Different evolution of trough and dose levels during the first year after transplantation for tacrolimus versus cyclosporine.

At present, the two calcineurin inhibitors-cyclosporine (CsA) and tacrolimus (FK506)-are among the most frequently used immunosuppressants in clinical transplantation. Both drugs share variable oral bioavailability, which necessitates intense drug monitoring. This variability is attributed to large interindividual differences in drug catabolism by cytochrome P450 3A4/5 (CYP3A4/5) and drug efflux by P-glycoprotein (PGP). In addition, the activity of both CYP3A4 and PGP can vary substantially within the same individual due to environmental factors such as concomitant intake of inducing/inhibiting medications (eg, rifampicin/sporanox) or food substances (eg, grapefruit juice). More recently, an inducing effect of methylprednisolone on intestinal and hepatic CYP3A4 has been shown. Also, an influence of gender on CYP3A4 activity (being higher in women) has been reported. Once CsA and FK506 are absorbed and reach the bloodstream, both drugs are avidly bound to erythrocytes (up to 95% for FK506 and 50% for CsA) and plasma proteins, leaving only a small fraction of circulating active drug. This phenomenon also limits further hepatic catabolism and hence clearance of drug, which is influenced by hematocrit and levels of plasma proteins such as albumin. The aim of the present study was to compare the influence of changing steroid doses, hematocrit, and albumin on trough and dose levels of FK506 versus CsA during the first year after transplantation. In addition, the evolution of trough and dose levels of FK506 versus CsA was stratified according to gender.

Differences in gastric motor activity in renal transplant recipients treated with FK-506 versus cyclosporine.

BACKGROUND: Little is known concerning gastric motility after renal transplantation and on the impact of immunosuppressants on gastric emptying. METHODS: Gastric emptying was measured in renal transplant recipients, taking different immunosuppressive therapy (steroids and cyclosporine/azathioprine/FK-506), and compared with normal volunteers. RESULTS: After renal transplantation, gastric emptying of liquids was normal, irrespective of the type of immunosuppression. However, solid gastric emptying was significantly faster in FK-506-treated patients compared with patients taking cyclosporine for all measured emptying parameters. Compared with normal volunteers solid gastric emptying was slower in patients taking cyclosporine, comparable in azathioprine treated patients, and characterized by an unusual short lag phase in patients taking FK-506. CONCLUSIONS: In stable renal transplant recipients gastric emptying of solids was significantly faster in patients on FK-506 compared with patients taking cyclosporine. Therefore, FK-506 may be the immunosuppressant of choice after solid organ transplantation in patients with problems related to gastroparesis.

Posttransplantation diabetes mellitus in FK-506-treated renal transplant recipients: analysis of incidence and risk factors.

BACKGROUND: The development of posttransplantation diabetes mellitus has a major impact on the quality of life and long-term outcome. METHODS: One hundred thirty-nine patients without known glucose metabolism abnormalities and treated with FK-506, methylprednisolone, and mycophenolate mofetil/azathioprine were analyzed for incidence of and risk factors for developing impaired fasting glycemia (IFG) and diabetes mellitus (DM). RESULTS: Using the American Diabetes Association criteria, 15% developed IFG and 32% developed DM in the first year after transplantation. High trough levels of FK-506 during the first month after transplantation (especially >15 ng/ml) and high body mass index (BMI) were significant risk factors for IFG or DM. Patients with (steroid-treated) acute rejections in addition to high trough levels of FK-506 were most prone to develop DM, whereas high BMI conferred risk of developing IFG. Patients with posttransplantation glycemic abnormalities also had higher levels of serum triglycerides at the time of transplantation, but they needed a lower dose of FK-506 to obtain higher trough levels of FK-506, suggesting metabolic differences already present before transplantation. The only risk factor retained for persistent IFG or DM beyond the first year was a higher number of trough levels of FK-506 >15 ng/ml during the first month after transplantation. CONCLUSIONS: Induction with an FK-506 based immunosuppressive regimen resulted in a high incidence of glucose metabolism disorders in renal transplantation recipients. Higher trough levels of FK-506 during the first month, acute rejections, and higher BMI were the most obvious risk factors.

Combined carbon-13-glycine/carbon-14-octanoic acid breath test to monitor gastric emptying rates of liquids and solids.

