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Intestinal drug absorption, cytochrome P450-mediated metabolism, and transport after small bowel transplantation

Bonner, Jennifer J. (2012) Intestinal drug absorption, cytochrome P450-mediated metabolism, and transport after small bowel transplantation. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Small bowel allograft recipients require multiple medications after transplant, many of which are orally administered cytochrome P450 3A (CYP3A) and/or p-glycoprotein (p-gp) substrates. A previous study in dogs has shown that surgical manipulation of the intestine, ischemia-reperfusion injury, and activation of the immune system lead to suppression of CYP3A and p-gp function in the early post-transplant period, presumably due to release of pro-inflammatory cytokines, a suppression that diminishes over time. The work presented in this dissertation compares intestinal CYP3A (using midazolam) and p-gp (using fexofenadine) expression and function in small bowel transplant recipients in the early post-transplant period (the first 40 days after surgery, n=16) and later (four to 12 months) post transplant (n=10) as well as with 16 age- and gender-matched healthy control subjects.
Oral bioavailability and oral AUC of midazolam were significantly higher in transplant subjects early post-transplant, but no different from controls at four to 12 months post-transplant. The oral AUC ratio of 1’hydroxymidazolam to midazolam, a measure of the extent of CYP3A-mediated metabolism, was significantly lower in the early post-transplant period compared with controls, but at the later period no difference was observed. No difference in fexofenadine AUC was observed between subject groups, and although Tmax of fexofenadine was significantly higher in transplant subjects at both time periods as compared with healthy controls, AUC and Cmax were more influenced by route of administration (jejunostomy tube vs. oral) and transplant subtype (modified multivisceral vs. isolated intestine) than by ileal ABCB1 expression. AUC0-7 and Cmax of oral tacrolimus (a CYP3A/p-gp substrate) were significantly higher early post transplant.
Overall this work presents strong evidence for an early immune-mediated suppression of intestinal CYP3A that eventually returns to normal in stable intestinal transplant patients, indicating that bioavailability of highly soluble, highly permeable CYP3A substrates such as midazolam will be significantly increased early post-transplant, requiring the use of caution in their dosing during this time and by extrapolation, during other times of high immune activation, such as acute rejection. These findings have clinical relevance for appropriate medication use in small bowel transplant recipients.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Bonner, Jennifer J.jjbonner@pitt.eduJJBONNER
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorVenkataramanan, Ramanrv@pitt.eduRV
Committee MemberPoloyac, Samuelpoloyac@pitt.eduPOLOYAC
Committee MemberVollmer, Regis R.vollm@pitt.eduVOLLM
Committee MemberMoore, Charity
Committee MemberAbu-Elmagd, Kareem
Committee MemberBies, Robert
Date: 7 June 2012
Date Type: Publication
Defense Date: 20 January 2012
Approval Date: 7 June 2012
Submission Date: 31 May 2012
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 336
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: pharmacokinetics intestinal transplantation small bowel transplantation midazolam CYP3A p-glycoprotein
Date Deposited: 07 Jun 2012 13:50
Last Modified: 15 Nov 2016 13:57


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