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Biomedical subjects

M F Hebert

Publications and source records attributed to M F Hebert.

13 recordsLinked to original sources
PubMed1999

Four-year follow-up of mycophenolate mofetil for graft rescue in liver allograft recipients.

BACKGROUND: Mycophenolate mofetil (MMF) has been shown to have promise in short-term liver transplantation graft rescue studies. The purpose of this study was to evaluate the long-term efficacy and safety of MMF in liver transplant patients who had failed cyclosporine (CsA)-based conventional immunosuppression. METHODS: Nineteen orthotopic liver allograft recipients were converted from azathioprine to MMF in combination with CsA and prednisone in this prospective, open-labeled, single-center, graft rescue, pilot study. Six patients were taken off CsA when MMF was initiated. A 4-year patient follow-up is reported here. Patients were considered to have failed CsA-based immunosuppression either for refractory rejection, chronic rejection, or severe CsA neurologic toxicity. RESULTS: Twelve patients had complete histologic resolution, two had partial resolution, and three had worsening of their rejection. Thirteen patients had a complete biochemical response; one had a partial response and four had worsening of their rejection. Two patients had no histologic and one no biochemical follow-up. Of the six patients treated with MMF and prednisone alone, four had complete resolution of rejection without recurrence. The majority of adverse reactions were gastrointestinal [nausea and/or vomiting (n=5); diarrhea (n=8); gastritis, duodenitis, or esophagitis (n=4); and ulcers (n=2)] or bone marrow suppressive [leukopenia (n=9), anemia (n=6), and thrombocytopenia (n=5)]. CONCLUSIONS: MMF seems to be an effective alternative immunosuppressive in patients failing CsA-based conventional therapy. MMF may be of particular benefit in patients who do not tolerate CsA or tacrolimus. The long-term safety profile is similar to that of other immunosuppressives.

Adult↗
PubMed1999

Effects of rifampin on tacrolimus pharmacokinetics in healthy volunteers.

Tacrolimus is a marketed immunosuppressant used in liver and kidney transplantation. It is subject to extensive metabolism by CYP3A4 and is a substrate for P-glycoprotein-mediated transport. A pharmacokinetic interaction with rifampin, an antituberculosis agent and potent inducer of CYP3A4 and P-glycoprotein, and tacrolimus was evaluated in six healthy male volunteers. Tacrolimus was administered at doses of 0.1 mg/kg orally and 0.025 mg/kg/4 hours intravenously. The pharmacokinetics of tacrolimus were obtained from serial blood samples collected over 96 hours, after single oral and intravenous administration prior to and during an 18-day concomitant rifampin dosing phase. Coadministration of rifampin significantly increased tacrolimus clearance (36.0 +/- 8.1 ml/hr/kg vs. 52.8 +/- 9.6 ml/hr/kg; p = 0.03) and decreased tacrolimus bioavailability (14.4% +/- 5.7% vs. 7.0% +/- 2.7%; p = 0.03). Rifampin appears to induce both intestinal and hepatic metabolism of tacrolimus, most likely through induction of CYP3A and P-glycoprotein in the liver and small bowel.

Administration, Oral↗
PubMed1999

Diltiazem increases tacrolimus concentrations.

OBJECTIVE: To describe a patient with increased tacrolimus concentrations due to a diltiazem drug interaction. CASE SUMMARY: A 68-year-old white man, four months following orthotopic liver transplantation secondary to hepatitis C and Laënnec's cirrhosis, was admitted to the intensive care unit for diarrhea, dehydration, and atrial fibrillation. He was stabilized on oral tacrolimus 8 mg twice daily, with a whole blood tacrolimus trough concentration of 12.9 ng/mL on admission. He was started on a continuous infusion of diltiazem for one day, followed by 30 mg orally every eight hours. Three days after admission, the patient became delirious, confused, and agitated; he was found to have a whole blood tacrolimus trough concentration of 55 ng/mL. The tacrolimus was withheld and diltiazem was discontinued. The tacrolimus concentrations fell over the next three days to 6.7 ng/mL, with a corresponding improvement in his mental status. The oral tacrolimus was restarted at 3 mg twice daily and increased gradually to 5 mg twice daily over the next four days; this produced tacrolimus trough concentrations between 9 and 10 ng/mL. DISCUSSION: Tacrolimus is known to be a substrate for P-glycoprotein and metabolized by CYP3A. Diltiazem inhibits CYP3A, P-glycoprotein, and tacrolimus metabolism in vitro. Although this interaction may have been predictable, this is the first detailed case report describing this clinically significant drug interaction. CONCLUSIONS: Diltiazem can dramatically increase tacrolimus concentrations and result in tacrolimus toxicity. Avoidance of this interaction or careful monitoring of tacrolimus concentrations along with tacrolimus dose reduction is recommended if diltiazem therapy cannot be avoided.