UNLABELLED: The aim of the present study was to develop a dual-carbon-labeled breath test for simultaneously measuring gastric emptying rates of liquids and solids with significantly less radiation burden to the patient than the radioscintigraphic technique. METHODS: A test meal was used in which the liquid phase was labeled with two markers, i.e., 3.7 MBq of 111In-DTPA and 100 mg of 13C-glycine; the solid phase also was dually labeled with 110 MBq of 99mTc-albumin colloid and 74 kBq of 14C-octanoic acid. Simultaneous radioscintigraphic and breath-test measurements were performed in 27 subjects, 10 normal controls and 17 patients with dyspeptic symptoms. Mathematic analysis of the excretion rate of labeled CO2 allowed the definition of four parameters, i.e., the gastric emptying coefficient, the gastric half-emptying time, the peak excretion time and the lag phase. RESULTS: There was a good to excellent correlation between the gastric emptying coefficient and the scintigraphic half-emptying time (r = 0.74 for liquids and r = 0.88 for solids), between the half-emptying time determined by breath test and the scintigraphic half-emptying time (r = 0.91 for liquids and r = 0.92 for solids), between the peak excretion time and the scintigraphic half-emptying time (r = 0.91 for liquids and r = 0.96 for solids) and between the lag phase of solid emptying determined by both techniques (r = 0.89). CONCLUSION: The dual carbon-labeled breath test is a valid, minimally invasive technique to measure the gastric emptying rate of both liquids and solids.

Influence of octreotide on the gastric emptying of solids and liquids in normal healthy subjects.

BACKGROUND: The effects of octreotide on small intestinal and gall-bladder motility are well established. However, the influence of octreotide on the gastric emptying rate of both solids and liquids in normal healthy volunteers has never been studied. METHODS: In nine healthy subjects, the gastric emptying rate of liquids and solids was studied in basal condition and 30 min after subcutaneous administration of 50 micrograms of octreotide, using the combined 14C-octanoic acid/13C-glycine breath test. To determine if the results were entirely due to alterations in gastric emptying, 14/13CO2 excretion rates of intraduodenally administered 14C-octanoic acid and 13C-glycine were measured in basal condition and after subcutaneous injection of octreotide. RESULTS: After subcutaneous injection of octreotide, the gastric emptying rate of solids was decreased in all but one subject, while the gastric emptying rate of fluids was decreased in all subjects. Nevertheless, 14/13CO2 excretion rates in the breath after intraduodenally administered 14C-octanoic acid and 13C-glycine, were similar in basal condition and after subcutaneous injection of octreotide. CONCLUSIONS: Subcutaneous injection of a single physiological dose of octreotide induces a marked delay in the gastric emptying of solids and liquids in young healthy volunteers. The combined 14C-octanoic acid/13C-glycine breath test is very well suited to demonstrate this effect, since the absorption and metabolism of octanoic acid and glycine remains unaltered after administration of octreotide.

Gastric emptying in hyperemesis gravidarum and non-dyspeptic pregnancy.

BACKGROUND: Emesis and hyperemesis are significant problems associated with early pregnancy. However, gastric emptying of solids has never been studied during early pregnancy in humans. AIM: To investigate gastric emptying of solids in patients recovering from hyperemesis gravidarum and in non-dyspeptic pregnant women and to compare these results with a group of healthy non-pregnant women. METHODS: Fourteen patients with hyperemesis gravidarum, 10 non-dyspeptic pregnant women and 36 non-pregnant women in the first half of the menstrual cycle underwent a gastric emptying study. Seven non-pregnant women repeated the test in the post-ovulatory period. RESULTS: Gastric emptying of solids was not significantly delayed in non-dyspeptic pregnant women compared with non-pregnant women. The emptying rate tended to be impaired in the post-ovulatory period of the menstrual cycle. Solid emptying was significantly accelerated in patients recovering from hyperemesis gravidarum, correlating well with thyroid function in the latter group. CONCLUSION: Pregnancy in humans is not associated with decreased solid gastric emptying. In subjects recovering from hyperemesis gravidarum, solid emptying is increased, correlating well with thyroid function abnormalities. Nausea and vomiting in hyperemesis are therefore probably not due to upper gastrointestinal disorders.

Cyclosporine: advantages versus disadvantages vis-à-vis tacrolimus.

