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• W2800558104 abstract "We thank Dr Neuhoff and Dr Tucker for their interest in our recent publication and appreciate their constructive comments 1, 2. In fact, we agree with the authors that the a priori probability that 4β-hydroxycholesterol (4βOH-C) would predict tacrolimus exposure or dose requirements in the first days after kidney transplantation is low. Importantly, the reasons why Storset et al. and we could not demonstrate a relationship between 4βOH-C/C and early tacrolimus exposure are, in our opinion, different from the theoretical arguments put forward by Neuhoff et al. 1, 3. First, the authors report that previous short-term studies performed in healthy volunteers showed only a slight positive correlation of 4βOH-C and 4βOH-C/C with (changes in) midazolam metrics 4. We recently performed a large study in a relevant phenotypic cohort of 147 stable kidney recipients on tacrolimus therapy 5. Especially in patients not expressing CYP3A5, 4βOH-C/C performed comparably to midazolam in a multivariable model of determinants of tacrolimus weight-corrected apparent oral clearance 5. Secondly, the authors indicate that CYP7A1 and CYP27A1 also play a role in the net elimination of 4βOH-C but it seems that the contribution of the latter enzymes is negligible in vivo 6. We learn from these in vitro experiments that only a small fraction of 4βOH-C is eliminated through 7α-hydroxylation (CYP7A1). The authors further estimated, based on deuterium labelled 4βOH-C administered to healthy volunteers, that 4βOH-C-derived bile acids make up less than 0.1% of the daily produced bile acids pool. We agree that the potential effects of drugs like rifampicin on CYP3A4 and CYP7A1 can result in contrasting effects on 4βOH-C/C and that inhibition of hepatic ABCA1-mediated cholesterol efflux would augment the effect of CYP3A4 induction on the latter. The relevance of these findings for explaining the lack of 4βOH-C as a useful marker of CYP3A4 activity in the immediate post-transplantation setting is low as perioperative use of strong inducers/inhibitors of the pregnane X receptor is routinely avoided. Thirdly, we would argue that the pre-existing uremic state (e.g. uremic toxins), the perioperative changes in gastrointestinal function (e.g. motility), fluid management (e.g. intravenous infusions), concomitant drugs (e.g. corticosteroids) and many other clinical variables (e.g. haematocrit) present at the time of transplantation are responsible for the large variability in early tacrolimus exposure. In contrast, 4βOH-C, characterized by its stable and long half-life extending up to 62–64 h, fails as an endogenous CYP3A probe to predict the rapid changes occurring in this acute setting, but not necessarily because of the intrinsic shortcomings claimed by Neuhoff et al. In fact, tacrolimus exposure data obtained just prior to transplantation failed to adequately predict postoperative dose requirements, indicating that acute perioperative changes are complex and variable 7. Finally, many if not all currently used (drug) probes are not specific substrates of just one enzyme or transporter and are inducible and/or susceptible to inhibition. Information obtained by a (drug) probe will have to be interpreted together with other specific genetic and nongenetic covariables affecting drug disposition. Whether 4βOH-C will prove to be a useful probe for predicting, for example, tacrolimus or quetiapine dose requirements or exposure in stable conditions needs to be further investigated by actually performing the studies in relevant patient populations. Irrespective of their outcome, in vivo studies will improve our knowledge of these very complex processes, in contrast to a priori refuting their relevance based on very limited in vitro data and theoretical assumptions. Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 8, and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 9-11. There are no competing interests to declare." @default.
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• W2800558104 date "2018-04-24" @default.
• W2800558104 modified "2023-09-25" @default.
• W2800558104 title "Kuypers and Vanhove reply to ‘Was 4β-hydroxycholesterol ever going to be a useful marker of CYP3A4 activity?’ by Neuhoff and Tucker" @default.
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• W2800558104 doi "https://doi.org/10.1111/bcp.13592" @default.
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