Disposition of intravenous and oral cyclosporine after administration with grapefruit juice.

OBJECTIVE: To examine the effect of grapefruit juice on the disposition of cyclosporine after administration of oral and intravenous doses to healthy male subjects. METHODS: Subjects received two oral doses of cyclosporine (7.5 mg/kg) and two intravenous doses (2.5 mg/kg infused for 3 hours), with each dose separated by a 1-week washout period. Grapefruit juice (250 ml) was ingested immediately before one oral and one intravenous dose and again 2 hours later. Blood samples were collected for a 24-hour period, and whole blood concentrations of cyclosporine were measured with use of a specific monoclonal radioimmunoassay. RESULTS: Grapefruit juice had no effect on any pharmacokinetic parameter when given with intravenous cyclosporine. After oral administration, grapefruit juice significantly increased peak concentration (936 versus 1340 ng/ml), as well as area under the curve (6722 versus 10,730 ng . hr/ml) but had no effect on elimination half-life. Absolute bioavailability of cyclosporine was increased from 0.22 to 0.36 (average increase, 62%) by grapefruit juice. CONCLUSIONS: The lack of effect on systemic clearance after intravenous cyclosporine suggests that grapefruit juice improves oral bioavailability by increasing absorption or reducing gut wall metabolism. The latter is more likely in view of studies that suggest significant gut wall metabolism of cyclosporine by CYP3A enzymes known to be inhibited by components of grapefruit juice.

Itraconazole and hydroxyitraconazole serum concentrations are reduced more than tenfold by phenytoin.

OBJECTIVE: To study the disposition of single doses of phenytoin and itraconazole when administered alone and after chronic treatment with the other drug. METHODS: Healthy male volunteers were randomized to two groups and studied in parallel. In group 1, a single 200 mg oral dose of itraconazole was administered on two occasions (alone and after 15 days of 300 mg oral phenytoin once daily). Subjects in group 2 were given a single 300 mg oral dose of phenytoin before and after 15 days of itraconazole (200 mg once daily). Blood was collected for 96 hours after each single dose of phenytoin or itraconazole. Serum was assayed for itraconazole and hydroxyitraconazole concentration by HPLC and for phenytoin concentration by fluorescence polarization immunoassay. RESULTS: Phenytoin decreased the area under the concentration-time curve (AUC) of itraconazole by more than 90%, from 3203 to 224 ng.hr/ml, accompanied by a decrease in half-life from 22.3 to 3.8 hours. Similar changes were observed for hydroxyitraconazole AUC (decreased from 6224 to 315 ng.hr/ml) and half-life (11.3 versus 2.9 hours). Itraconazole increased the AUC of phenytoin (10.3%; p < 0.05), with no change in any other pharmacokinetic parameter. CONCLUSIONS: The striking decrease in itraconazole concentrations with phenytoin is due to induction of metabolism combined with a reduction in the degree of saturable metabolism normally exhibited by itraconazole at this dose. The magnitude of interaction likely accounts for reports of therapeutic failures in patients with fungal infections who are receiving both itraconazole and phenytoin.

6',7'-Dihydroxybergamottin in grapefruit juice and Seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein.

BACKGROUND: 6',7'-Dihydroxybergamottin is a furanocoumarin that inhibits CYP3A4 and is found in grapefruit juice and Seville orange juice. Grapefruit juice increases the oral bioavailability of many CYP3A4 substrates, including cyclosporine (INN, ciclosporin), but intestinal P-glycoprotein may be a more important determinant of cyclosporine availability. OBJECTIVES: To evaluate the contribution of 6',7'-dihydroxybergamottin to the effects of grapefruit juice on cyclosporine disposition and to assess the role of CYP3A4 versus P-glycoprotein in this interaction. METHODS: The disposition of oral cyclosporine was compared in healthy subjects after ingestion of water, grapefruit juice, and Seville orange juice. Enterocyte concentrations of CYP3A4 were measured in 2 individuals before and after treatment with Seville orange juice. The effect of 6',7'-dihydroxybergamottin on P-glycoprotein was assessed in vitro. RESULTS: Area under the whole blood concentration-time curve and peak concentration of cyclosporine were increased by 55% and 35%, respectively, with grapefruit juice (P < .05). Seville orange juice had no influence on cyclosporine disposition but reduced enterocyte concentrations of CYP3A4 by an average of 40%. 6',7'-Dihydroxybergamottin did not inhibit P-glycoprotein at concentrations up to 50 micromol/L. CONCLUSIONS: 6',7'-Dihydroxybergamottin is not responsible for the effects of grapefruit juice on cyclosporine. Because the interaction did not occur with Seville orange juice despite reduced enterocyte concentrations of CYP3A4, inhibition of P-glycoprotein activity by other compounds in grapefruit juice may be responsible. Reduced enterocyte CYP3A4 by 6',7'-dihydroxybergamottin could be important for other drugs whose bioavailability is less dependent on P-glycoprotein.

