Pharmacokinetics of mycophenolic acid after mycophenolate mofetil administration in liver transplant patients treated with tacrolimus.

The pharmacokinetics of mycophenolic acid (MPA) was studied after oral administration of mycophenolate mofetil (MMF) in 8 liver transplant patients. The mean (+/- SD) maximum MPA plasma concentration of 10.6 (+/- 7.5) mg/ml was achieved within 0.5 to 5 hours. The mean (+/- SD) steady-state area under the plasma concentration versus time curve (AUC(0-12)) was 40 (+/- 30.9) mg/ml/h. The mean (+/- SD) half-life was 5.8 (+/- 3.8) hours. There was poor correlation between trough blood concentrations of tacrolimus (r = -0.004) or serum creatinine (r = 0.689) with MPA AUC, while the serum bilirubin concentrations correlated (r = 0.743) well with MPA AUC, suggesting impairment in MPA conjugation in patients with liver dysfunction. The mean (+/- SD) ratio of the AUC of mycophenolic acid glucuronide (MPAG) to MPA was 64 (+/- 84), which correlated significantly with serum creatinine (r = 0.72) but not with serum bilirubin concentrations (r = 0.309), indicating accumulation of MPAG in patients with renal dysfunction. In 7 primary liver transplant patients on the same dose of MMF, the trough plasma concentrations of MPA during the first week of therapy ranged from < 0.3 to 1.5 microg/ml. The MPA concentrations increased by several folds during the next few weeks, which correlates well with increases in serum albumin concentrations. Changes in albumin appear to partially contribute to the variations in the pharmacokinetics of MPA in liver transplant patients.

Effect of t-tube clamping on the pharmacokinetics of mycophenolic acid in liver transplant patients on oral therapy of mycophenolate mofetil.

The aim of the study was to evaluate the effect of t-tube clamping on the pharmacokinetics of mycophenolic acid (MPA) after oral administration of mycophenolate mofetil (MMF) in primary liver transplant recipients treated with tacrolimus as the primary immunosuppressive drug. We evaluated the pharmacokinetics of MPA and its primary metabolite, mycophenolic acid glucuronide (MPAG), before and after clamping the t-tube in 8 primary liver transplant recipients treated with oral MMF and tacrolimus. The concentration of MPA and MPAG in plasma, bile, and urine samples obtained over one dosing interval was measured by high-pressure liquid chromatography. Pharmacokinetic parameters of MPA estimated before and after clamping the t-tube were compared to evaluate any significant differences at a P of.05 or less. There were no significant differences in the time to reach peak plasma concentration (1.8 +/- 1.7 v 1.0 +/- 0.5 hours), trough plasma concentration of MPA (1.1 +/- 1.4 v 1.4 +/- 1.1 microgram/mL), peak plasma concentration of MPA (10.6 +/- 7.5 v 11.1 +/- 4.6 microgram/mL), area under the plasma concentration-versus-time curve (AUC) (40.1 +/- 31.9 v 43.2 +/- 21.1 microgram/mL/h) of MPA, or the percentage of MPA that is free or unbound in the plasma (3.9% +/- 1.6% v 4.1% +/- 3.0%). There was also no significant difference in the ratio of the AUC of MPAG to MPA. These observations suggest that t-tube clamping does not affect the kinetics of MPA or MPAG and that no dosing alterations of MMF are required when the t-tube is clamped in liver transplant recipients.

Comparison of tacrolimus absorption in transplant patients receiving continuous versus interrupted enteral nutritional feeding.

OBJECTIVE: To determine the effect of enteral nutritional feeding on the absorption of tacrolimus administered through a nasoduodenal tube to organ transplant patients. METHODS: A nonrandomized, prospective study of tacrolimus absorption was performed in 10 liver or lung transplant patients who received Osmolite enteral nutrition through a nasoduodenal feeding tube. Multiple blood samples were collected just prior to and at 30 minutes, 1, 2, 3, 4, 6, 8, 10, and 12 hours after nasoduodenal administration of tacrolimus on 2 consecutive days, once when tacrolimus was administered along with the continuous enteral feeding and the other time when the enteral feeding was withheld 1 hour prior to and 8 hours after tacrolimus administration, to assess tacrolimus absorption. The whole blood tacrolimus concentrations were measured by the microparticulate enzyme immunoassay method. Pharmacokinetic parameters between the two time periods were compared by using a paired t-test at a significance level of a p value of 0.05 or less. RESULTS: The time to reach peak blood concentrations (p = 0.055), dose-normalized trough concentrations (p = 0.617), maximum blood concentrations (p = 0.197), and dose-normalized AUC (p = 0.755) were not significantly different between two study periods. CONCLUSIONS: This study demonstrated that simultaneous administration of Osmolite enteral feedings with tacrolimus did not interfere with tacrolimus absorption in transplant patients.

Natural history, prognosis, and lipid abnormalities of idiopathic ischemic childhood stroke.

