Pharmacokinetics of Neoral Before and After Total Gastrectomy in a Renal Transplant Patient T. Chapelle, G. Roeyen, K. De Greef, G.A. Verpooten, J.L. Bosmans, M. Martin, M.E. De Broe, and D.K. Ysebaert A BUNDANT information is available about improved gastrointestinal absorption of the newer form of Cyclo- sporine CsA, Neoral, compared with the older formulation, Sandimmun. However, no studies have investigated the pos- sibility that an abnormal gastrointestinal tract could influence the absorption of Neoral (N). Because N absorption and pharmacokinetic profiles after a gastrectomy (Gx) have not yet been described, we present a case of altered absorption of N in the early post-Gx period with an even more remarkable restoration of absorption at 1 year post-Gx. CASE REPORT A 56-year-old male patient underwent kidney transplan- tation 6 years previously and had a stable renal function (creatinine 1.3 mg/dL). We performed a total Gx for early gastric cancer (T1, N0, M0). Intestinal continuity was reconstructed by an end-to-end esophagojejunal anastomosis and a Roux–Y loop (R-Y). A feeding jeju- nostomy (Jjy) tube was inserted; during enteral feeding, the length of the intestinal bypass consisted of at least 80 cm of jejunum. The postoperative course was uneventful. The patient started oral feeding on day 8 and was discharged from the hospital on day 14. Immunosuppres- sive therapy pre-Gx was: N, 325 mg, divided into two daily doses; azathioprine (Imuran), 125 mg; and pred- nisolone, 5 mg. During the postoperative period, he received consecutive intravenous (IV) cyclosporine (4 days), N suspension by the Jjy (3 days), N suspension (susp) orally (7 days), and N capsules (caps) after discharge from the hospital. There was stable renal function at all timepoints after Gx and no rejection occurred. METHODS For each mode of N administration we measured drug exposure during 12 hours by means of the area under the curve (AUC) 1 and bioavailability [F(%)]. Serial blood samples for cyclosporine concentrations were obtained at 0 hour (pre-dose) and 1, 2, 4, 8, and 12 hours (post-dose). AUC was calculated using the trapezoidal rule. The for- mula for calculating bioavailability was: F(%) = (AUC oral or jejunost dose/AUC IV dose)  (daily IV dose/oral or daily jejunost dose)  100. The daily IV dose was 60 mg via continuous infusion. Data were expressed as mean  standard deviation (Table 1). RESULTS AND DISCUSSION Before Gx, we observed a high AUC and an optimal F(%) (Table 1). After Gx, N suspension was given during 3 days by the Jjy (BID) together with enteral feeding. We observed a fall in AUC and a low F(%) compared with pre-Gx levels. This can be explained by the reduced intestinal absorption capacity (RIAC). Different factors may have contributed to this RIAC. First, the length of small bowel available for drug absorption was reduced by R-Y reconstruction. A similar influence of R-Y on CsA absorption has been described in pediatric liver trans- plant patients, 2,3 as well as in a renal transplant patient under treatment with Sandimmun after a partial Gx and ileal resection. 4 A second factor is the temporary bypass created by the Jjy, entering the small bowel more distally. A third factor could be the villous atrophy of the small bowel due to the temporary absence of enteral feeding. After restarting oral feeding, we first gave N susp orally and, after discharge from the hospital, as N caps; we adjusted the dose up to 500 mg/d. Between the weeks 1 and 6 of oral feeding, we observed a gradual increase in AUC and F(%), which could be explained by recovery from villous atrophy. One year post-Gx, AUC and F(%) reached pre-Gx values, despite lower daily doses (300 mg/d). In our opinion, this was due to remarkable intestinal adaptation. Fig 1 shows the AUC curves at different timepoints and type of drug administration; there was a significant differ- ence in C max after 1 and 2 hours (absorption phase), but the elimination phase of the curve (after 4 hours) was quite similar for all curves. The differences in AUC and F(%) were due to differences in the absorption phase. 5 From the Departments of Transplantation Surgery (T.C., G.R., K.D.G., D.K.Y.), Nephrology (G.A.V., J.L.B., M.E.D.B.), and Clin- ical Biology (M.M.), University Hospital of Antwerp, Antwerp, Belgium. Address reprint requests to Dr Thie ´ ry Chapelle, Department of Surgery, Universitair Ziekenhuis Antwerpen, Wilrijkstraat 10, B-2650 Edegem, Belgium. E-mail: thiery.chapelle@uza.uia.ac.be © 2002 by Elsevier Science Inc. 0041-1345/02/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0041-1345(01)02917-7 Transplantation Proceedings, 34, 805– 806 (2002) 805