Cumulative exposure to immunomodulators increases risk of cervical neoplasia in women with inflammatory bowel disease.

BACKGROUND: Women with inflammatory bowel disease (IBD) are at increased risk of high-grade cervical intraepithelial neoplasia and cervical cancer (CIN2+). AIM: To assess the association between cumulative exposure to immunomodulators (IM) and biologic agents (BIO) for IBD and CIN2+ METHODS: Adult women diagnosed with IBD before December 31st 2016 in the Dutch IBD biobank with available cervical records in the nationwide cytopathology database were identified. CIN2+ incidence rates in IM- (i.e., thiopurines, methotrexate, tacrolimus and cyclosporine) and BIO- (anti-tumour necrosis factor, vedolizumab and ustekinumab) exposed patients were compared to unexposed patients and risk factors were assessed. Cumulative exposure to immunosuppressive drugs was evaluated in extended time-dependent Cox-regression models. RESULTS: The study cohort comprised 1981 women with IBD: 99 (5%) developed CIN2+ during median follow-up of 17.2 years [IQR 14.6]. In total, 1305 (66%) women were exposed to immunosuppressive drugs (IM 58%, BIO 40%, IM and BIO 33%). CIN2+ risk increased per year of exposure to IM (HR 1.16, 95% CI 1.08-1.25). No association was observed between cumulative exposure to BIO or both BIO and IM and CIN2+. In multivariate analysis, smoking (HR 2.73, 95%CI 1.77-4.37) and 5-yearly screening frequency (HR 1.74, 95% CI 1.33-2.27) were also risk factors for CIN2+ detection. CONCLUSION: Cumulative exposure to IM is associated with increased risk of CIN2+ in women with IBD. In addition to active counselling of women with IBD to participate in cervical screening programs, further assessment of the benefit of intensified screening of women with IBD on long-term IM exposure is warranted.

Effect of multiple administration of orphenadrine or mono-N-desmethylorphenadrine on cytochrome P-450 catalyzed reactions in the rat.

Multiple administration (i.p.) of orphenadrine or its mono-N-demethylated metabolite, tofenacine (day 1, 20 mg/kg; day 2-5, 30 mg/kg) results in a considerable induction (50%) of the total cytochrome P-450 content. In addition, approximately 6% of the total amount of cytochrome P-450 was found to be blocked by a metabolic intermediate, formed from orphenadrine or tofenacine. Induction is apparent in enhancing the in vitro N-demethylation of aminopyrine and ethylmorphine and the p-hydroxylation of aniline. Pretreatment induced orphenadrine metabolism in vitro. The metabolism of tofenacine, however, was reduced. Probably this is due to a specific inhibition caused by the irreversible interaction of the metabolic intermediate with cytochrome P-450. In vivo, no induction of the aminopyrine metabolism (30 mg/kg, i.v.) is apparent, i.e., no change in the clearance was observed after pretreatment. This is probably due to the presence of relatively high, inhibitory concentrations of tofenacine (in the vicinity of cytochrome P-450). These results show that during chronic administration of orphenadrine or tofenacine, the in vivo disposition of concomitantly ingested compounds is determined by the influence of induction, high substrate and/or metabolite levels and complexation of cytochrome P-450. Moreover, based on these results an hypothesis is put forward in order to explain the phenomenon of product inhibition, which has been suggested to occur in man under chronic orphenadrine dosing conditions.

Product inhibition in orphenadrine metabolism as a result of a stable cytochrome P-450-metabolic intermediate complex formed during the disposition of mono-N-desmethylorphenadrine (tofenacine) in the rat.

Product inhibition is thought to be involved in unexpected accumulation of orphenadrine, which occurs during chronic medication with this anti-Parkinson drug in man. In previous studies (Biochem. Pharmacol. 31, 2745-2753 (1982) we established the formation of reactive metabolic intermediates (MI) during metabolism of orphenadrine and its mono-N-demethylated metabolite tofenacine, which may block cytochrome P-450 (MI-complex). In this study we investigated the role of MI-complexation in product inhibition. Three different assays were used to establish the amount of cytochrome P-450 involved in MI-complexation, which was induced by tofenacine (30 mg/kg i.p.) in phenobarbital pretreated rats. If liver microsomes were prepared 3 hours after tofenacine injection, both spectral titration of oxidized cytochrome P-450, determination of loss of metyrapone binding sites at reduced cytochrome P-450 as well as ferricyanide oxidation of the MI-complex revealed 8-13% complexation of cytochrome P-450. Our data also suggest that MI-complexation is generated on phenobarbital induced cytochrome P-450 species. Phenobarbital induction was also shown to activate orphenadrine metabolism in vitro. Moreover, with a newly developed capillary GLC method, using nitrogen detection, we showed inhibition of orphenadrine- and tofenacine metabolism in vitro, by MI-complexation. This study therefore showed that MI-complexation may produce product inhibition.