Despite a different molecular structure and biochemical properties, cyclosporine and tacrolimus--by inhibiting calcineurin activity--have been shown in the previous two decades of solid organ transplantation to be well tolerated and effective immunosuppressants. Initial randomized clinical trials showed a lower incidence of acute rejection in tacrolimus than in cyclosporine-treated patients, in combination with steroids and azathioprine. But in conjunction with mycophenolate mofetil, the difference in the incidence of acute rejection episodes is less clear. In general, short- and medium-term outcome variables (1-year serum creatinine, graft and patient survival) with cyclosporine and tacrolimus are excellent, and (almost) identical, with both substances having the same intrinsic nephrotoxic potential. On the other hand, cyclosporine and tacrolimus have a different impact on cardiovascular risk factors with tacrolimus having a better profile on arterial tension and lipid metabolism and cyclosporine on glucose metabolism. However, at present no data are available to discern that these differences in risk profile alter patient or graft survival or long-term cardiovascular morbidity/mortality. Therefore, prospective long-term trials are needed to study the quantitative impact of different immunosuppressive agents and concomitant cardiovascular risk factors on long-term patient and graft survival, before evidence-based (patient, graft, or cardiovascular) risk reduction can be firmly claimed by tailoring calcineurin inhibitors.

Localised plasma-cell type Castleman's disease and AA-amyloidosis cured by resection. A case report and review of the literature.

Castleman's disease (CD) is a rare atypical lymphoproliferative disorder with frequent, yet less well known renal involvement. We describe the case of a 58-year-old woman with localised abdominal plasma-cell type CD complicated by nephrotic syndrome due to renal amyloidosis. 18Fluorodeoxyglucose (FDG) positron emission tomography (PET) confirmed the unicentric nature. Resection of the mass resulted in regression of the signs of inflammation, a negative FDG-PET and complete remission of the nephrotic syndrome. A review of the literature of renal involvement (incidence, clinical and pathological manifestations, treatment and prognosis) in CD is provided.

Crohn's-like changes in the colon due to mycophenolate?

OBJECTIVE: Mycophenolate mofetil (MMF) is used for prevention of allograft rejection in kidney transplant patients. A subset of patients suffers from chronic diarrhoea of unknown origin. The aim of the study was to investigate the effect of MMF on the colonic mucosa. MATERIALS AND METHODS: Colonic mucosal biopsies from 24 kidney transplant patients receiving MMF and presenting with chronic diarrhoea were analysed using routine stainings and immunohistochemistry for Ki67 and E-cadherin. Results were compared with a control group of 19 kidney transplant patients not receiving MMF. In all patients routine clinical and laboratory investigations were performed in order to explain the diarrhoea. RESULTS: In 11 patients, the diarrhoea seemed to be of infectious origin. Furthermore, 19/24 of MMF-patients showed characteristic histological alterations of the mucosa that were Crohn's disease-like: discontinuous crypt architectural distortion, increased epithelial mucin secretion, mildly active inflammation and focal presence of dilated and inflamed crypts. Ki67 staining was abnormal in 6/24 MMF patients but also in 4/19 control patients. E-Cadherin staining was normal in most MMF and control patients. CONCLUSIONS: Diarrhoea following MMF treatment is frequently infectious in origin and associated with morphological changes with a Crohn's-like pattern in the colonic mucosa in a subset of patients. MMF does not induce major alteration in the proliferative compartment of colonic epithelium. The diarrhoea is not associated with altered E-cadherin expression in the colonic epithelium.

Combined therapy with atorvastatin and calcineurin inhibitors: no interactions with tacrolimus.

Increased systemic exposure to statins and consequent risk for complications has been reported in patients concomitantly treated with cyclosporin A (CsA). This has been ascribed to inhibition of drug catabolism by cytochrome P450 3A4 (CYP3A4) or drug transport by P-glycoprotein (PGP) and organic anion transporting polypeptide (OATP1B1). It is not known whether the combination of statins and tacrolimus (Tac) also suffers from this drawback. Therefore, a pharmacokinetic study of atorvastatin and its metabolites was performed in 13 healthy volunteers after 4 days' treatment, and after short (12 h) concomitant exposure to CsA and Tac. A complementary assessment of overall CYP, and hepatic and intestinal CYP3A4+PGP activity was performed after each treatment episode and compared to baseline (no drugs). Systemic exposure to atorvastatin acid and its metabolites was significantly increased when administered with CsA. In contrast, intake of Tac did not have any impact on atorvastatin pharmacokinetics. Concomitantly, a profound decrease of hepatic and intestinal PGP and an increase of intestinal CYP3A4 were noted with CsA, whereas no effect was seen after atorvastatin therapy with or without Tac. Based on these findings treatment with Tac appears a safer option for patients needing a combination of statins and calcineurin inhibitors.