The dual diagnosis of attention-deficit/hyperactivity disorder and substance abuse: case reports and literature review.

BACKGROUND: It is now recognized that attention-deficit/hyperactivity disorder (ADHD) may persist into adulthood. A number of studies have found an association between ADHD and substance abuse. This article describes three adult patients with both ADHD and substance abuse who were treated successfully with psychostimulants. A review of the relevant literature is included. METHOD: The patients were drawn from a university-based referral center for adults with ADHD. Evaluations for ADHD and substance abuse were completed. Medical therapy and follow-up were completed by the first author. RESULTS: All of the patients responded to psychostimulants and have remained abstinent from alcohol and other drugs for the past 2 to 3 years. CONCLUSION: This case series and review of the literature suggest that specific treatment for ADHD with psychostimulants is feasible in patients who also have substance abuse. Future studies should evaluate the prevalence of this "dual diagnosis" and the efficacy of differing management strategies.

Absence of "red man syndrome" in patients being treated with vancomycin or high-dose teicoplanin.

Twenty-five febrile patients with a history of intravenous drug use who were receiving either vancomycin (15 patients) or teicoplanin (10 patients) as part of a multicenter, double-blind, randomized, clinical efficacy trial were enrolled, upon receipt of their first dose of antibiotic, into a study to evaluate the effect of 1 g of vancomycin and high-dose teicoplanin (30 mg/kg of body weight) on histamine release and the occurrence of "red man syndrome" (RMS). In addition, 10 healthy volunteer subjects (HVS) were randomized to receive either 1 g of vancomycin intravenously or a saline infusion in a double-blind, crossover design study. Patients and HVS were observed for the presence of erythema, flushing, pruritus, and hypotension during and for up to 1 h postinfusion by a blinded investigator. Histamine concentrations in plasma were measured at baseline and during and after drug infusion. No significant differences were noted in baseline temperature between patients (vancomycin recipients, 102.3 degrees F [39.1 degrees C]; teicoplanin recipients, 102.4 degrees F [39.1 degrees C]) or incidence of bacteremia (7 of 15 vancomycin recipients; 5 of 10 teicoplanin recipients). There were no significant differences in peak vancomycin concentrations in the sera of patients (40.8 micrograms/ml) and HVS (49.9 micrograms/ml). There were no reactions consistent with RMS in any patient who received teicoplanin (0 of 10); there was a significant difference in the occurrence of RMS in patients in comparison with that in HVS (0 of 15 patients, 9 of 10 HVS; P less than 0.001) who received vancomycin. The predominant reaction was erythema and pruritus. Histamine concentrations in plasma and the area under the histamine plasma concentration-time curve were highly variable within groups and were not statistically different between patients and HVS. The incidence of RMS secondary to vancomycin or teicoplanin in our patient population appears to be low and consistent with clinical observations. Similar to previous investigations, RMS secondary to vancomycin in HVS was high (90%). However, we found no relationship between the histamine concentration in plasma or the area under the plasma histamine concentration-time curve and the severity of RMS in HVS. The reason for the discrepancy of RMS in patients versus that in HVS in unknown, but it may be related to a blunted effect of glycopeptides to produce the reaction in the presence of infection or it may be specific to our patient population.

Vancomycin protein binding in patients with infections caused by Staphylococcus aureus.

The protein binding of vancomycin has been reported to range from less than 10 percent to 82 percent. We examined the binding of vancomycin in 34 patients (14 intravenous drug abusers, 10 burn patients, and 10 control patients) with Staphylococcus aureus infections. Blood samples were collected serially over an 8- or 12-hour dosing interval following a one-hour infusion. In vitro studies were also performed using albumin solutions of varying concentrations. Binding characteristics were determined through ultrafiltration with vancomycin concentrations analyzed for fluorescence polarization immunoassay. The unbound fraction of vancomycin ranged from 0.41 to 0.77 with a mean of 0.54 +/- 0.08. Unbound fractions was significantly correlated with serum albumin concentration (r = -0.344, p less than 0.046) and renal clearance (r = 0.394, p less than 0.021) but not with total body clearance or volume of distribution. In vitro data also showed an association between albumin concentration and unbound fraction (r = -0.94, p less than 0.017). Although vancomycin protein binding changes with serum albumin, this finding may have limited clinical significance.

