Page 78 - Basic _ Clinical Pharmacology ( PDFDrive )

64 SECTION I Basic Principles

A Esterases METABOLISM OF DRUGS TO TOXIC
CYP1A1/2 Epoxide
CYP1B1 Others hydrolase PRODUCTS
CYP2A6 DPYD
CYP2B6 Metabolism of drugs and other foreign chemicals may not always
CYP2C8/9 be an innocuous biochemical event leading to detoxification and
CYP2C19
elimination of the compound. Indeed, as previously noted, several
compounds have been shown to be metabolically transformed to
reactive intermediates that are toxic to various organs. Such
CYP2D6 CYP3A4/5 toxic reactions may not be apparent at low levels of exposure to
CYP2E1 parent compounds when alternative detoxification mechanisms
are not yet overwhelmed or compromised and when the avail-
TPMT NATs
B GSTs ability of endogenous detoxifying cosubstrates (GSH, glucuronic
Others acid, sulfate) is not limited. However, when these resources are
exhausted, the toxic pathway may prevail, resulting in overt organ
toxicity or carcinogenesis. The number of specific examples of
such drug-induced toxicity is expanding rapidly. An example
is acetaminophen (APAP; paracetamol)-induced hepatotoxicity
(Figure 4–5). Acetaminophen, an analgesic antipyretic drug, is
SULTs UGTs quite safe in therapeutic doses (1.2 g/d for an adult). It normally
undergoes glucuronidation and sulfation to the corresponding
FIGURE 4–4 Relative contributions of various cytochrome P450 conjugates, which together make up 95% of the total excreted
isoforms (A) and different phase II pathways (B) to metabolism of metabolites. The alternative P450-dependent GSH conjugation
drugs in clinical use. Many drugs are metabolized by two or more pathway accounts for the remaining 5%. When acetaminophen
of these pathways. Note that two pathways, CYP3A4/5 and UGT, are intake far exceeds therapeutic doses, the glucuronidation and
involved in the metabolism of more than 75% of drugs in use. DPYD, sulfation pathways are saturated, and the P450-dependent path-
dihydropyrimidine dehydrogenase; GST, glutathione-S-transferase;
NAT, N-acetyltransferase; SULT, sulfotransferase; TPMT, thiopurine way becomes increasingly important. Little or no hepatotoxic-
methyltransferase; UGT, UDP-glucuronosyltransferase. (Reproduced, ity results as long as hepatic GSH is available for conjugation.
with permission, from Brunton LL, Chabner BA, Knollman BC: Goodman & Gilman’s However, with time, hepatic GSH is depleted faster than it can
The Pharmacological Basis of Therapeutics, 12th ed. McGraw-Hill, 2011. Copyright © be regenerated, and a reactive, toxic metabolite accumulates.
The McGraw-Hill Companies, Inc.) In the absence of intracellular nucleophiles such as GSH, this

TABLE 4–3 Phase II reactions.
Type of Endogenous Transferase
Conjugation Reactant (Location) Types of Substrates Examples
Glucuronidation UDP glucuronic acid UDP glucuronosyl- Phenols, alcohols, carboxylic Nitrophenol, morphine, acetaminophen,
(UDPGA) transferase acids, hydroxylamines, diazepam, N-hydroxydapsone, sulfathia-
(microsomes) sulfonamides zole, meprobamate, digitoxin, digoxin
Acetylation Acetyl-CoA N-Acetyltransferase Amines Sulfonamides, isoniazid, clonazepam,
(cytosol) dapsone, mescaline
Glutathione Glutathione (GSH) GSH-S-transferase Epoxides, arene oxides, nitro Acetaminophen, ethacrynic acid,
conjugation (cytosol, microsomes) groups, hydroxylamines bromobenzene
Glycine Glycine Acyl-CoA glycinetrans- Acyl-CoA derivatives of Salicylic acid, benzoic acid, nicotinic
conjugation ferase (mitochondria) carboxylic acids acid, cinnamic acid, cholic acid,
deoxycholic acid
Sulfation Phosphoadenosyl Sulfotransferase Phenols, alcohols, aromatic Estrone, aniline, phenol,
phosphosulfate (cytosol) amines 3- hydroxycoumarin, acetaminophen,
(PAPS) methyldopa
Methylation S-Adenosylmethionine Transmethylases Catecholamines, phenols, Dopamine, epinephrine, pyridine,
(SAM) (cytosol) amines histamine, thiouracil
Water Water Epoxide hydrolase Arene oxides, cis-disubsti- Benzopyrene 7,8-epoxide,
conjugation (microsomes) tuted and monosubstituted styrene 1,2-oxide, carbamazepine
oxiranes epoxide
(cytosol) Alkene oxides, fatty acid Leukotriene A 4
epoxides