Sixty-seven percent of total standard digoxin clearance is renal, so the standard renal clearance is 0.67 × 9 L/h = 6 L/h/70 kg with creatinine clearance of 100 mL/min and nonrenal clearance is (1 0.67) × 9 L/h = 3 L/h/70 kg (see Table 3–1 for standard pharmacokinetic parameters). Her predicted creatinine clearance is 22 mL/min (Cockcroft and Gault), so for digoxin, her renal clearance is 6 × 22/100 × 60/70 = 1.1 L/h, nonrenal clearance 2.7 × 60/70 = 2.6 L/h, and total clearance 3.7 L/h. The parenteral maintenance dose rate is 1 mcg/L × 3.7 L/h = 3.7 mcg/h. Once-a-day oral dosing with bioavailability of 0.7 would require a daily maintenance dose of 3.7/0.7 × 24 = 127 mcg/day. A practical dose would be two 62.5 mcg tablets per day.
Maria Almira Correia, PhD
A 40-year-old woman presents 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 examina-tion, the sclera of her eyes shows yellow discoloration. Labora-tory 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 amino-transferase (ALT) 351 (7–56),* aspartate aminotransferase (AST) 1045 (0–35),* bilirubin 3.33 mg/dL (0.1–1.2),* and pro-thrombin 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 acetaminophen concentra-tion 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? *Normal values are in parentheses.
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?