A study was performed to assess the natural history, prognostic factors, and lipid and apolipoprotein abnormalities of idiopathic ischemic childhood stroke. A case series of 42 children, retrospectively identified with idiopathic ischemic strokes, were reassessed an average of 7.4 years (range, 1 to 19 years) after presentation. Patients were interviewed and examined, and fasting serum was obtained for lipid and apolipoprotein analysis. Poor outcome was defined as moderate to severe hemiparesis, special educational needs, epilepsy, recurrent stroke, or stroke-related death. Eighteen (43%) of the patients had a poor outcome. Among them were moderate to severe hemiparesis in 14 (78%), recurrent strokes in seven (39%), and one death. Poor outcome was evident early in their clinical course. Independent of outcome, lipid abnormalities including an elevated triglyceride and low-density lipoprotein cholesterol, and a depressed high-density lipoprotein cholesterol were seen in one third of all patients. A depressed ratio of apolipoprotein A-1 to apolipoprotein B (using adult normative values) was seen in half of the entire cohort. Clinical features of children with unexplained ischemic strokes at presentation and their subsequent course are described. Significant risk factors for a poor outcome include (1) persistence of hemiparesis 1 month after the stroke, (2) cortical as opposed to subcortical location, and (3) bilateral occlusive disease with telangiectasia on cerebral angiography. Previously described risk factors for an unfavorable prognosis, including occurrence during infancy and presentation with seizures, were not substantiated. Lipid abnormalities occur at an increased frequency in children after unexplained ischemic strokes. Prospective assessment of lipoprotein profiles are needed to further assess clinical significance. Assessing apolipoproteins may provide further insight than lipid values alone.

Lipid and volume analysis of neck drainage in patients undergoing neck dissection.

PURPOSE: We seek to establish normative values for the volume of postoperative neck drainage from patients undergoing ablative oncologic procedures that include a neck dissection and to analyze neck drainage for lipid content to establish guidelines that may be helpful in identifying chylous fistula when this diagnosis is not clinically straightforward. PATIENTS AND MATERIALS: Neck drainage obtained through continuous suction percutaneous drainage catheters was evaluated following 23 neck dissections performed on 19 patients. In every case, either radicle or modified type I neck dissection was performed. The volume of drainage was quantitated on a day-to-day basis. In a separate group of 27 patients undergoing neck dissection, neck drainage was compared with serum levels of triglyceride, cholesterol, and chylomicron content. RESULTS: The mean duration of neck drainage was 5 days. Maximum drainage (160 mL) was noted on the first day and dropped daily to less than 10 mL by the fifth postoperative day. A statistically significant difference between serum and neck drainage triglyceride and cholesterol content was observed in nearly all cases. Neck drainage fat content was lower than that noted in serum in nearly all cases. Chylomicron content of 4% was encountered in neck drainage. CONCLUSIONS: This study provides normative data on lipid content of neck drainage. With only a rare exception, the triglyceride and cholesterol levels are higher in the serum than in the neck drainage. A triglyceride level of 100 mg/dL seems to be the upper limit of normal (mean plus 1 standard deviation). A low level of chylomicron (> 4%) is consistent with normal healing and may be due to breakdown of fatty tissue.

Radioreceptor assay for quantifying FK-506 immunosuppressant in whole blood.

We describe a quantitative radioreceptor assay (RRA) for quantifying FK-506 in whole blood. FK-506 extracted from whole blood with a cyclohexyl-sorbent column competes with [3H]dihydro-FK-506 for binding to a partially purified preparation of FK-506 binding protein (FK-BP). Free and protein-bound FK-506 are separated on LH 20 Sephadex chromatographic columns. We compared the results of this method with those of an enzyme immunoassay that uses a monoclonal antibody: r = 0.97, Sy/x = 0.039. Between-day precisions (CV) at FK-506 concentrations of 8 and 17 micrograms/L were 9.2% and 8.2%, respectively. Within-run precisions were 5.9%, 8.1%, and 9.4%, respectively, at 4, 8, and 15 micrograms/L. Analytical recovery, evaluated at 5, 10, 15, 20, and 25 micrograms/L for FK-506 added to whole blood, ranged from 98% to 103%. The assay can reliably quantify FK-506 blood concentrations between 1.0 and 25 micrograms/L.

The effect of bile duct ligation and bile diversion on FK506 pharmacokinetics in dogs.

Mongrel or beagle dogs were submitted to bile duct ligation, or to extraenteric biliary diversion by means of choledochoureterostomy. The kinetics of intravenously administered FK506 was not changed from control status two weeks after bile duct ligation, but the bioavailability of orally administered FK506 was nearly quadrupled. Following oral administration, the absorption of FK506 was highly variable. The results indicate that in dogs FK506 is absorbed from the intestine just as efficiently in the absence of enteric bile and in presence of exogenous bile salt supplement when compared with its absorption in presence of normal bile drainage. These findings with FK506 are different from those with cyclosporine after biliary obstruction or diversion and will have important practical as well as experimental ramifications.

The effect of graft function on FK506 plasma levels, dosages, and renal function, with particular reference to the liver.

