Non-steroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: Insight into the mechanism and reversal of NSAID-induced gastrointestinal injury

Lichtenberger, Lenard M.; Wang, Zu Mo; Romero, Jimmy J.; Ulloa, Carlos Manuel Ulloa; Perez, Joseph C.; Giraud, M; Barreto, José C.

doi:10.1038/nm0295-154

Cited by 287 publications

(201 citation statements)

References 18 publications

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“…Ibuprofen and other NSAIDs have been found to spontaneously associate with zwitterionic phospholipids such as PC due to both electrostatic and hydrophobic interactions (17,18). Accordingly we investigated whether pre-association of ibuprofen and purified soy PC (90G) had an influence on COX activity that differed from the inhibitory effect when the same concentrations of ibuprofen and PC were added separately.…”

Section: Effects Of Premixing Ibuprofen With Phospholipid On Inhibitomentioning

confidence: 99%

“…In humans, pre-associating PC with aspirin or other NSAIDs produced less gastric damage than aspirin alone, without decreasing the COX inhibition (17,18,33), and formulations of NSAID with PC are being considered as one approach to lowering gastrointestinal side effects of these agents (34). The protective action of PC in this setting has been attributed to actions at the surface of gastric mucosal cells that is distinct from COX inhibition (35).…”

Section: In Vivo Implications Of Cox Inhibitor Potentiation By Pcmentioning

confidence: 99%

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Phospholipid actions on PGHS-1 and -2 cyclooxygenase kinetics

Doyen

Yucer

Lichtenberger

et al. 2008

Prostaglandins & Other Lipid Mediators

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Cyclooxygenase (COX) catalysis by prostaglandin H synthase (PGHS) is a key control step for regulation of prostanoid biosynthesis. Both PGHS isoforms are integral membrane proteins and their substrate fatty acids readily partition into membranes, but the impact of phospholipids and lipid membranes on COX catalysis and the actions of COX inhibitors are not well understood. We have characterized the COX kinetics and ibuprofen inhibition of the purified PGHS isoforms in the presence of phosphatidylcholine (PC) with varying acyl chain structure and physical state. PC was found to directly inhibit COX activity, with non-competitive inhibition by PC monomers binding away from the COX active site and competitive inhibition by micellar/bilayer forms of PC due to sequestration of the arachidonate substrate. Competitive inhibition by native membranes was observed in a comparison of COX kinetics in sheep seminal vesicle microsomes before and after solubilization of PGHS-1. PC liposomes significantly increase the inhibitory potency of ibuprofen against both PGHS isoforms without changing the reversible character of ibuprofen action or requiring binding of PGHS to the liposomes. These results suggest a useful conceptual framework for analyzing the complex interactions among the PGHS proteins, substrates, inhibitors and phospholipid.

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Section: Effects Of Premixing Ibuprofen With Phospholipid On Inhibitomentioning

confidence: 99%

Section: In Vivo Implications Of Cox Inhibitor Potentiation By Pcmentioning

confidence: 99%

Phospholipid actions on PGHS-1 and -2 cyclooxygenase kinetics

Doyen

Yucer

Lichtenberger

et al. 2008

Prostaglandins & Other Lipid Mediators

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“…The diffusion of salicylates from the aqueous phase to the oil phase was monitored by pipetting samples from the cyclohexane phase after 1 h. The presence of salicylates in the organic phase was assessed¯uorometrically (excitation 280 nm, emission 310 nm). 13 …”

Section: Diffusion Studiesmentioning

confidence: 99%

Effect of omeprazole on the bioavailability of unmodified and phospholipid‐complexed aspirin in rats

Giraud

Sanduja

Felder

et al. 1997

Aliment Pharmacol Ther

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Background: Treatment and prevention of non‐steroidal anti‐inflammatory drug‐induced gastropathy involve the concurrent use of antisecretory drugs. Recently, we have shown that the ability of these drugs to increase the intragastric pH to values pKa of NSAIDs compromises their therapeutic activity. In the present study, we evaluated the potential of omeprazole to interfere with the bioavailability of aspirin administered to rats either alone or complexed with the zwitterionic phospholipid, dipalmitoylphosphatidylcholine (DPPC). Methods: Aspirin or aspirin/DPPC was administered intragastrically to rats pre‐dosed with either saline or omeprazole. Concentrations of aspirin and salicylic acid in the blood and the gastric mucosa were assessed by HPLC and the 6‐keto‐PGF1α gastric mucosal concentration by radioimmunoassay. Results: Gastric absorption of aspirin and its relative bioavailability were reduced by an antisecretory dose of omeprazole; its inhibitory effect on gastric prostaglandin synthesis was consequently attenuated. However, these effects could be partly overcome if aspirin was administered as a complex with DPPC. Conclusions: These observations suggest that: (i) DPPC increases the lipid solubility and gastric permeability of NSAIDs; and (ii) neutralization of the gastric pH results in a shift of aspirin absorption toward the intestine where it could be degraded to salicylic acid.

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“…This work led to reports by our lab and those of other investigators that NSAIDs can induce surface injury to the GI mucosa by chemically associating with PC present in mucus and cell membranes [30,31], thereby compromising these important barriers. These findings ultimately led to the development of a family of soy-derived PC-NSAIDs that have been demonstrated to have reduced GI toxicity in rodents [30] and in a number of clinical endoscopic trials, while fully maintaining the therapeutic activity of the NSAIDs [32,33].…”

mentioning

confidence: 86%

“…Revisiting the Sippy diet approach, our lab demonstrated the importance of phospholipids in milk in ulcer protection and healing (overriding the effects of increased gastric acid secretion) [29], and also demonstrated that synthetic and soy lecithin-derived (PC) could protect against damaging agents or conditions (e.g., stress) [10]. This work led to reports by our lab and those of other investigators that NSAIDs can induce surface injury to the GI mucosa by chemically associating with PC present in mucus and cell membranes [30,31], thereby compromising these important barriers. These findings ultimately led to the development of a family of soy-derived PC-NSAIDs that have been demonstrated to have reduced GI toxicity in rodents [30] and in a number of clinical endoscopic trials, while fully maintaining the therapeutic activity of the NSAIDs [32,33].…”

mentioning

confidence: 97%