lll ELIMINATION

Elimination is the process of excreting drugs or their metabolites

from the body. The kidneys play a large role in drug
remoal. !hen glomerular filtration rates are decreased in
disease" as eidenced by decreased creatinine clearance #see
$hapter %&" the dose of drugs that are eliminated by the kidney
must be reduced to aoid toxicity. In other 'ords" renal disease
leads to reduced drug excretion" drug accumulation"
and increases the risk of drug toxicities. (hysicians often need
to lo'er drug dosages for patients 'ith renal disease.
As blood enters the renal glomeruli" plasma is filtered of all
substances that #)& are smaller than *+ ,a in si-e and #.& are not protein bound. ,rugs that are un/ioni-ed
and lipid soluble
are readily reabsorbed into the peritubular capillaries from
the renal tubules" 'hereas drugs that are ioni-ed or polar tend
to be retained in the renal tubule and excreted in the urine
#0ig. )/1&. $hanges in urine p2 can alter #increase or decrease&
drug elimination" 3ust as discussed in the section on absorption.
4riefly" acidifying the urine #'ith itamin $ or N25$l&
promotes reabsorption of drugs that are 'eakly acidic #acidic
enironments render 'eak acids un/ioni-ed" 2
A672A&.
On the other hand" alkalini-ing the urine #Na2$O8& causes a
'eak acid to be ioni-ed and thus accelerates its excretion. This
is a great 'ay to detoxify 'eak acids #i.e." salicylate&. E9ually"
toxins that are 'eak bases can be preferentially excreted by
acidifying the urine.
In addition" some drugs are actiely secreted out of the
bloodstream and into the proximal renal tubule ia energydependent
cationic and anionic transport pumps #Table )/%&.
,rugs can compete 'ith one another for binding sites on these
transport pumps: as a result" one drug can inhibit the elimination
of another. (robenecid #used for chronic gout& competes
'ith penicillins and cephalosporins for binding to the anionic
transporter" hence extending the actions of the antibiotics.
Like'ise" cimetidine competes 'ith metformin #an antihyperglycemic&
for the cationic transporter" causingmetformin leels
to increase substantially. These types of competitie interactions
are another classical example of ho' drug/drug interactions
may lead to toxicity.
Other organs also play roles in drug elimination. The mammary
glands typically secrete drugs" such that drug concentrations
found in breast milk approximate ); of the total
maternal dose. 4ecause breast milk is slightly acidic" some
'eak bases may be preferentially concentrated #trapped&
and eliminated through this <excretory= organ. >ome drugs
are eliminated ia s'eat glands" salia" or tears. Although
these are minor routes of drug elimination" they may account
for skin rashes associated 'ith use of some drugs. >ubstances
such as alcohol and olatile anesthetics are eliminated by the
lungs. The lier also plays a role in elimination because some
drugs are eliminated ia the bile and pass out of the body 'ith
fecal matter. This latter route of elimination is also associated
'ith enterohepatic recirculation for some lipid/soluble drugs.
0or example" polar estrogen metabolites are excreted by the
lier into the bile and are then returned to the intestines by the
bile duct. Once in the intestines" normal gut flora can cleae
the estrogen glucuronide" thus recycling the estrogenic parent
compound. 4ecause of the lipophilic nature of steroids" estrogen
can then be reabsorbed and recycled. The end result for a
drug that is recycled in this manner is a prolonged t?. Note
that 'hen antibiotics are administered and the gut flora
has been reduced" estrogen is less likely to be recycled and
hence excreted in feces. !heneer antibiotics are administered
to 'omen using hormonal contraception" there is a possible
risk of reduced efficacy of the contraceptie and a backup
barrier method of contraception should be used