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CHAPTER 4 Drug Biotransformation 63

TABLE 4–2 Human liver P450s (CYPs), and some of the drugs metabolized (substrates), inducers, and
selective inhibitors. Note: Some P450 substrates can be potent competitive inhibitors and/or
mechanism-based inactivators. (Continued)

CYP Substrates Inducers Inhibitors
3A4 1 Acetaminophen, alfentanil, alfuzosin, almotriptan, alprazolam, Aminoglutethimide, Amprenavir, azamulin, boceprevir,
amiodarone, amlodipine, aprepitant, astemizole, atazanavir, avasimibe, barbiturates, clarithromycin, conivaptan, diltiazem,
atorvastatin, bepridil, bexarotene, bosentan, bromocriptine, carbamazepine, efavirenz, erythromycin, fluconazole, grapefruit
budesonide, buspirone, carbamazepine, cisapride, clarithro- glucocorticoids, nevirapine, juice (furanocoumarins), indinavir,
mycin, clonazepam, clopidogrel, cocaine, colchicine, conivap- pioglitazone, phenytoin, itraconazole, ketoconazole, lopinavir,
tan, cortisol, cyclosporine, dapsone, darunavir, dasatinib, primidone, rifampin, rifa- mibefradil, nefazodone, nelfinavir,
delavirdine, dexamethasone, diazepam, dihydroergotamine, pentine, St. John’s wort posaconazole, ritonavir, saquinavir,
dihydropyridines, diltiazem, disopyramide, doxorubicin, telaprevir, telithromycin, troleandomycin,
droperidol, dutasteride, ebastine, efavirenz, eletriptan, eplere- verapamil, voriconazole
none, ergotamine, erlotinib, erythromycin, estazolam, eszopi-
clone, ethinyl estradiol, ethosuximide, etoposide, everolimus,
exemestane, felodipine, fentanyl, finasteride, flurazepam,
fluticasone, fosamprenavir, galantamine, gefitinib, gestodene,
granisetron, halofantrine, ifosfamide, imatinib, indinavir,
irinotecan, isradipine, itraconazole, ixabepilone, lapatinib,
lidocaine, loperamide, lopinavir, loratadine, lovastatin, mac-
rolides, maraviroc, mefloquine, methadone, methylpred-
nisolone, miconazole, midazolam, mifepristone, modafinil,
nefazodone, nevirapine, nicardipine, nifedipine, nimodipine,
nisoldipine, paclitaxel, paricalcitol, pimozide, pioglitazone,
praziquantel, prednisolone, prednisone, progesterone, que-
tiapine, quinacrine, quinidine, quinine, ranolazine, rapamycin,
repaglinide, rifabutin, ritonavir, saquinavir, sibutramine,
sildenafil, simvastatin, sirolimus, solifenacin, spironolactone,
sufentanil, sulfamethoxazole, sunitinib, tacrolimus, tadalafil,
tamoxifen, tamsulosin, teniposide, terfenadine, testoster-
one, tetrahydrocannabinol, tiagabine, tinidazole, tipranavir,
tolvaptan, topiramate, triazolam, troleandomycin, vardenafil,
verapamil, vinblastine, vincristine, ziprasidone, zolpidem,
zonisamide, zopiclone
1 CYP3A5 has similar substrate and inhibitor profiles but, except for a few drugs, is generally less active than CYP3A4.

PHASE II REACTIONS (NATs), encoded by NAT1 and NAT2 genes, which utilize acetyl-
CoA as the endogenous cofactor.
Parent drugs or their phase I metabolites that contain suitable S-Adenosyl-l-methionine (SAMe; AdoMet)-mediated O-, N-,
chemical groups often undergo coupling or conjugation reac- and S-methylation of drugs and xenobiotics by methyltransfer-
tions with an endogenous substance to yield drug conjugates ases (MTs) also occurs. Finally, endobiotic, drug, and xenobiotic
(Table 4–3). In general, conjugates are polar molecules that are epoxides generated via P450-catalyzed oxidations can also be
readily excreted and often inactive. Conjugate formation involves hydrolyzed by microsomal or cytosolic epoxide hydrolases (EHs).
high-energy intermediates and specific transfer enzymes. Such Conjugation of an activated drug such as the S-CoA derivative of
enzymes (transferases) may be located in microsomes or in benzoic acid, with an endogenous substrate, such as glycine, also
the cytosol. Of these, uridine 5′-diphosphate (UDP)-glucuronosyl occurs. Because the endogenous substrates originate in the diet,
transferases (UGTs) are the most dominant enzymes (Figure 4–4). nutrition plays a critical role in the regulation of drug conjugations.
These microsomal enzymes catalyze the coupling of an activated Phase II reactions are relatively faster than P450-catalyzed
endogenous substance (such as the UDP derivative of glucuronic reactions, thus effectively accelerating drug biotransformation.
acid) with a drug (or endogenous compound such as bilirubin, the Drug conjugations were once believed to represent terminal
end product of heme metabolism). Nineteen UGT genes (UGTA1 inactivation events and as such have been viewed as “true detoxifi-
and UGT2) encode UGT proteins involved in the metabolism cation” reactions. However, this concept must be modified, because
of drugs and xenobiotics. Similarly, 11 human sulfotransferases it is now known that certain conjugation reactions (acyl glucuroni-
(SULTs) catalyze the sulfation of substrates using 3′-phospho- dation of nonsteroidal anti-inflammatory drugs, O-sulfation of
adenosine 5′-phosphosulfate (PAPS) as the endogenous sulfate N-hydroxyacetylaminofluorene, and N-acetylation of isoniazid)
donor. Cytosolic and microsomal glutathione (GSH) transferases may lead to the formation of reactive species responsible for the
(GSTs) are also engaged in the metabolism of drugs and xenobiot- toxicity of the drugs. Furthermore, sulfation is known to activate
ics, and in that of leukotrienes and prostaglandins, respectively. the orally active prodrug minoxidil into a very efficacious vasodila-
Chemicals containing an aromatic amine or a hydrazine moiety tor, and morphine-6-glucuronide is more potent than morphine
(eg, isoniazid) are substrates of cytosolic N-acetyltransferases itself.