjugation) of subgroups to
OH-NH2- & -SH functions on the drug molecule. The added subgroups include glucuronate, acetate, glutathione, glycine, sulfate, and methyl groups. Most of these are polar and make the product less lipid soluble than the original drug molecule.
Site of drug metabolism – the liver is the major site. A few drugs are metabolized in many tissues (liver, blood, intestinal wall, etc.), because of broad distribution of their enzymes.
may vary among different individuals. This variation is most often due to
genetic or drug induced differences. Age or disease related differences in drug
metabolism are significant. Gender is important for only a few drugs.
Smoking, a common cause of enzyme induction in the liver, may increase metabolism of some drugs.
Genetic factors several drug metabolizing systems have shown to differ among families or populations in genetically determined ways (e.g. hydrolysis of esters, acetylation of amines, oxidation, etc.). Co-administration of certain agents may stimulate or inhibit the metabolism of many drugs (drug interactions).
Removal of a drug from the body may occur via the kidney into the urine (most important), as well as bile, intestine, lung, body fluids, or milk in nursing mothers. A patient with renal failure may undergo extracorporeal dialysis which will remove small molecules such as drugs.
Quantitative aspects of renal drug elimination – plasma clearance is expressed as the volume of plasma from which all drug appears to be removed in a given time, e.g. as ml/min. Clearance equals the amount of RPF multiplied by the extraction ratio, and since these are normally invariant over time, clearance is constant.
Extraction ratio: the decline of drug plasma conc. from the arterial to the venous side of the kidney:
Extraction = C2 / C1 (the drug enters the kidney at conc. C1 and exits at conc. C2).
Excretion rate (mg/min) = Clearance (ml/min) x Plasma conc. (mg/ml).
The elimination of a drug usually follows 1st order kinetics, and the conc. of drug in the plasma drops exponentially with time. This may be used for determining the t½ of the drug.
Total body (systemic) clearance (CLtotal) – is the sum of the clearances from the various drug metabolizing and drug eliminating organs.
The kidney is often the major organ of excretion. The liver can also contribute to drug loss through metabolism &/or excretion into the bile.
Some drugs may be reabsorbed through the enterohepatic circulation, thus prolonging their T½.
CLtotal = CLhepatic + CLrenal + CLpulmonary + CLother
It is not possible to measure and sum these individual clearances. The total clearance can be derived from the steady state equation: CLtotal = Ke x Vd
Volume of distribution & the t½ of a drug – the half life of a drug is inversely related to its clearance and directly proportional to its volume of distribution:
t½ = 0.693 x (Vd / CLtotal)
The equation shows that as the volume of distribution increases, the t½ of a drug becomes longer. The larger the Vd, the more drug is outside the plasma compartment & is unavailable for excretion by the kidney or metabolism by the liver.
Clinical situations resulting in t½
Diminished RPF, e.g. in cardiogenic shock, CHF or hemorrhage.
Addition of a second drug that displaces the first from albumin and ↑ its Vd.
extraction ratio, e.g. in renal disease.
metabolism, e.g. when another drug inhibits its biotransformation, or hepatic insufficiency.
Rate of drug elimination from the body
First order elimination – the elimination of most drugs at therapeutic doses is ‘first order’, ie the rate of elimination linearly depends on the conc. of drug in the plasma and is equal to the drug plasma conc. multiplied by a proportionality constant:
Elimination rate (mass/time) = constant (vol./time) x drug plasma conc. (vol./time)
This constant is referred to as the clearance of the drug. 1st order elimination occurs when elimination systems aren’t saturated by the drug.
Zero order kinetics: infrequently, the rate of elimination of a drug is ‘zero order’. In this case the mechanism by which the body eliminates the drug is saturated. The rate of drug elimination from the body is thus constant and doesn’t depend on plasma conc.
In this model, the plot of the plasma conc. log vs. time will be concave upward, and a constant amount of drug will be eliminated per unit time.
Zero order elimination may occur when therapeutic doses of drugs exceed the capacity of elimination mechanisms.
Drug interactions can be produced by plasma protein binding of several drugs (or drugs and endogenous compounds), which compete for the binding site on the protein molecule.
Multiple drugs competing for the same binding site can result in higher free blood levels of one or more of the drugs, thereby possibly contributing to toxic effects (e.g. warfarin has many interactions).
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