Possible Interaction: Tretinoin and Indinavir

“Evidence supporting this supposition is provided by several remarks: the presence of other retinoid-like secondary effects like xerosis and cheilitis associated with … binding protein) and the catalytic region of the HIV-1 proteasis and, finally, the inhibition of cytochrome P450 3 (demonstrated in patients taking indinavir) … retinoid acid.”

“ Indinavir leads to altered retinoic acid signaling most likely by an activation of the RAR/RXR heterodimer, perhaps by displacing all-trans-retinoic acid from CRABP.”

“Since LMNA is regulated by a retinoic acid responsive element (L-RARE) in the promoter region, we propose that indinavir impairs retinoic acid homeostasis and/or interact via the L-RARE within the LMNA promoter.”

“Editor,—There is increasing speculation that indinavir may cause side effects which have been previously associated with high concentrations of retinoids.”

“Growth of ATRA-resistant UF-1 cells was also inhibited when cultured with the combination of ATRA and indinavir.”

“Moreover, indinavir enhanced the ability of ATRA to induce expression of the myeloid differentiation-related transcription factor C/EBPepsilon messenger RNA in NB4 cells by 9.5-fold.”

“Conclusion: Considerable evidence advocates the mediation of indinavir side effects by impaired oxidative metabolism of retinoic acid through the inhibition of cytochromes P450 3A by indinavir rather than by impaired formation of 9-cis-retinoic acid.”

“AGN 193109 (4-[[5,6-dihydro-5, 5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl]ethynyl]-benzoic acid), a retinoic acid receptor (RAR) antagonist, inhibited the synergistic effects of indinavir and ATRA , indicating that indinavir increases RAR signaling.”

“Moreover, indinavir increased the effects of ATRA on lipid accumulation during fat cell differentiation.”

“Of the PIs tested, only indinavir stimulated ATRA-dependent ALP activity and altered stem cell morphology; the effects of indinavir occurred in the presence of ATRA , but not in its absence.”

“These observations support the proposal that altered retinoid signaling promotes some of the adverse reactions associated with indinavir therapy , such as altered lipid metabolism.”