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Identification of the human P450 enzymes involved in lansoprazole metabolism.
J Pharmacol Exp Ther. 1996 May; 277(2):805-16.JP

Abstract

The aim of this study was to identify which human P450 enzymes are involved in the metabolism of lansoprazole. In the presence of NADPH and oxygen, human liver microsomes converted lansoprazole to lansoprazole sulfide, lansoprazole sulfone and 5-hydroxylansoprazole. Formation of lansoprazole sulfide occurred nonenzymatically. The formation of lansoprazole sulfone appeared to be catalyzed by a single, low-affinity enzyme (apparent Km approximately 100 microM). In contrast, lansoprazole 5-hydroxylation appeared to be catalyzed by two kinetically distinct enzymes (apparent Km approximately 100 microM and approximately 15 microM). When human liver microsomes (n = 16) were incubated with 100 microM lansoprazole, both the 5-hydroxylation and sulfoxidation of lansoprazole appeared to be catalyzed by CYP3A4/5 (based on correlation analyses). Antibodies against rat CYP3A enzymes inhibited the rate of both 5-hydroxylation (approximately 55%) and sulfoxidation (approximately 70%) and cDNA-expressed CYP3A4 catalyzed both the 5-hydroxylation and sulfoxidation of lansoprazole (apparent Km approximately 100 microM). However, at the pharmacologically relevant substrate concentration of 1 microM, lansoprazole sulfoxidation was still highly correlated with CYP3A4/5 activity (r2 = .905), but lansoprazole 5-hydroxylation appeared to be catalyzed by CYP2C19 (r2 = .875) rather than CYP3A4/5 (r2 = .113). Antibodies and chemical inhibitors of CYP2C enzymes preferentially inhibited the 5-hydroxylation of lansoprazole, whereas lansoprazole sulfoxidation was preferentially inhibited by antibodies and chemical inhibitors of CYP3A4/5. The cDNA expressed enzymes CYP2C8, CYP2C9 and CYP2C19 catalyzed varying rates of lansoprazole 5-hydroxylation at a substrate concentration of 50 microM, but only CYPC19 catalyzed this reaction at 1 microM. These results suggest that at pharmacologically relevant concentrations, the 5-hydroxylation of lansoprazole is primarily catalyzed by CYP2C19, whereas the sulfoxidation of lansoprazole is primarily catalyzed by CYP3A4/5. It is possible that individuals lacking CYP2C19 will be poor metabolizers of lansoprazole.

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Authors+Show Affiliations

Pearce RE
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, USA.
Rodrigues AD
No affiliation info available
Goldstein JA
No affiliation info available
Parkinson A
No affiliation info available

MeSH

2-PyridinylmethylsulfinylbenzimidazolesAnimalsAnti-Ulcer AgentsCytochrome P-450 Enzyme InhibitorsCytochrome P-450 Enzyme SystemHumansIsoenzymesLansoprazoleMicrosomes, LiverOmeprazoleRatsRecombinant Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8627562

Citation

Pearce, R E., et al. "Identification of the Human P450 Enzymes Involved in Lansoprazole Metabolism." The Journal of Pharmacology and Experimental Therapeutics, vol. 277, no. 2, 1996, pp. 805-16.
Pearce RE, Rodrigues AD, Goldstein JA, et al. Identification of the human P450 enzymes involved in lansoprazole metabolism. J Pharmacol Exp Ther. 1996;277(2):805-16.
Pearce, R. E., Rodrigues, A. D., Goldstein, J. A., & Parkinson, A. (1996). Identification of the human P450 enzymes involved in lansoprazole metabolism. The Journal of Pharmacology and Experimental Therapeutics, 277(2), 805-16.
Pearce RE, et al. Identification of the Human P450 Enzymes Involved in Lansoprazole Metabolism. J Pharmacol Exp Ther. 1996;277(2):805-16. PubMed PMID: 8627562.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of the human P450 enzymes involved in lansoprazole metabolism. AU - Pearce,R E, AU - Rodrigues,A D, AU - Goldstein,J A, AU - Parkinson,A, PY - 1996/5/1/pubmed PY - 1996/5/1/medline PY - 1996/5/1/entrez SP - 805 EP - 16 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 277 IS - 2 N2 - The aim of this study was to identify which human P450 enzymes are involved in the metabolism of lansoprazole. In the presence of NADPH and oxygen, human liver microsomes converted lansoprazole to lansoprazole sulfide, lansoprazole sulfone and 5-hydroxylansoprazole. Formation of lansoprazole sulfide occurred nonenzymatically. The formation of lansoprazole sulfone appeared to be catalyzed by a single, low-affinity enzyme (apparent Km approximately 100 microM). In contrast, lansoprazole 5-hydroxylation appeared to be catalyzed by two kinetically distinct enzymes (apparent Km approximately 100 microM and approximately 15 microM). When human liver microsomes (n = 16) were incubated with 100 microM lansoprazole, both the 5-hydroxylation and sulfoxidation of lansoprazole appeared to be catalyzed by CYP3A4/5 (based on correlation analyses). Antibodies against rat CYP3A enzymes inhibited the rate of both 5-hydroxylation (approximately 55%) and sulfoxidation (approximately 70%) and cDNA-expressed CYP3A4 catalyzed both the 5-hydroxylation and sulfoxidation of lansoprazole (apparent Km approximately 100 microM). However, at the pharmacologically relevant substrate concentration of 1 microM, lansoprazole sulfoxidation was still highly correlated with CYP3A4/5 activity (r2 = .905), but lansoprazole 5-hydroxylation appeared to be catalyzed by CYP2C19 (r2 = .875) rather than CYP3A4/5 (r2 = .113). Antibodies and chemical inhibitors of CYP2C enzymes preferentially inhibited the 5-hydroxylation of lansoprazole, whereas lansoprazole sulfoxidation was preferentially inhibited by antibodies and chemical inhibitors of CYP3A4/5. The cDNA expressed enzymes CYP2C8, CYP2C9 and CYP2C19 catalyzed varying rates of lansoprazole 5-hydroxylation at a substrate concentration of 50 microM, but only CYPC19 catalyzed this reaction at 1 microM. These results suggest that at pharmacologically relevant concentrations, the 5-hydroxylation of lansoprazole is primarily catalyzed by CYP2C19, whereas the sulfoxidation of lansoprazole is primarily catalyzed by CYP3A4/5. It is possible that individuals lacking CYP2C19 will be poor metabolizers of lansoprazole. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/8627562/Identification_of_the_human_P450_enzymes_involved_in_lansoprazole_metabolism_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8627562 DB - PRIME DP - Unbound Medicine ER -