Going Beyond Common Drug Metabolizing Enzymes: Case Studies of Biotransformation Involving Aldehyde Oxidase, γ-Glutamyl Transpeptidase, Cathepsin B, Flavin-Containing Monooxygenase, and ADP-Ribosyltransferase.
The significant roles that cytochrome P450 (P450) and UDP-glucuronosyl transferase (UGT) enzymes play in drug discovery cannot be ignored, and these enzyme systems are commonly examined during drug optimization using liver microsomes or hepatocytes. At the same time, other drug-metabolizing enzymes have a role in the metabolism of drugs and can lead to challenges in drug optimization that could be mitigated if the contributions of these enzymes were better understood. We present examples (mostly from Genentech) of five different non-P450 and non-UGT enzymes that contribute to the metabolic clearance or bioactivation of drugs and drug candidates. Aldehyde oxidase mediates a unique amide hydrolysis of GDC-0834 (N-[3-[6-[4-[(2R)-1,4-dimethyl-3-oxopiperazin-2-yl]anilino]-4-methyl-5-oxopyrazin-2-yl]-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide), leading to high clearance of the drug. Likewise, the rodent-specific ribose conjugation by ADP-ribosyltransferase leads to high clearance of an interleukin-2-inducible T-cell kinase inhibitor. Metabolic reactions by flavin-containing monooxygenases (FMO) are easily mistaken for P450-mediated metabolism such as oxidative defluorination of 4-fluoro-N-methylaniline by FMO. Gamma-glutamyl transpeptidase is involved in the initial hydrolysis of glutathione metabolites, leading to formation of proximate toxins and nephrotoxicity, as is observed with cisplatin in the clinic, or renal toxicity, as is observed with efavirenz in rodents. Finally, cathepsin B is a lysosomal enzyme that is highly expressed in human tumors and has been targeted to release potent cytotoxins, as in the case of brentuximab vedotin. These examples of non-P450- and non-UGT-mediated metabolism show that a more complete understanding of drug metabolizing enzymes allows for better insight into the fate of drugs and improved design strategies of molecules in drug discovery.
Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco (P.W.F., D.Z., S.C.K.); Anacor Pharmaceuticals, Inc., Palo Alto (J.S.H.); MyoKardia, Inc., South San Francisco (J.P.D.), California.
Peter W
PW
Fan
Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco (P.W.F., D.Z., S.C.K.); Anacor Pharmaceuticals, Inc., Palo Alto (J.S.H.); MyoKardia, Inc., South San Francisco (J.P.D.), California.
Donglu
D
Zhang
Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco (P.W.F., D.Z., S.C.K.); Anacor Pharmaceuticals, Inc., Palo Alto (J.S.H.); MyoKardia, Inc., South San Francisco (J.P.D.), California.
Jason S
JS
Halladay
Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco (P.W.F., D.Z., S.C.K.); Anacor Pharmaceuticals, Inc., Palo Alto (J.S.H.); MyoKardia, Inc., South San Francisco (J.P.D.), California.
James P
JP
Driscoll
Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco (P.W.F., D.Z., S.C.K.); Anacor Pharmaceuticals, Inc., Palo Alto (J.S.H.); MyoKardia, Inc., South San Francisco (J.P.D.), California pars@gene.com.
S Cyrus
SC
Khojasteh
D036002:ADP Ribose Transferases / Q000378:metabolism*; D042931:Aldehyde Oxidase / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D002401:Cathepsin B / Q000378:metabolism*; D006801:Humans; D010105:Oxygenases / Q000378:metabolism*; D013045:Species Specificity; D013379:Substrate Specificity; D015262:Xenobiotics / Q000378:metabolism* / Q000493:pharmacokinetics; D005723:gamma-Glutamyltransferase / Q000378:metabolism*
D015262:Xenobiotics; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D042931:Aldehyde Oxidase; D005723:gamma-Glutamyltransferase; C554782:gamma-glutamyltransferase, human; D036002:ADP Ribose Transferases; C533912:CTSB protein, human; D002401:Cathepsin B