Effects of ciprofloxacin on testosterone and cortisol concentrations in healthy males.

Several inhibitors of oxidative drug metabolism inhibit the synthesis of endogenous compounds such as testosterone and cortisol. Since ciprofloxacin is a potent inhibitor of the metabolism of a number of drugs, we studied its effect on serum testosterone and cortisol concentrations in eight healthy male subjects. Blood samples were collected over a 12-h period under baseline conditions and following the first and final doses of ciprofloxacin (500 mg orally every 12 h for 4 days). No significant differences in concentrations or area under the concentration-time curve were found when baseline values were compared with those observed for either testosterone or cortisol after ciprofloxacin administration. These results suggest that ciprofloxacin is unlikely to have either antiandrogenic side effects or clinical utility in lowering testosterone or cortisol concentration.

Influence of subject age on the inhibition of oxidative metabolism by ciprofloxacin.

Case reports suggest that the magnitude of inhibition of oxidative metabolism produced by ciprofloxacin may be greater in elderly subjects. We examined the effect of oral ciprofloxacin on antipyrine disposition in 13 young (ages, 23 to 34 years) and 9 elderly (ages, 65 to 82 years) healthy volunteers. Ciprofloxacin decreased antipyrine oral clearance in young and elderly subjects (P less than 0.05), with the average decreases being similar in both groups (23.3% for the young subjects and 27.9% for the elderly subjects). Ciprofloxacin concentrations in serum were significantly higher (mean, 57%) in the elderly. The formation clearance of 4-hydroxyantipyrine and 3-hydroxymethylantipyrine was also significantly decreased in both groups of subjects; however, norantipyrine formation, accounting for 15 to 20% of antipyrine clearance, was reduced only in the elderly. These results suggest that elderly subjects are not more sensitive to the inhibitory effect of ciprofloxacin on antipyrine metabolism. However, careful clinical monitoring is necessary with all patients, irrespective of age, taking ciprofloxacin concomitantly with drugs primarily eliminated by the cytochrome P-450 system.

Prospective evaluation of red man syndrome in patients receiving vancomycin.

The incidence of red man syndrome (RMS) and its relationship to histamine were investigated in patients receiving vancomycin or an aminoglycoside (control). During the 60-min infusions, patients were observed for signs or symptoms consistent with RMS, including pruritus, erythema, angioedema, and cardiovascular depression. Four blood samples were obtained at 30-min intervals for determination of histamine concentrations. One (3.4%) of 29 vancomycin- and none of 8 aminoglycoside-treated patients had documented RMS. The mean maximum changes in blood pressure and heart rate were not significant and were similar between groups. Increases in histamine concentrations to > 1 ng/mL occurred only in 25% (2/8) of the aminoglycoside patients. Vancomycin induced minimal changes in histamine concentrations despite the occurrence of RMS. From these observations, it appears that RMS is not closely associated with histamine release, and elevated histamine concentrations do not predict RMS. Further investigation is needed to elucidate other mediators of RMS.

Vancomycin pharmacokinetics in burn patients and intravenous drug abusers.

The pharmacokinetics of vancomycin were evaluated in 34 patients (10 burn patients, 14 intravenous drug abusers [IVDA], and 10 controls). Multiple serum samples were drawn following a 1-h vancomycin infusion at steady state over an 8- to 12-h dosing interval. Pharmacokinetic parameters were derived by noncompartmental analysis. There were no significant differences among the groups with respect to age, weight, serum creatinine, volume of distribution, or protein binding. Burn patients had a significantly higher creatinine clearance than did IVDA or controls. Vancomycin clearances averaged 142.8, 98.0, and 67.7 ml/min in burn patients, IVDA, and controls, respectively. The renal clearance of vancomycin was also higher in burn patients than in the other groups. IVDA tended to have a higher vancomycin clearance (31% higher) than did controls, but the difference was not statistically significant. Vancomycin clearance was much higher in burn patients requiring dosage individualization and close monitoring. A considerable amount of vancomycin was eliminated through renal tubular secretion, making dosage predictions based on creatinine clearance more difficult. Further work with IVDA will be needed to determine if they represent a group requiring aggressive vancomycin dosages.