2C10, 2C18 and 2C19, as well). A few percent of
all drugs are metabolized by either CYP450 1A2 or
2E1 isoenzymes in humans.
Genetic polymorphisms in CYP450 isoenzymes
are common. Among whites, 5–10% of the
population carries a mutation of CYP450 2D6,
causing them to be ‘slow metabolizers’ of debriso-
quine, mephenytoin, quinidine, metoprolol and
dextromethorphan; standard doses are more likely
to be associated with adverse events as a conse-
quence, especially when a second substrate drug is
interacting.
The elderly have livers that are functionally less
effective than younger adults; CYP450 enzyme
activity reduces correspondingly. The newborns
have relatively reduced CYP450 capability,
although this is uneven, and glucuronidation of
bilirubin at birth is especially poor. The human
fetus uniquely expresses CYP450 3A7; this disap-
pears soon after birth, for reasons that are
unknown.
Wanted interactions at the site of metabolism
include acetaminophen (paracetamol)–N-acetyl
and cysteamine; note above the comments that
this is an atypical isobologram.
‘Methylated spirits’ are used as a fuel for lamps
or heating in some places, and is a mixture of
methanol and ethanol. The methanol component
is supposed to deter ethanol abusers, but, none-
theless, methylated spirits are still drunk in pursuit
of intoxication, especially by the indigent. Both
alcohols are substrates for the same dehydro-
genases. Formaldehyde is more toxic than acetal-
dehyde, and formate is more toxic than acetate,
with the optic nerve being an especially vulnerable
tissue to these toxins. Thus, treating methylated
spirit toxicity with pureethanol can save the
patient’s eyesight because,at theexpense of greater
acetaldehyde exposure, enzyme competition
will lead to increased excretion of unchanged
methanol.
Site of excretion
The principal site of excretion that is liable to drug
interactions is in the kidney. The classic example is
forced alkaline diuresis using intravenous sodium
bicarbonate solution to hasten the excretion of
aspirin. Aspirin is freely filtered by the glomerulus
into the nephron, and is then reabsorbed across the
lipid membrane into the renal parenchyma, and
thence the renal vein. When not ionized, resorption
across the lipid membrane is more than when sal-
icylate is ionized. Salicylate (like sulfate, nitrate,
etc.) is the ion resulting from dissolving an acid.
Making the urine alkaline increases the proportion
of salicylate that is ionized, reduces its resorption
and hence increases its urinary excretion. Note also
that this all worksvice versa. Metamphetamine
(like other compounds ending-amine) is a base:
its excretion can be hastened by acidifying the
urine by using oral ammonium sulfate. These inter-
actions are also beloved by multiple-choice ques-
tion composers.
The techniques of forced diuresis must be
contrasted with the tactics that can be employed to
alter the excretion of drugs that are actively secreted
into the postglomerular nephron. Acidic drugs (e.g.
penicillin) are good candidates for these transpor-
ters. The coadministration of another organic acid
(classically a redundant analgesic called probene-
cid), by competing for the acid transport mechan-
ism, can reduce the urinary excretion of penicillin,
and hence enhance its residence in the body.
Historically, this was used for economy of penicillin
supplies when this drug was very precious during
the Second World War; today, the same tactic can be
used for single-dose treatment of gonorrhea.
There are rare, alternative examples for drug
interactions at other sites of excretion. For exam-
ple, volatile general anesthetics are exhaled, and
drugs that reduce minute ventilation (e.g. benzo-
diazepines perioperatively) consequently reduce
the rate of excretion of isoflurane. Arguably,
because one might also consider these as sites of
absorption interactions, drug excretion rates in the
stool can be increased using oral polyethylenegly-
col to reduce the absorption of oral poisons
(wanted), and oral paraffins (used for constipation)
can increase fat-soluble vitamin excretion
(unwanted).
The clinical laboratoryis the final place where
drug interactions can occur, although only a small
proportion of false-positive, false-negative and
inaccurately quantitated clinical laboratory results260 CH20 DRUG INTERACTIONS