A 40-year-old woman presents herself to the emergency department of her local hospital somewhat disoriented, complaining of midsternal chest pain, abdominal pain, shaking, and vomiting for 2 days. She admits to having taken a “handful” of Lorcet (hydrocodone/acetaminophen, an opioid/nonopioid analgesic combination), Soma (carisoprodol, a centrally acting muscle relaxant), and Cymbalta (duloxetine HCl, an antidepressant/antifibromyalgia agent) 2 days earlier. On physical examination, the sclera of her eyes shows yellow discoloration. Laboratory analyses of blood drawn within an hour of her admission reveal abnormal liver function as indicated by the increased indices: alkaline phosphatase 302 (41–133)*, alanine aminotransferase (ALT) 351 (7–56)*, aspartate aminotransferase (AST) 1,045 (0–35)*, bilirubin 3.33 mg/dL (0.1–1.2)*, and prothrombin time of 19.8 seconds (11–15)*. In addition, plasma bicarbonate is reduced, and she has ∼45% reduced glomerular filtration rate from the normal value at her age, elevated serum creatinine and blood urea nitrogen, markedly reduced blood glucose of 35 mg/dL, and a plasma APAP concentration of 75 mcg/mL (10–20)*. Her serum titer is significantly positive for hepatitis C virus (HCV). Given these data, how would you proceed with the management of this case?
Humans are exposed daily to a wide variety of foreign compounds called xenobiotics—substances absorbed across the lungs or skin or, more commonly, ingested either unintentionally as compounds present in food and drink or deliberately as drugs for therapeutic or “recreational” purposes. Exposure to environmental xenobiotics may be inadvertent and accidental or—when they are present as components of air, water, and food—inescapable. Some xenobiotics are innocuous, but many can provoke biologic responses. Such biologic responses often depend on conversion of the absorbed substance into an active metabolite. The discussion that follows is applicable to xenobiotics in general (including drugs) and to some extent to endogenous compounds.
WHY IS DRUG BIOTRANSFORMATION NECESSARY?
The mammalian drug biotransformation systems are thought to have first evolved from the need to detoxify and eliminate plant and bacterial bioproducts and toxins, which later extended to drugs and other environmental xenobiotics. Renal excretion plays a pivotal role in terminating the biologic activity of some drugs, particularly those that have small molecular volumes or possess polar characteristics, such as functional groups that are fully ionized at physiologic pH. However, many drugs do not possess such physicochemical properties. Pharmacologically active organic molecules tend to be lipophilic and remain unionized or only partially ionized at physiologic pH; these are readily reabsorbed from the glomerular filtrate in the nephron. Certain lipophilic compounds are often strongly bound to plasma proteins and may not be readily filtered at the glomerulus. Consequently, most drugs would have a prolonged duration of action if termination of their action depended solely on renal excretion.
An alternative process that can lead to the termination or alteration of biologic activity is metabolism. In general, ...