Aged↗
PubMed1998

Tamoxifen in liver disease: potential exacerbation of hepatic dysfunction.

Tamoxifen, a non-steroidal anti-estrogen, has been used successfully for a decade as post-operative adjuvant therapy for breast cancer. Tamoxifen is generally well tolerated with few side effects, especially at the typical dose of 10 mg twice daily. However, hepatic effects have been reported after tamoxifen administration and are usually found to be cholestatic in nature. Although previous reports concentrate on tamoxifen as a probable cause of drug-induced hepatotoxicity, very little attention has been focused on the use of tamoxifen in patients with pre-existing liver dysfunction and the possible need for dose adjustment. We present the case of a 48-year-old woman with an acute exacerbation of her pre-existing liver dysfunction and subsequent elevations of tamoxifen blood levels after approximately one year of tamoxifen therapy for adjuvant treatment of breast cancer. Tamoxifen dosing was adjusted based on serum levels.

Antineoplastic Agents, Hormonal↗
PubMed1997

Tacrolimus oral bioavailability doubles with coadministration of ketoconazole.

OBJECTIVE: To quantitate the effect of ketoconazole, an azole antifungal agent and potent inhibitor of CYP3A4 and P-glycoprotein, on the bioavailability of tacrolimus, a substrate of the CYP3A system and of P-glycoprotein. SUBJECTS AND METHODS: The pharmacokinetics of tacrolimus were studied in six healthy volunteers (two women and four men) in a four-dose study after each received single doses of tacrolimus alone (0.1 mg/kg orally and 0.025 mg/kg intravenously) and with coadministered ketoconazole (200 mg orally at bedtime for 12 days). The dose of tacrolimus was reduced during the ketoconazole phase (0.04 mg/kg orally; 0.01 mg/kg intravenously). Ketoconazole and tacrolimus doses were separated by approximately 10 hours. Whole blood tacrolimus concentrations were determined by enzyme-linked immunosorbent assay. Estimated pharmacokinetic parameters in whole blood (mean +/- SD) before and with ketoconazole were calculated with noncompartmental techniques. RESULTS: Coadministration of ketoconazole did not consistently affect tacrolimus clearance (55.6 +/- 16.7 ml/hr/kg versus 42.5 +/- 7.6 ml/hr/kg), and steady-state volume of distribution was unchanged (0.99 +/- 0.26 L/kg versus 0.93 +/- 0.25 L/kg). However, a significant increase in tacrolimus bioavailability (14% +/- 5% versus 30% +/- 8%; p < 0.01) was observed with coadministered ketoconazole. Hepatic bioavailability was unchanged by the presence of ketoconazole (96% +/- 1% versus 97% +/- 1%). CONCLUSIONS: Because ketoconazole did not alter hepatic bioavailability and because 10 hours separated administration times of the drugs, it appears that the marked increase in tacrolimus bioavailability can be explained by ketoconazole having a local inhibitory effect on tacrolimus gut metabolism or on intestinal P-glycoprotein activity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

The effect of water-soluble vitamin E on cyclosporine pharmacokinetics in healthy volunteers.

