Intestinal drug absorption, cytochrome P450 3A-mediated metabolism, and transport after small bowel transplantation

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 and ischemia-reperfusion injury lead to suppression of CYP3A and p-gp function in the early posttransplant period, presumably due to release of pro-inflammatory cytokines, a suppression that diminished 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 age- and gender-matched (n=16) healthy control subjects.;Oral AUC and oral bioavailability of midazolam were significantly higher in transplant subjects early post-transplant, but not 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 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. Dose-normalized AUC0-7 and Cmax of oral tacrolimus (a CYP3A/p-gp substrate) were significantly higher early post transplant compared with later.;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 higher early post-transplant, requiring 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.