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

Pharmacokinetics 815

structure, polarity, and molecular weight are important change, and the preferential distribution of flow to the
factors in determining whether a drug is excreted in brain, heart, and muscle may result in drug accumulation
the bile. in these organs. Both autopsy studies as well as in vivo
ultrasound examinations have shown that between 20 and
80 years of age, liver size decreases 18–24%. The de-
V. PHARMACOKINETIC VARIABILITY crease in liver size may be a major factor in the decreased
elimination of drugs which are metabolized by enzyme
Age, sex, altered physiologic states such as pregnancy, and systems with limitations in capacity. Clearance studies of
disease states such as hepatic cirrhosis, renal failure, and indocyanine green have demonstrated that liver blood flow
congestive heart failure can produce significant changes in decreases 35% in those over 65 years and that the blood
drug binding, distribution, and elimination. Data are often flow per unit of liver volume falls by 11%. However, due
limited in specific patient conditions, but the following to lack of long term-data, the clinical significance of these
summarizes selected topics. changes in a normal elderly individual is uncertain.

A. Pharmacokinetic Changes in the Elderly B. Transplacental Transfer of Drugs

As the populations of Western countries age, the changes Due to ethical restraints, in vivo human data of drug trans-
which occur with additional years of life have received fer from mother to fetus are very sparse. Because of the
more attention. Studies of healthy adults have demon- lack of knowledge of toxicity to the fetus of many agents,
strated that there is a linear decrease in the following drug usage must be restricted to those medications which
physiologic variables from age 30 to 90: nerve conduc- are absolutely necessary to treat the mother and the child.
tion velocity, basal metabolic rate, standard cell water, Maternal drug absorption will be altered by the physio-
cardiac index, glomerular filtration rate [see Eq. (15)], re- logic changes during pregnancy including decreased in-
nal plasma flow, vital capacity, and maximum breathing testinal motility, a slowing of gastric emptying during
capacity. It is not surprising that there may be changes in late term, and emesis during early pregnancy. These may
drug absorption, distribution, metabolism, excretion in the all contribute to a reduced absorption, a delay in peak
urine, or biological response to the drug. concentration, and a reduced peak concentration. During
While there is evidence that aging likely results in re- pregnancy, the plasma volume increases with concomi-
ducedgastricmotility,increasedgastricpH,decreasedsur- tant changes in red cell volume, and total body fat usually
face area of small intestine, and reduced portal circulation, increases. Although binding affinities remain the same,
there is no evidence that these factors limit absorption after the protein concentration decreases. These alterations af-
oral ingestion. However, drug distribution and elimination fect the volume of distribution of drugs. Metabolism is
may change as a patient ages. Protein binding is quite vari- affected by alteration of the proportion of cardiac output
able in the elderly, with over-65-year-old patients demon- which flows to the liver. Renal elimination during preg-
strating significantly less binding of warfarin and pheny- nancy increases for drugs which are cleared by glomerular
toin than patients 20–40 years old. However, studies of filtration, but secretion by renal tubules is more variable.
diazepam, sulfadiazine, and phenylbutazone revealed no Transferacrosstheplacentaisdependentonanumberof
difference between the elderly and younger patients. With factors: (a) surface area of the membrane, (b) thickness of
aging, the lean body mass tends to decrease, while the the membrane, which thins from 50–100 µm at 2 months
proportion of adipose tissue increases. Thus, an unbound, to 4–5 µm at term, (c) maternal blood flow and intervillous
lipid-soluble drug may have a larger apparent volume of blood pressure, (d) blood pressure in fetal capillaries, and
distribution in an elderly individual than in a younger per- (e) the fetal–maternal osmotic gradient. A large number of
son, while water-soluble drugs may be more concentrated substances such as pituitary and thyroid-stimulating hor-
with a smaller volume of distribution. Because of dimin- mones,insulin,corticotrophin,amines,andlow-molecular
ishedGFRintheelderly[seeEq.(15)],theplasmahalf-life weight heparins are incapable of crossing the placental
of an antibiotic may be prolonged and the urinary concen- membrane. Unbound, nonionized low-molecular weight
tration diminished. If the antibiotic is prescribed to treat a substances transfer by passive diffusion, while large anti-
urinary tract infection, urinary concentrations may be in- bodies cross by endocytosis. Higher lipid solubility also
sufficient to completely treat the infection and this could favors transfer. The standard reference substance in this
cause recurrent or incompletely treated infections in the class is phenazone (antipyrine), and the clearance of a
elderly. given substance is often listed as a clearance index or
Since cardiac output declines 1%/year between ages 19 the ratio of the fetal transfer rate of drug “x” to that of
and 86, regional blood flow to a variety of tissues may phenazone.