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These results suggest that pomelo juice increases the bioavailability of cyclosporine, possibly by inhibiting CYP3A or P-gp activity (or both) in the gut wall. However, drinking a glass of cranberry juice does not appear to significantly influence the disposition of cyclosporine.

ABSTRACT:In humans, indirect evidence suggests that hypoxia reduces the rate of biotransformation of drugs cleared by cytochrome P450 (P450) subfamilies CYP1A, 2B, and 2C. The aim of this study was to assess whether acute moderate hypoxia modulates the expression of CYP2B4, 2C5, and 2C16 in vivo, and to determine whether the changes in hepatic P450 are conveyed by serum mediators. Moreover, because hypoxia increases the expression of P-glycoprotein in vitro, we examined whether in vivo acute moderate hypoxia modulates the expression of several membrane transporters in the liver. Rabbits and rats were exposed to a fractional concentration of oxygen of 8% for 48 h to generate a stable arterial partial pressure of O 2 of 34 ؎ 1 mm Hg. Compared with rabbits breathing room air, hypoxia in rabbits reduced the amount of CYP1A1, 1A2, 2B4, 2C5, and 2C16 proteins and increased the expression of CYP3A6. Sera of rabbits with hypoxia were fractionated by size exclusion chromatography, the fractions were tested for their ability to modify the expression of P450 isoforms, and serum mediators were identified through neutralization experiments. The serum mediators responsible for the downregulation of P450 isoforms were interferon-␥, interleukin-1␤ (IL-1␤), and IL-2. In vivo, in rats, hypoxia increased the mRNA and protein expression of P-glycoprotein but did not affect the mRNA of breast cancer resistance protein and organic anion-transporting polypeptide 2. It is concluded that in vivo, hypoxia down-regulates rabbit hepatic CYP1A1, 1A2, 2B4, 2C5, and 2C16 and up-regulates CYP3A6. CYP3A11 and P-glycoprotein were up-regulated in the livers of hypoxic rats.In patients with cardiorespiratory diseases, acute hypoxemia appears to reduce the ability of cytochrome P450 isoforms to catalyze the biotransformation of xenobiotics. Patients with pulmonary insufficiency who show an impairment of their general state present an increased incidence of adverse effects, e.g., grand mal seizures, associated with the administration of "usual" doses of theophylline. Theophylline clearance is significantly reduced in patients with acute cardiogenic pulmonary edema (Piafsky et al., 1977) and in patients with worsening airway obstruction, severe bronchial obstruction, congestive heart failure, and pneumonia (Vozeh et al., 1978).In humans, at therapeutic concentrations, the biotransformation of theophylline is primarily catalyzed by CYP1A2, whereas CYP2D6, 2E1, and 3A4 exhibit low affinity and variable capacity (Ha et al., 1995). Rabbits exposed to a fractional concentration of inspired O 2 (FiO 2 ) of 10% for 24 h demonstrate a reduced clearance of theophylline and decreased expression of CYP1A1 and 1A2, although the expression of CYP3A6 is increased (Kurdi et al., 1999). In rabbits subjected to acute moderate hypoxia, hepatic down-regulation of CYP1A1 and 1A2 is triggered by serum mediators, e.g., interferon-␥ (IFN-␥), interleukin 2 (IL-2), and IL-1␤; the up-regulation of CYP3A6 is, at least in part, associated with erythropoietin (Epo) (Fradette et ...

Mixed-effect modeling was used to compare the population pharmacokinetics of 2 formulations of cyclosporine in patients. An open-label, multicenter, conversion study in stable, 6-month post-renal allograft recipients was conducted to compare the safety and pharmacokinetics of oral Pliva Cyclosporine Soft Gelatin Capsules (USP Modified) with Neoral (cyclosporine soft gelatin capsules, USP Modified) in stable post-renal transplant patients. Blood samples were collected predose and for 12 hours postdose on days 1, 14, 15, 28, and 29. Whole-blood samples were analyzed for cyclosporine using high-performance liquid chromatography and mass spectroscopy. Estimates of pharmacokinetic parameters were generated using noncompartmental and population compartmental pharmacokinetic analysis. Moreover, the effects of demographic factors on the pharmacokinetics of cyclosporine were evaluated using the nonlinear mixed-effects modeling program NONMEM. The rate and extent of bioavailability of cyclosporine did not differ between Pliva Cyclosporine Soft Gelatin Capsules and Neoral. In the final model, gender and actual body weight significantly affected the central and peripheral volumes of distribution. In addition, the pharmacokinetics of cyclosporine was defined robustly in this patient population using population pharmacokinetic approaches. Results indicate that the Pliva Cyclosporine Soft Gelatin Capsules and Neoral are bioequivalent when administered to renal transplant patients. Pliva Cyclosporine Soft Gelatin Capsules can then be substituted for Neoral in stabilized patients without anticipating dose adjustments.