Gastric emptying rate of solids in patients with nonulcer dyspepsia.

The underlying role of motility disorders and delayed gastric emptying in nonulcer dyspepsia is still questioned. This study aimed to determine the role of the gastric emptying rate of solids in patients with nonulcer dyspepsia. By means of breath test technology, gastric emptying results of 344 consecutive patients with nonulcer dyspepsia were compared with those of 70 normal healthy volunteers. Although gastric emptying was significantly delayed in patients with nonulcer dyspepsia compared with normal volunteers, there was a great overlap between the two groups. Using 5-95% confidence intervals of the control group in about 30% of the patients with nonulcer dyspepsia gastric emptying was delayed. No correlation was found between gastric emptying rate and age, weight, height, or sex of the subjects in both groups. These findings suggest that, apart from gastric emptying, other mechanisms are very important in the etiology of nonulcer dyspepsia.

CYP3A4 and P-glycoprotein activity in healthy controls and transplant patients on cyclosporin vs. tacrolimus vs. sirolimus.

This study aimed to determine the impact of maintenance immunosuppressive therapy with cyclosporin A (CsA), tacrolimus (FK506) and sirolimus (Rapa) on the in vivo activity of both intestinal and hepatic cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (PGP) in renal transplant patients. The activity of these four elimination pathways was measured by the recently validated intravenous (iv) and per oral (po)14C erythromycin breath and urine test. In addition, overall hepatic P450 activity was measured by the (13)C aminopyrin breath test. Three groups of stable renal transplant patients on maintenance therapy with corticosteroids (CS) and mycophenolate mofetil (MMF) plus either CsA or FK506 or Rapa were examined. A significant increase in intestinal CYP3A4 activity and a significant decrease in hepatic and intestinal PGP activity was seen in patients on CsA in comparison with those on FK506 or Rapa (p < 0.01). A similar analysis in six healthy volunteers at baseline and after intake of CsA, FK506 and Rapa confirmed the results seen in the patients. There was no difference in CYP3A4 and PGP activity in the patients taking either FK506 or Rapa and healthy controls. These data suggest that a different pattern of drug interactions might be expected in patients treated with CsA vs. FK506/Rapa.

[*C]octanoic acid breath test to measure gastric emptying rate of solids.

We have developed a breath test to measure solid gastric emptying using a standardized scrambled egg test meal (250 kcal) labeled with [14C]octanoic acid or [13C]octanoic acid. In vitro incubation studies showed that octanoic acid is a reliable marker of the solid phase. The breath test was validated in 36 subjects by simultaneous radioscintigraphic and breath test measurements. Nine healthy volunteers were studied after intravenous administration of 200 mg erythromycin and peroral administration of 30 mg propantheline, respectively. Erythromycin significantly enhanced gastric emptying, while propantheline significantly reduced gastric emptying rates. We conclude that the [*C]octanoic breath test is a promising and reliable test for measuring the gastric emptying rate of solids.

Pharmacological modulation of gastric emptying rate of solids as measured by the carbon labelled octanoic acid breath test: influence of erythromycin and propantheline.

The *C (13C or 14C) labelled octanoic acid breath test was recently developed to measure the gastric emptying rate of solids. This study aimed to investigate whether it is sensitive enough to detect pharmacologically induced changes in the gastric emptying rate. Nine healthy volunteers were studied in basal condition, after intravenous administration of 200 mg erythromycin, and after peroral administration of 30 mg propantheline. Erythromycin significantly enhanced gastric emptying in all subjects, with an increase of the gastric emptying coefficient (p = 0.0043) in eight of nine and a fall in both the gastric half emptying time (p = 0.0020) and the lag phase (p = 0.0044) in all nine. Propantheline significantly reduced the gastric emptying rate, with a decreased gastric emptying coefficient (p = 0.0007) and an increased gastric half emptying time (p = 0.0168) in all subjects, but no change in the lag phase (p = 0.1214). Further mathematical analysis showed that breath sampling at 15 minutes intervals over a four hour period is recommended to guarantee accuracy and the discriminative value of the breath test in various gastric emptying patterns. In conclusion the *C labelled octanoic acid breath test is sufficiently sensitive to show pharmacologically induced changes of gastric emptying rates of solids.

Relation between gastric emptying rate and rate of intraluminal lipolysis.