Plasma FK506 was studied in 49 liver, 13 heart, 3 double-lung or heart-lung, and 21 kidney recipients. The levels were correlated with the drug doses used, kidney function, and liver function. In all varieties of recipients, there was an early rise in the FK506 plasma levels that occurred at the time of intravenous administration of the drug. At the same time or shortly after, there were increases in serum creatinine that were transitory except in liver recipients with continuing suboptimal graft function. The quality of hepatic function dominated all aspects of FK506 management in the liver recipients. Those who received well-functioning grafts could be given about the same drug doses as recipients of kidneys and the thoracic organs. Liver recipients with defective grafts had astronomical rises in plasma FK506, a high incidence of renal failure, and probably increased neurotoxicity. In kidney transplant recipients, the FK506 plasma levels and doses were essentially the same in patients with prompt versus delayed renal function. These studies have highlighted the necessity, first, of close pharmacologic monitoring of patients who are given FK506 in the presence of abnormal liver function, and second, of using smaller intravenous induction doses than in past practice.

Mechanisms of vein graft atherosclerosis: LDL metabolism and endothelial actin reorganization.

We have explored the effect of arterial hemodynamics on endothelial cell morphology and low-density lipoprotein metabolism in human saphenous vein segments harvested from tissue donors. An arterial pulsatile perfusion system was used to impose physiologic pressures and flows for 20 hours on saphenous vein and companion (control) femoral artery segments. A venous perfusion apparatus was also employed for the perfusion of a second (control) saphenous vein segment for the same period of time. Calculations of fluid shearing and wall tensile stresses were performed and related to induced changes in endothelial cell geometry and cytoskeletal actin organization and the incorporation, degradation, and localization of intact low-density lipoprotein within the vessel wall. Our results indicate that, compared with native arteries and veins, a 20-hour exposure of test saphenous veins to arterial hemodynamics induced (1) a significant increase in endothelial cell luminal surface area and perimeter independent of alignment with flow, (2) disassembly of the dense peripheral band of actin with a concomitant assembly of stress fibers, and (3) a two- to fourfold elevation in the undegraded low-density lipoprotein content, localized primarily within the subendothelial intima. Although the exact mechanisms underlying these results are uncertain, the focal accumulation of intramural low-density lipoprotein may be related to the loss of normal barrier function during endothelial cell enlargement, which is accompanied by transient cytoskeletal reorganization during the adaptation to arterial flow.

Cyclosporine enhances the growth of carcinogen-induced enzyme-altered foci in rat liver.

Cyclosporine, a powerful immunosuppressant, has been used successfully for organ transplantation. Its efficacy on liver transplants of patients with primary hepatic tumors remains controversial because of a high rate of recurrence of the original tumors in the transplanted livers. In this study, we experimentally tested whether cyclosporine exerts any effects on the growth of carcinogen-initiated liver cells using the short-term assays of rat liver carcinogenesis. Dietary cyclosporine, which maintained sufficient levels of blood cyclosporine and suppressed host immune functions, enhanced the development of the glutathione S-transferase, placental form-positive hepatocyte foci in the liver of male F-344 rats treated with a single weekly dose of diethylnitrosamine (75 mg/kg) for 3 wk. Dietary cyclosporine also accelerated the growth of preformed glutathione S-transferase, placental form-positive foci induced by a single dose of diethylnitrosamine (250 mg/kg) followed by the promoting regimen of a choline-deficient diet. It is possible that the enhancement of the size of hepatocyte foci by cyclosporine could be due to stimulation of growth or inhibition of regression. The mechanisms by which cyclosporine modifies the growth of preneoplastic lesions in the liver are not yet fully understood. Possible involvement of immunologically relevant cells in the liver, Kupffer cells and pit cells in the process is suggested.

Cyclosporine promotes the induction of thymic lymphomas in C57BL/6 mice initiated by a single dose of gamma-radiation.

We previously demonstrated that a single dose of gamma-radiation (350 rads) was able to induce thymic lymphomas in C57BL mice when followed by promoting treatment with oral cyclosporine (CsA), a non-genotoxic immunosuppressant. We have now tested the efficacy of various doses of gamma-radiation as an initiator of CsA promotion of the induction of thymic lymphomas in male C57BL mice. The effects of oral CsA on the splenic natural killer (NK) cell activity of non-irradiated and irradiated (400 rads, 1x) mice were tested by the standard 51Cr release assays against YAC-1 cells. The cumulative incidence of thymic lymphomas induced by a single dose of gamma-radiation at 100, 200, 400 and 600 rads were 10, 25, 63 and 75% respectively, after 42 weeks of CsA promotion. The splenic NK cell activity in non-irradiated mice given CsA for 4 weeks was twice as high as that in the control mice. CsA inhibited poly I:C-induced augmentation of the splenic NK cell activity. In mice given a single dose (400 rads) of gamma-radiation and CsA for 4 weeks, a similar but reduced enhancement of the splenic NK cell activity as seen in non-irradiated mice was observed. These results indicate that the efficacy of CsA promotion in the induction of thymic lymphomas is dependent on the initiating doses of gamma-radiation, and that CsA enhances host splenic NK cell activity during the early stage of tumor promotion.