We evaluated the effect of water-soluble vitamin E (d-alpha-tocopheryl polyethylene glycol 1000 succinate [TPGS]; Liqui-E) on the oral pharmacokinetics of the cyclosporine, a poorly available (approximately 30%) drug, in healthy volunteers. Ten healthy subjects were given two doses of oral cyclosporine (10mg/kg) separated by a 7-day washout period. Oral TPGS (2.6 IU/kg) was administered concomitantly with one of the cyclosporine doses in a randomized order. A significant increase was observed in area under the blood concentration-time curve (AUC;mean +/ SD) with concomitant TPGS administration (3908 +/- 2601 versus 6296 +/- 5102 ng x hr/ml). Significant decreases were observed in apparent oral clearance (0.24 +/- 0.14 versus 0.15 +/- 0.08 L/hr/kg) and apparent oral steady-state volume of distribution (1.57 +/- 0.95 versus 1.07 +/- 0.73 L/kg). No significant changes were observed in the ratios of metabolites to parent drug AUC values. The comparable relative decreases in apparent oral clearance (38%) and apparent oral steady-state volume of distribution (30%) with TPGS are most likely explained by enhanced absorption, decreased counter transport back into the intestine by P-glycoprotein, or some unknown mechanism by which cyclosporine is protected from metabolism in the gut, thereby increasing bioavailability.

Administration, Oral↗
PubMed1995

The effects of ketoconazole on the intestinal metabolism and bioavailability of cyclosporine.

The pharmacokinetics of cyclosporine were studied in the blood of five normal healthy volunteers (two men and three women) after each received oral and intravenous cyclosporine alone and with concomitant oral ketoconazole. Administration of ketoconazole caused a significant decrease in intravenous cyclosporine clearance (0.18 +/- 0.05 L/kg/hr versus 0.32 +/- 0.09 L/hr/kg) and a significant increase in cyclosporine oral bioavailability (56.4% +/- 11.7% versus 22.4% +/- 4.8%) compared with values before ketoconazole administration. Steady-state volume of distribution for intravenously administered cyclosporine was unchanged (1.26 +/- 0.44 L/kg versus 1.10 +/- 0.27 L/kg). Hepatic bioavailability (1 - hepatic extraction ratio) calculated for intravenous cyclosporine increased by 11% in the presence of ketoconazole (86.3% +/- 3.7% versus 75.2% +/- 6.6% without ketoconazole), which accounts for only one third of the observed increase in cyclosporine oral bioavailability. Because it is unlikely that ketoconazole had a significant effect on either cyclosporine absorption or hepatic blood flow, the increase in cyclosporine bioavailability observed in this study is most likely explained by inhibition of gastrointestinal cytochrome P450 enzymes.

Administration, Oral↗
PubMed1995

Pharmacokinetics of tacrolimus in liver transplant patients.

OBJECTIVE: To characterize the pharmacokinetics of the immunosuppressive agent tacrolimus (FK 506) in liver transplant patients. METHODS: Patients (n = 16) were assessed during and after 1- to 3-day intravenous infusions followed by a 2-week course of oral dose therapy. Plasma and whole blood data were fitted simultaneously with equations accounting for nonlinear drug binding by red blood cells to generate clearance (CL) and volume of distribution (V). RESULTS: The maximum blood/plasma ratio of tacrolimus was 55.5 +/- 26.8 (SD) and half-life averaged 12.1 +/- 4.7 hours. The CL and V were relatively high based on plasma concentrations (CL, 1.7 L/hr/kg; V, 30 L/kg) and low based on whole blood (CL, 54 ml/hr/kg; V, 0.9 L/kg), with moderate variability (coefficient of variation, 34% to 49%) among the patients. Correlations of plasma CL and V with maximum blood/plasma ratios (ranging from 13 to 114) were strong (r = 0.65 and r = 0.73). Blood binding affects the disposition of tacrolimus, and plasma concentrations are indirectly and inversely related to red cell binding. The oral dose data for tacrolimus yielded a brief absorption lag time (tlag, 0.39 hour), a variable first-order absorption rate constant (ka, 4.5 +/- 3.0 hr-1), and consistent bioavailability (F, 25% +/- 10%). The area under the concentration-time curve versus 12-hour minimum concentration relationships for both whole blood and plasma were nearly linear, confirming the utility of trough values for monitoring drug exposure. CONCLUSION: This study provides pharmacokinetic guidelines for the use of tacrolimus in patients undergoing hepatic transplantation. Nonlinear blood binding is a major source of interpatient variation in the disposition of tacrolimus.

Administration, Oral↗
PubMed1995

Differentiation of absorption and first-pass gut and hepatic metabolism in humans: studies with cyclosporine.