The variable gastric emptying rate of a test meal is one of the major problems in evaluating accurately gastrointestinal physiological functions beyond the stomach. The aim of this study was to evaluate the effect of the gastric emptying rate on the rate of intraluminal lipolysis. Thirty four subjects without pancreatic disease (21 with a normal gastric emptying and 13 with a known slow gastric emptying) and 14 subjects with pancreatic disease (four without and 10 with pancreatic insufficiency) were studied using a dual labelled breath test. The test meal consisted of one egg, 60 grams of white bread, 10 grams of margarine, and 150 ml of water (350 kcal). The egg yolk was labelled with 91 mg of 13C-octanoic acid, the margarine was labelled with 296 kBq of distearyl-2-14C-octanoyl-glycerol. Breath samples were taken every 15 minutes during six hours and analysed for 13CO2 and 14CO2 content. The gastric emptying rate of the meal was evaluated by the gastric emptying coefficient, the half emptying time, and the lag phase; the rate of intraluminal lipolysis was evaluated by the six hours cumulative 14CO2 excretion. Despite a clear distinction in the rate of intraluminal lipolysis, no difference could be detected in gastric emptying rate of the test meal between subjects without and with pancreatic disease. In subjects with pancreatic insufficiency, intraluminal hydrolysis was the rate limiting process in fat assimilation; in patients without pancreatic insufficiency, however, gastric emptying could be rate limiting. Therefore, patients with known slow gastric emptying, displayed a significantly decreased rate of intraluminal lipolysis compared with normal controls. This decrease could be corrected for accurately using a correction factor based on the gastric emptying coefficient. In conclusion, the combined 13C-octanoic acid and 14C-mixed triglyceride breath test permits the measurement of gastric emptying rate and intraluminal lipolysis simultaneously in a minimally invasive way. Correction of intraluminal lipolysis rate for gastric emptying rate of the given test meal permits evaluation of fat assimilation rates in a physiological way regardless of gastric emptying disorders.

Measurement of hepatic and intestinal CYP3A4 and PGP activity by combined po + iv [14C]erythromycin breath and urine test.

The aim of the present study was to develop a test for measuring hepatic and intestinal removal of cytochrome p-450 3A4 (CYP3A4)- and P-glycoprotein (PGP)-dependent xenobiotics that would be applicable for clinical use in humans. Orally and intravenously administered [N-methyl-14C]erythromycin was used for evaluation of 14C-labeled excretion dynamics in breath and urine. Simultaneous breath and urine test measurements were performed in 32 healthy volunteers and in 23 renal transplant recipients. Mathematical analysis of the excretion rate of labeled CO2 in breath and labeled carbon in urine resulted in 1). separation of both CYP3A4 and PGP activity in the liver and the intestinal mucosa and 2). numerical calculation of the dynamics of the different processes. The test was sufficiently sensitive to detect theoretically predicted process-specific pharmacological modulations by different drugs in healthy volunteers and after recent renal transplantation. It is concluded that the combined oral and intravenous erythromycin breath and urine test is a reliable and noninvasive test to measure phenotypic intestinal and hepatic CYP3A4 and PGP activity and may be a promising tool for prediction of drug interactions and dose adjustment of many pharmacotherapeutics in clinical practice, e.g., immunosuppressive agents after renal transplantation.

Gastric emptying of the liquid, solid and oil phase of a meal in normal volunteers and patients with Billroth II gastrojejunostomy.

BACKGROUND: The relationship between gastric emptying of different phases of a meal in humans has only been partly studied in normal subjects and in patients with previous gastric surgery. METHODS: In the present study, gastric emptying of the liquid, solid and oil phase and the relationship between the phases was evaluated in 10 normal control subjects and in seven patients with Billroth II gastrojejunostomy using breath test technology. RESULTS: Gastric emptying in normal subjects showed a clear separation between the emptying of the liquid, solid and oil phase. In healthy volunteers, the liquid phase emptied in the same manner in the presence of a solid phase as in the presence of an oil phase. In contrast, the oil phase emptied more slowly with liquids than with solids. The emptying rate of the oil phase was not only inversely related to the amount administered but was also dependent on its chemical composition. Gastric emptying in patients with Billroth II gastroenterostomy was characterized by a complete loss of discrimination between the different phases of the meal, with an extremely fast emptying of the oil phase compared with normal control subjects. CONCLUSION: In normal subjects, the liquid, solid and oil phase of a meal are emptied differently. In patients with Billroth II gastrojejunostomy, dumping of the oil phase is the most pronounced difference from the normal physiology of gastric emptying. This could be one of the reasons why Billroth II gastrectomy may be associated with fat malabsorption.