Chapter 6: Biotransformation of Xenobiotics

Introduction

In 2003, my father (and Oliver's grandfather), Edward William Parkinson, died of Lou Gehrig disease, otherwise known as amyotrophic lateral sclerosis (ALS) in America and as motor neuron disease (MND) in Britain. He died beeping. The beeping came from a portable, electronic syringe that periodically injected my father with glycopyrrolate, an anticholinergic drug that blocks the production of saliva that many ALS patients have difficulty swallowing. Glycopyrrolate is a quaternary ammonium salt; hence, it is positively charged at physiological pH. As such, glycopyrrolate does not readily cross lipid bilayers, which is why it is injected intravenously or intramuscularly; it has few CNS effects (it does not readily cross the blood–brain barrier), and a relatively small volume of distribution at steady state (V_ss = 0.42 L/kg). Unchanged glycopyrrolate is rapidly eliminated in urine. The mean elimination half-life increases from 19 minutes in patients with normal kidney function to 47 minutes in patients with severe kidney impairment, indicating that renal disease impairs the elimination of glycopyrrolate. Although it is excreted in urine largely as unchanged drug, glycopyrrolate reinforces a number of principles about xenobiotic biotransformation, the most important of which is: xenobiotic biotransformation is the process—actually a series of enzyme-catalyzed processes—that alters the physiochemical properties of foreign chemicals (xenobiotics) from those that favor absorption across biological membranes (namely, lipophilicity) to those favoring elimination in urine or bile (namely, hydrophilicity). Without xenobiotic biotransformation, the numerous foreign chemicals to which we are exposed (which includes both man-made and natural chemicals such as drugs, industrial chemicals, pesticides, pollutants, pyrolysis products in cooked food, alkaloids, secondary plant metabolites, and toxins produced by molds, plants, etc) either unintentionally or, in the case of drugs, intentionally would—if they are sufficiently lipophilic to be absorbed from the gastrointestinal tract and other sites of exposure—eventually accumulate to toxic levels. Furthermore, absent xenobiotic biotransformation, many of the drugs in use today would have an unacceptably long duration of action. In contrast, drugs that are not lipophilic, such as glycopyrrolate, are not absorbed from the gastrointestinal tract unless their uptake is mediated by a transporter protein (hence, they are not orally active), and if they are administered parenterally, they are not obligated to undergo ...