Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: effect of ketoconazole.

BACKGROUND: The cytochrome P450 3A (CYP3A) isoforms are responsible for the metabolism of a majority of therapeutic compounds, and they are abundant in the intestine and liver. CYP3A activity is highly variable, causing difficulty in the therapeutic use of CYP3A substrates. A practical in vivo probe method that characterizes both intestinal and hepatic CYP3A activity would be useful. OBJECTIVES: To determine the intestinal and hepatic contribution to the bioavailability of midazolam with use of the CYP3A inhibitor ketoconazole. METHODS: The pharmacokinetics of midazolam was assessed in nine (six men and three women) healthy individuals after single doses of 2 mg intravenous and 6 mg oral midazolam (phase I). These pharmacokinetic values were compared with those obtained after single doses of 2 mg intravenous and 6 mg oral midazolam and three doses of 200 mg oral ketoconazole (phase II). RESULTS: After ketoconazole therapy, area under the concentration versus time curve of midazolam increased 5-fold after intravenous midazolam administration (P < or = .001) and 16-fold after oral midazolam administration (P < or = .001). Intrinsic clearance decreased by 84% (P = .003). Total bioavailability increased from 25% to 80% (P < .001). The intestinal component of midazolam bioavailability increased to a greater extent than the hepatic component (2.3-fold [P = .003] and 1.5-fold [P < or = .001], respectively). In the control phase, female subjects had greater midazolam clearance values than the male subjects. CONCLUSIONS: Ketoconazole caused marked inhibition of CYP3A activity that was greater in the intestine than the liver. Administration of single doses of oral and intravenous midazolam with and without oral ketoconazole exemplifies a practical method for differentiating intestinal and hepatic CYP3A activity.

Red wine decreases cyclosporine bioavailability.

BACKGROUND: Many commonly ingested substances such as grapefruit juice and Hypericum perforatum (St John's wort) have been found to interact with important therapeutic agents such as cyclosporine (INN, ciclosporin). The mechanism for these interactions is thought to involve modulation of the activity of the drug-metabolizing enzyme cytochrome P4503A4 (CYP3A4) and/or the drug transport protein Pglycoprotein. In vitro data suggest that red wine may interact with CYP3A4 substrates such as cyclosporine. METHODS: We conducted a randomized, 2-way crossover study of 12 healthy individuals. Subjects received a single 8-mg/kg dose of oral cyclosporine with water (control) and with 12 oz of red wine (Blackstone Merlot, 1996; Blackstone Winery, Graton, Calif). Whole blood was analyzed for cyclosporine and 6 metabolites by specific fluorescence polarization immunoassay and tandem liquid chromatography-mass spectrometry. Blood levels of cyclosporine were compared between the 2 arms. RESULTS: Red wine caused a 50% increase in the oral clearance of cyclosporine. Systemic exposure as measured by the area under the concentration-versus-time curve (AUC) and peak concentration (C(max)) were significantly decreased by red wine. However, half-life was not affected, suggesting that red wine decreased cyclosporine absorption. In vitro, the solubility of cyclosporine in red wine appeared to be lower than in water. CONCLUSIONS: Administration of cyclosporine with red wine causes a significant decrease in cyclosporine exposure. Because cyclosporine is a narrow therapeutic range compound, caution may be warranted with concomitant intake of red wine and cyclosporine.

A randomized trial comparing double-drug and triple-drug therapy in primary cadaveric renal transplants.

A controlled trial was carried out in 209 primary cadaveric renal transplants to compare the effects of cyclosporine and steroids (double therapy) with those of cyclosporine in lower initial dose, azathioprine, and steroids (triple therapy). Patients have been followed 1-36 months since transplantation. Actuarial two-year graft survival (double 74%, triple 76%) and two-year patient survival (double 90%, triple 93%) were similar for both groups. Further analysis of particular risk factors including age, diabetes, HLA matching, acute renal failure, and use of sequential Minnesota antilymphocyte globulin in patients with delayed graft function also showed similar outcomes with both immunosuppressive regimens. Initial hospitalization time, rate of rejection, incidence of serious infection, and rate of rehospitalization were not different. Mean CsA doses and mean trough whole-blood levels were higher in double-therapy patients at hospital discharge but not by three months posttransplant. There were no differences between the two groups in iothalamate clearance at any time. Hypertension was more frequent six months posttransplant in the triple-therapy group (p less than 0.05). Thus, similar results were obtained with both regimens, and except for hypertension no regimen appeared to have increased side effects up to three years posttransplant.

A review of interleukin-2 receptor antagonists in solid organ transplantation.

Daclizumab and basiliximab, engineered human IgG monoclonal antibodies to the interleukin-2 (IL-2) receptor alpha-subunit, were approved to prevent acute rejection after renal transplantation. Daclizumab was studied in adult and pediatric renal allograft recipients, liver allograft recipients, and calcineurin-sparing protocols in renal transplant recipients. Basiliximab was studied in renal allograft recipients and subgroups of recipients of living-related and cadaveric transplants, and in patients with diabetes mellitus. Both agents reduced acute rejection and were associated with few adverse effects. However, information regarding their long-term effects on infection, malignancy, chronic rejection, and patient survival must be available before a final decision is made regarding their proper administration. We propose that a likely role the drugs will play in the field of solid organ transplantation is in new protocols that allow sparing of other more toxic immunosuppressive agents.

Acetate and bicarbonate hemodialysis in patients with and without autonomic dysfunction.

To test the contribution of bicarbonate (Bi) to hemodynamic stability during hemodialysis (HD), we compared the effects of ultrafiltration dialysis with bicarbonate and with acetate under conditions of high-sodium (141 mEq/liter) and low-sodium (130 mEq/liter) dialysate concentrations in 12 stable HD patients. Group 1 was patients (N = 5) who had normal findings on autonomic testing; group 2, patients (N = 7) who had abnormal findings on autonomic testing. All patients and staff were unaware of which dialysis was being used. During the high-sodium dialysate studies, changes in mean blood pressure (MBP), cardiac output (CO), and orthostatic tolerance to standing after HD were similar in both groups of patients with both acetate and bicarbonate dialysate. When the studies were repeated under low-sodium dialysate conditions, several differences emerged between acetate and bicarbonate HD. In group 1, the frequency of adverse symptoms upon standing after HD were reduced with bicarbonate (P less than 0.05). In group 2, bicarbonate HD prevented a significant decrease in orthostatic MBP after HD. These results suggest that bicarbonate affords no greater hemodynamic stability than does acetate if a dialysate sodium of 141 mEq/liter is used. With lower sodium dialysate, bicarbonate appears to provide a modest improvement in decreasing orthostatic symptoms and signs in patients with and without autonomic insufficiency.