Page 70 - Basic _ Clinical Pharmacology ( PDFDrive )

4 Drug Biotransformation
C H A P T E R

Maria Almira Correia, PhD

C ASE STUD Y

A 40-year-old woman presents to the emergency department reveal abnormal liver function as indicated by the increased
*
of her local hospital somewhat disoriented, complaining of indices: alkaline phosphatase 302 (41–133), alanine amino-
*
midsternal chest pain, abdominal pain, shaking, and vomiting transferase (ALT) 351 (7–56), aspartate aminotransferase
*
*
for 2 days. She admits to having taken a “handful” of Lorcet (AST) 1045 (0–35), bilirubin 3.33 mg/dL (0.1–1.2), and pro-
*
(hydrocodone/acetaminophen, an opioid/nonopioid analgesic thrombin time of 19.8 seconds (11–15). In addition, plasma
combination), Soma (carisoprodol, a centrally acting muscle bicarbonate is reduced, and she has ~45% reduced glomerular
relaxant), and Cymbalta (duloxetine HCl, an antidepressant/ filtration rate from the normal value at her age, elevated serum
antifibromyalgia agent) 2 days earlier. On physical examina- creatinine and blood urea nitrogen, markedly reduced blood
tion, the sclera of her eyes shows yellow discoloration. Labora- glucose of 35 mg/dL, and a plasma acetaminophen concentra-
*
tory analyses of blood drawn within an hour of her admission tion of 75 mcg/mL (10–20). Her serum titer is significantly
positive for hepatitis C virus (HCV). Given these data, how
* Normal values are in parentheses. would you proceed with the management of this case?

Humans are exposed daily to a wide variety of foreign compounds drugs and other environmental xenobiotics. Renal excretion plays
called xenobiotics—substances absorbed across the lungs or skin a pivotal role in terminating the biologic activity of some drugs,
or, more commonly, ingested either unintentionally as compounds particularly those that have small molecular volumes or possess
present in food and drink or deliberately as drugs for therapeutic polar characteristics, such as functional groups that are fully ion-
or “recreational” purposes. Exposure to environmental xenobiotics ized at physiologic pH. However, many drugs do not possess such
may be inadvertent and accidental or—when they are present as physicochemical properties. Pharmacologically active organic
components of air, water, and food—inescapable. Some xenobiot- molecules tend to be lipophilic and remain unionized or only
ics are innocuous, but many can provoke biologic responses. Such partially ionized at physiologic pH; these are readily reabsorbed
biologic responses often depend on conversion of the absorbed from the glomerular filtrate in the nephron. Certain lipophilic
substance into an active metabolite. The discussion that follows is compounds are often strongly bound to plasma proteins and may
applicable to xenobiotics in general (including drugs) and to some not be readily filtered at the glomerulus. Consequently, most
extent to endogenous compounds. drugs would have a prolonged duration of action if termination
of their action depended solely on renal excretion.
WHY IS DRUG BIOTRANSFORMATION An alternative process that can lead to the termination or
NECESSARY? alteration of biologic activity is metabolism. In general, lipophilic
xenobiotics are transformed to more polar and hence more readily
The mammalian drug biotransformation systems are thought to excreted products. The role that metabolism plays in the inactiva-
have first evolved from the need to detoxify and eliminate plant tion of lipid-soluble drugs can be quite dramatic. For example,
and bacterial bioproducts and toxins, which later extended to lipophilic barbiturates such as thiopental and pentobarbital would

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