The low and variable bioavailability of cyclosporine has been attributed to poor absorption. However, recent studies have suggested that intestinal first-pass metabolism exerts a significant effect on bioavailability. We describe theory and methods to differentiate the contribution from oral absorption and intestinal and hepatic metabolism to overall cyclosporine bioavailability. Analysis of data from previous studies in our laboratories shows that in the absence of intestinal metabolism, cyclosporine absorption from its presently available dosage form averages at least 65% +/- 12% in healthy volunteers and 77% +/- 19% in kidney transplant patients. Analysis also suggests that the extraction ratio for cyclosporine in the gut is approximately twice the hepatic extraction and that cyclosporine absorption does not present a problem, with an average of 86% of the drug absorbed intact from its commercially available product in healthy volunteers. The boundary condition analysis described should have broad application in the differentiation of factors responsible for poor bioavailability.

Administration, Oral↗
PubMed1993

Endstage liver disease associated with nitrofurantoin requiring liver transplantation.

OBJECTIVE: To report the apparent development of endstage liver disease secondary to nitrofurantoin administration. PATIENT: A 40-year-old woman developed hepatic failure after receiving nitrofurantoin 200 mg po bid for one month for prophylaxis against urinary-tract infections. Symptoms first occurred after two weeks of nitrofurantoin therapy. Other causes of hepatic failure (e.g., viral infection, autoimmune disorder, concomitant medications, cancer, Wilson's disease, ethanol abuse, pregnancy) were ruled out. CONCLUSIONS: Acute and chronic hepatic injury has previously been reported with the use of nitrofurantoin. The proposed mechanism may be immunoallergic or metabolic in origin. On evaluating concomitant diseases and medications in our patient as well as the temporal sequence of her signs and symptoms, it appears that she developed hepatic failure secondary to the use of nitrofurantoin, ultimately necessitating orthotopic liver transplantation. The potential for the development of such a severe adverse reaction warrants careful evaluation of symptoms that may potentially be caused by hepatic damage as well as immediate discontinuation of nitrofurantoin in patients presenting with jaundice.

Adult↗
PubMed1992

Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction.

The pharmacokinetics of cyclosporine was studied in six healthy volunteers after administration of the drug orally (10 mg/kg) and intravenously (3 mg/kg) with and without concomitant rifampin administration. Both blood and plasma (separated at 37 degrees C) samples were analyzed for cyclosporine concentration. For blood and plasma, respectively, clearances of cyclosporine were calculated to be 0.30 and 0.55 L/hr/kg, values for volume of distribution at steady state were 1.31 and 1.68 L/kg, and bioavailabilities were 27% and 33% during the pre-rifampin phase. Post-rifampin phase clearances of cyclosporine were 0.42 and 0.79 L/hr/kg, values for volume of distribution at steady state were 1.36 and 1.35 L/kg, and bioavailabilities were 10% and 9% for blood and plasma, respectively. Rifampin not only induces the hepatic metabolism of cyclosporine but also decreases its bioavailability to a greater extent than would be predicted by the increased metabolism. The decreased bioavailability most probably can be explained by an induction of intestinal cytochrome P450 enzymes, which appears to be markedly greater than the induction of hepatic metabolism.

Administration, Oral↗
PubMedDate not supplied

What is the clinical role of aerosolized ribavirin?

Aerosolized ribavirin is the first approved agent for the treatment of respiratory syncytial virus (RSV) infection. However, the clinical use of ribavirin is controversial. Although ribavirin-treated patients appear to be subjectively improved, the benefit in terms of decreased morbidity and mortality is not well established. Furthermore, the drug has been found to be teratogenic, carcinogenic, and mutagenic, depending upon the scientific model. Because of its unique mode of administration, environmental exposure of healthcare personnel and other patients may occur. Although administration in mechanically ventilated patients decreases the amount of ribavirin liberated into the atmosphere, the drug crystallizes in the endotracheal tube, occasionally resulting in reduced ventilation. The lack of data documenting efficacy and the above environmental concerns result in difficult decisions for hospitals. Further studies are necessary to clarify the value and safety of ribavirin in the treatment of RSV infection.

Aerosols↗