Regioselective oxidation of phospho-NSAIDs by human cytochrome P450 and flavin monooxygenase isoforms: implications for their pharmacokinetic properties and safety.

Abstract

BACKGROUND AND PURPOSE:

Phospho-ibuprofen (MDC-917) and phospho-sulindac (OXT-328) are highly effective in cancer and arthritis treatment in preclinical models. Here, we investigated their metabolism by major human cytochrome P450s (CYPs) and flavin monooxygenases (FMOs).

EXPERIMENTAL APPROACH:

The CYP/FMO-catalysed metabolism of phospho-ibuprofen and phospho-sulindac was studied by using in silico prediction modelling and a direct experimental approach.

KEY RESULTS:

The CYP isoforms catalyse the oxidation of non-steroidal anti-inflammatory drugs (NSAIDs) and phospho-NSAIDs, with distinct activity and regioselectivity. CYP1A2, 2C19, 2D6 and 3A4 oxidize phospho-ibuprofen, but not ibuprofen; whereas CYP2C9 oxidizes ibuprofen, but not phospho-ibuprofen. All CYPs tested oxidize phospho-sulindac, but not sulindac. Among the five CYPs evaluated, CYP3A4 and 2D6 are the most active in the oxidation of phospho-ibuprofen and phospho-sulindac respectively. FMOs oxidized phospho-sulindac and sulindac, but not phospho-ibuprofen or ibuprofen. FMOs were more active towards phospho-sulindac than sulindac, indicating that phospho-sulindac is a preferred substrate of FMOs. The susceptibility of phospho-NSAIDs to CYP/FMO-mediated metabolism was also reflected in their rapid oxidation by human and mouse liver microsomes, which contain a full complement of CYPs and FMOs. Compared with conventional NSAIDs, the higher activity of CYPs towards phospho-ibuprofen and phospho-sulindac may be due to their greater lipophilicity, a key parameter for CYP binding.

CONCLUSIONS AND IMPLICATIONS:

CYPs and FMOs play an important role in the metabolism of phospho-NSAIDs, resulting in differential pharmacokinetic profiles between phospho-NSAIDs and NSAIDs in vivo. The consequently more rapid detoxification of phospho-NSAIDs is likely to contribute to their greater safety.

• Authors: Gang Xie, Chi C Wong, Ka-Wing Cheng, Liqun Huang, Panayiotis P Constantinides, Basil Rigas
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 167 Issue 1 Pg. 222-32 (Sep 2012) ISSN: 1476-5381 [Electronic] England
• PMID: 22489789 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Chemical References

• 2-(4-isobutylphenyl)propionic acid 4-(diethoxyphosphoryloxy)butyl ester
• Anti-Inflammatory Agents, Non-Steroidal
• Organophosphates
• Recombinant Proteins
• Sulindac
• Cytochrome P-450 Enzyme System
• Oxygenases
• Ibuprofen

Topics

• Anti-Inflammatory Agents, Non-Steroidal (metabolism)
• Cytochrome P-450 Enzyme System (metabolism)
• Humans
• Ibuprofen (analogs & derivatives, metabolism)
• Microsomes, Liver (metabolism)
• Models, Biological
• Organophosphates (metabolism)
• Oxidation-Reduction
• Oxygenases (metabolism)
• Recombinant Proteins (metabolism)
• Sulindac (metabolism)