FURTHER READING Fix JA. Strategies for delivery of peptides utilizing absorptionenhancing agents. Journal of Pharmaceutical Sciences 1996; 85: 1282–5. Goldberg M, Gomez-Orellana I. Challenges for the oral delivery of macromolecules. Nature Reviews Drug Discovery 2003; 2: 289–95. Mahato RI, Narang AS, Thoma L, Miller DD. Emerging trends in oral delivery of peptide and protein drugs. Critical Reviews in Therapeutic Drug Carrier Systems 2003; 20: 153–2. ROUTES OF ADMINISTRATION 23 Mathiovitz E, Jacobs JS, Jong NS et al. Biologically erodable microspheres as potential oral drug delivery systems. Nature 1997; 386: 410–14. Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications, 3rd edn. Baltimore, MD: Williams and Wilkins, 1995: 11–50. Skyler JS, Cefalu WT, Kourides I A et al. Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomized proof-of-concept study. Lancet 2001; 357: 324–5. Varde NK, Pack DW. Microspheres for controlled release drug delivery. Expert Opinion on Biological Therapy 2004; 4: 35–51.
● Introduction 24 ● Phase I metabolism 24 ● Phase II metabolism (transferase reactions) 25 ● Enzyme induction 27 INTRODUCTION CHAPTER 5 DRUG METABOLISM Drug metabolism is central to biochemical pharmacology. Knowledge of human drug metabolism has been advanced by the wide availability of human hepatic tissue, complemented by analytical studies of parent drugs and metabolites in plasma and urine. The pharmacological activity of many drugs is reduced or abolished by enzymatic processes, and drug metabolism is one of the primary mechanisms by which drugs are inactivated. Examples include oxidation of phenytoin andof ethanol. However, not all metabolic processes result in inactivation, and drug activity is sometimes increased by metabolism, as in activation of prodrugs (e.g. hydrolysis of enalapril, Chapter 28, to its active metabolite enalaprilat). The formation of polar metabolites from a non-polar drug permits efficient urinary excretion (Chapter 6). However, some enzymatic conversions yield active compounds with a longer half-life than the parent drug, causing delayed effects of the long-lasting metabolite as it accumulates more slowly to its steady state (e.g. diazepam has a half-life of 20–50 hours, whereas its pharmacologically active metabolite desmethyldiazepam has a plasma half-life of approximately 100 hours, Chapter 18). It is convenient to divide drug metabolism into two phases (phases I and II: Figure 5.1), which often, but not always, occur sequentially. Phase I reactions involve a metabolic modification of the drug (commonly oxidation, reduction or hydrolysis). Products of phase I reactions may be either pharmacologically active or inactive. Phase II reactions are synthetic conjugation reactions. Phase II metabolites have increased polarity compared to the parent drugs and are more readily excreted in the urine (or, less often, in the bile), and they are usually – but not always – pharmacologically inactive. Molecules or groups involved in phase II reactions include acetate, glucuronic acid, glutamine, glycine and sulphate, which may combine with reactive groups introduced during phase I metabolism (‘functionalization’). For example, phenytoin is initially oxidized to 4-hydroxyphenytoin which is then glucuronidated to ● Enzyme inhibition 28 ● Presystemic metabolism (‘first-pass’ effect) 28 ● Metabolism of drugs by intestinal organisms 29 4-hydroxyphenytoin-glucuronide, which is readily excreted via the kidney. PHASE I METABOLISM The liver is the most important site of drug metabolism. Hepatocyte endoplasmic reticulum is particularly important, but the cytosol and mitochondria are also involved. ENDOPLASMIC RETICULUM Hepatic smooth endoplasmic reticulum contains the cytochrome P450 (CYP450) enzyme superfamily (more than 50 different CYPs have been found in humans) that metabolize foreign substances – ‘xenobiotics’, i.e. drugs as well as pesticides, fertilizers and other chemicals ingested by humans. These metabolic reactions include oxidation, reduction and hydrolysis. OXIDATION Microsomal oxidation causes aromatic or aliphatic hydroxylation, deamination, dealkylation or S-oxidation. These reactions all involve reduced nicotinamide adenine dinucleotide phosphate (NADP), molecular oxygen, and one or more of a group of CYP450 haemoproteins which act as a terminal oxidase in the oxidation reaction (or can involve other mixed function oxidases, e.g. flavin-containing monooxygenases or epoxide hydrolases). CYP450s exist in several distinct isoenzyme families and subfamilies with different levels of amino acid homology. Each CYP subfamily has a different, albeit often overlapping, pattern of substrate specificities. The major drug metabolizing CYPs with important substrates, inhibitors and inducers are shown in Table 5.1. CYP450 enzymes are also involved in the oxidative biosynthesis of mediators or other biochemically important intermediates. For example, synthase enzymes involved in the oxidation of arachidonic acid (Chapter 26) to prostaglandins