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Encyclopedia of Physical Science and Technology EN011J-559 July 25, 2001 18:57

814 Pharmacokinetics

of filtered or secreted drug which is reabsorbed in the effect” is so important to pharmacokinetics and the ulti-
tubules. The pH of the urine can affect the secretion, re- mate effect of a certain dose of drug. Most reactions which
absorption, and overall excretion of ionized compounds; result in conjugation of the drug or metabolite decrease the
an acidic pH promotes excretion of weak bases, while pharmacologic activity of the drug. Thus, administration
an alkaline pH will promote excretion of weak bases. If of a drug via a route without an initial pass through the
there is no secretion or reabsorption, Eq. (16) simplifies liver will usually result in a greater effect for a given drug
to Clr kidney = f d × GFR. dose.
For substances whose transport is limited by the blood
flow in the kidneys, Eq. (16) becomes
C. Extrahepatic Metabolism
Clr kidney = ( f d × GFR + RBF)(1 − f R ), (17)
Although the liver is the major organ of metabolism,
where RBF is the renal blood flow. other tissues, such as mucosa of the gastrointestinal tract,
kidney, lung, brain, and skin also possess enzymes which
metabolize drugs. Indirect evidence of extrahepatic
B. Hepatic Metabolism
metabolism is derived from studies in which observed
Transformation mechanisms of drugs by the liver include rates of metabolism exceed the maximum rate of liver
metabolism, detoxification, and biotransformation. Most blood flow or in which severe liver disease or anhep-
metabolism in the body occurs in the hepatic microsomes, atic conditions have not affected metabolic clearance. En-
a cellular fraction of the endoplasmic reticulum. The four zymeslocatedintheintestinalmucosaarelikelythereason
major processes of metabolism are oxidation, reduction, whyorallydosedmedicationssuchasisoproterenol,terbu-
hydrolysis, and conjugation. Oxidation is carried out by taline, or albuterol must be administered in much larger
the microsomal mixed-function oxidases including cy- doses than if given i.v. The kidney carries out conjuga-
tochrome P450. Reduction involves the biotransforma- tion reactions (such as glucuronidation) and sulfation in

tion of drugs with azo linkages (RN NR ), nitro groups the cortex and medulla. The lung has a high affinity for
(RNO 2 ), and carbonyl compounds (RCOR ). Drugs which basic amines such as meperidine, lidocaine, and fentanyl.

contain ester functions (RCOOR ), amides, or peptides Brain contains monoamine oxidase as well as enzymes

are hydrolyzed in the liver. These three processes often for ketone production; P450 enzyme levels are highest in
produce a compound which is then conjugated with glu- the brain stem and cerebellum. The skin possesses sev-
curonic acid or glutathione for excretion. eral enzyme systems which hydrolyze, reduce, and con-
Often a single drug will have many metabolites includ- vert steroids to active or inactive factors. All of these dis-
ing some which have effects similar to the parent (cy- parate sites play a minor role in relation to the normal liver.
closporin, chlorpromazine). Microsomal drug metabolism However, in severe liver dysfunction, their role in drug
can be stimulated by medications such as the barbiturate metabolism may become prominent.
phenobarbital or by cigarette smoke. Metabolism may be
slowed by medications such as the monoamine oxidase
D. Biliary Excretion
inhibitors which are used in treatment of psychiatric dis-
ease. There are genetic and sex-related differences as well Drugs taken up by hepatocytes may be secreted into the
as age-related effects which may affect an individual pa- bile and flow into the intestine. The drug or metabolite
tient’s metabolism. may either be excreted in the feces or be reabsorbed in
Michaelis–Menten kinetics is often used to describe an the intestine in the process of enterohepatic recycling.
enzymatic process and can be described mathematically This recycling may result in the persistence of the drug
by Eq. (6) [rate = V max C/(K m + C)]. In this case, C is and active metabolites in the body. Some drugs are con-
the drug concentration in plasma, V max indicates the to- centrated in the bile with bile to plasma drug concentra-
tal amount of metabolizing enzyme, K m is the Michaelis tion ratios of 1–1000. Since biliary flow is approximately
constant , and 1/K m is a measure of the affinity between 0.2–0.5 ml/min, the effective biliary clearance can be as
the drug and the enzyme. If C K m , Eq. (6) reduces to: high as 500 ml/min. If, for example, bile is surgically
drained via a T-tube, clearance of a drug which is nor-
V max
rate of metabolism = C = k m C, (18) mally recycled could be considerable, and the half-life of
K m the drug would be markedly decreased. Cardiac glyco-
where k m is the apparent first-order metabolic rate con- sides undergo extensive enterohepatic recycling, and the
stant, which can be used to calculate rates of metabolism. half-life of digitoxin can be significantly decreased by bil-
The liver plays the major role in metabolism of iary drainage or administration of cholestyramine (which
substances in the blood stream. This is why the “first-pass absorbs bile salts and prevents their recycling). Chemical