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

816 Pharmacokinetics

Once across the placenta, a drug distributes to the fetus. D. Removal of Drugs by Dialysis
During growth to term, fetal body water decreases while
Patients with less than 10% of normal kidney function
fat volume increases from near zero to 12% at term. The
require renal replacement therapy for removal of waste
amountofproteinforbindingofdrugsandtheiraffinityare
metabolites. In patients undergoing hemodialysis, the total
reduced in the fetus. Metabolism of some drugs by the fe-
clearance of a drug is equal to sum of the clearances due
tal liver is almost nil, while for others it may increase to
to nonrenal routes of elimination (Clr NR ), residual renal
over 30% of the adult capacity. Although fetal urine flow
function (Clr RRF ), and the dialyzer (Clr dialyzer ):
increases progressively through gestation, because of oral
recirculation, most of the elimination is through the mater- Clr total = Clr NR + Clr RRF + Clr dialyzer . (19)
nal circulation. Unfortunately, data are available on only a
Intermittent hemodialysis is the most widely used modal-
limited number of drugs. Extrapolations from substances
ity of renal replacement therapy in the United States.
with similar physical properties may produce large errors
Unbound low-molecular weight drugs are cleared from
of estimation.
the blood in the same way as creatinine. The absolute
mass rate of drug removal can be estimated by measur-
C. Renal Failure ing the drug concentration at the inlet (C inlet ) and outlet
(C outlet ) of the dialyzer and multiplying the difference by
Renal insufficiency, whether due to pre-, post-, or intrin-
sic renal causes, will result in the decreased elimination the blood flow rate (Q B ) through the dialyzer (rate = Q B ×
(C outlet − C inlet ). The clearance will depend on the type
of many drugs. Often, the physician may anticipate a de-
and size of the artificial membrane, properties of the drug
creased renal function from unanticipated high trough lev-
molecule, and blood and dialyzate flow rates. If measure-
els of a drug such as the antibiotic gentamicin, even if
ment of drug levels are not an option, the Clr dialyzer can
the increased drug levels occur prior to an obvious rise
be estimated from characteristics of the membrane for
in serum creatinine. For a substance primarily excreted
substances of similar molecular weight by the following
unchanged via the kidney, intrinsic renal disease such as
in acute tubular necrosis would cause a decrease in GFR equation:
and perhaps a marked decrease in secretion (Clr KS ). From HCT
Eq. (16), this would cause a proportionate decrease in Clr dialyzer = Clr est × f d 1 − , (20)
100
clearance and result in a longer half-life. If the drug is
blood flow-limited, severe hypotension would result in a where Clr est is the estimated dialyzer clearance from dia-
decreased RBF and a decrease in clearance, in accordance lyzer manufacturer specifications, HCT is the hematocrit,
with Eq. (17). In some cases, renal failure does not result and f d is the unbound fraction of drug. If the physician
in the decreased clearance of a highly bound substance does not have the necessary information to use Eq. (20),
which is primarily excreted by the kidney. As the fraction then levels must be closely monitored in the case of drugs
of unbound drug increases due to renal insufficiency, the which are toxic at high concentration. Drugs with mini-
increase in f d offsets the decrease in GFR and Clr KS in mal toxicity must be dosed with the assumption that in the
Eq. (16). “standard” dialysis treatment a certain percentage of drug
Uremia has a variable effect on hepatic metabolism. is cleared. This latter method is the basis of tabulations of
In uremic rats, demethylation enzymes and cytochrome recommended dosing after dialysis.
P450 decrease their activity 30–40% compared to lev- Drugs are cleared from the blood during peritoneal dial-
els in nonuremic rats. On the other hand, alcohol dehy- ysis in an analogous fashion to the clearance of creati-
drogenase activity is increased in uremia 50–90% above nine or other plasma constituents. Transport between the
normal physiologic conditions, but uremia produces in- blood and the peritoneal cavity is symmetric in the sense
hibiting factors of hepatic systems. Indeed, the nonrenal that transport rates are equivalent in each direction, and
clearances of many drugs used daily in hospitals such as therefore if the PA (mass transfer–area coefficient) for a
the cephalosporins, imipenem, metoclopramide, or pro- substance of equivalent molecular weight is available, the
cainamide are significantly decreased by end-stage renal transfer rate can be estimated from
disease (ESRD). The half-life of many anxiolytic drugs
drug transfer rate = PA × (C B − C PC ). (21)
such as benzodiazepines are markedly prolonged in renal
failure. The dosage interval must be adjusted carefully. Clearances and recommendations on dosing are tabulated
Guidelines for dosing many commonly used medications in several references. All of these tabulations assume that
are typically based on ranges of GFR or creatinine clear- the peritoneum is normal; inflammation which results
ance and are readily available in pocket-size form (e.g., from acute peritonitis can cause significant increases in
Bennett et al., 1994; Chernow, 1995). rates of transport.