N-Dealkylation Morphine, ethylmorphine, benzphetamine, aminopyrine, ca˜eine, theophylline O-Dealkylation Codeine, p-nitroanisole RNHCH3 RNH2 + CH2O ROCH3 ROH + CH2O 6-Methylthiopurine, methitural
N-Oxidation Primary amines Aniline, chlorphentermine Secondary amines 2-Acetylamino°uorene, acetaminophen RNH2 RNHOH NH R1 R2 N R1 R2 OH
Tertiary amines Nicotine, methaqualone
S-Oxidation Thioridazine, cimetidine, chlorpromazine S R1 R2 S R1 R2 O
TABLE 4–1 Phase I reactions. (Continued)
Flavin monooxygenase (Ziegler’s enzyme) Chlorpromazine, amitriptyline, benzphetamineR3N+˜O – R3N R3N+OH H+
Methimazole, propylthiouracil N N SH N N SOH N N SO2H
Phenylethylamine, epinephrine
Carbonyl reductions Metyrapone, methadone, naloxoneRCR˜ RCHR˜O OH
Esters Procaine, succinylcholine, aspirin, cloÿbrate, methylphenidate R1COOR2 R1COOH + R2OH
RCOOH + R1NH2 Procainamide, lidocaine, indomethacin quasi-irreversibly inactivates the enzyme, thereby inhibiting the metabolism of potential substrates.
Some substrates irreversibly inhibit P450s via covalent interaction of a metabolically generated reactive intermediate that may react with the P450 apoprotein or heme moiety or even cause the heme to fragment and irreversibly modify the apoprotein. The antibiotic chloramphenicol is metabolized by CYP2B1 to a species that modifies the P450 protein and thus also inactivates the enzyme. A growing list of such suicide inhibitors—inactivators that attack the heme or the protein moiety—includes certain steroids (ethinyl estradiol, norethindrone, and spironolactone); fluroxene; allobarbital; the analgesic sedatives allylisopropylacetylurea, diethylpentenamide, and ethchlorvynol; carbon disulfide; grapefruit furanocoumarins; selegiline; phencyclidine; ticlopidine and clopidogrel; ritonavir; and propylthiouracil. On the other hand, the barbiturate secobarbital is found to inactivate CYP2B1 by modification of both its heme and protein moieties. Other metabolically activated drugs whose P450 inactivation mechanism is not fully elucidated are mifepristone, troglitazone, raloxifene, and tamoxifen.
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.