Effect of rifampicin on the pharmacokinetics of atenolol.

Also poorly metabolized drugs, including certain beta-blocking agents, can be susceptible to drug interactions caused by transporter inhibitors and inducers. Thus, our aim was to investigate the effect of rifampicin on the pharmacokinetics of atenolol in healthy people. In a randomized cross-over study with two phases, nine healthy volunteers received a 5-day pretreatment with rifampicin (600 mg daily) or placebo. On day 6, a single 100 mg dose of atenolol was administered orally. The plasma concentrations of atenolol and its excretion into urine were measured up to 33 hr after dosing. Systolic and diastolic blood pressures and heart rate were recorded in a sitting position before the intake of atenolol and 2, 4, 6, and 10 hr later. During the rifampicin phase, the mean area under the plasma concentration-time curve (AUC(0-infinity)) of atenolol was decreased to 81% and renal clearance increased to 109% of the placebo phase values (P<0.05). Rifampicin pretreatment reduced, albeit not statistically significantly, also the peak plasma concentration (Cmax), AUC(0-33 hr), and amount of atenolol excreted to 85% (P=0.139), 81% (P=0.053), and 86% (P=0.12) of the respective placebo phase values. The average heart rate and diastolic blood pressure were slightly higher during the rifampicin phase compared with the placebo phase (P<0.05). To conclude, although the inducing effect of rifampicin may not have been at its maximum by day 6, rifampicin has only a minor effect on the pharmacokinetics of atenolol evidenced by a slight reduction in its bioavailability.

Drug-related visits to a district hospital emergency room.

The role of adverse drug reactions (ADRs) as a cause of hospital visits varies depending on the type of hospitals. Our aim was to determine the incidence of drug-related emergency department visits to a district hospital, and to identify the drugs and patient groups involved. All patient visits to the emergency department of a Finnish district hospital were evaluated prospectively for 6 months. The physician on duty and a clinical pharmacologist selected all possibly drug-related visits for further scrutinising. The causality assessment (drug-related or not) was judged according to WHO criteria, based on the patients' files, including laboratory and other data. Of the 7113 evaluated visits, 167 (2.3%) were "certainly" or "probably" drug-related; 102 (1.4% of all) were related to ADRs and 65 (0.9%) to intentional overdoses. The most common ADRs were gastrointestinal symptoms (n=17) caused by antibiotics, opioids, nonsteroidal antiinflammatory or cytostatic drugs. The International Classification of Disease (ICD-10) codes on patients' files were insensitive to disclose ADRs. The ADR patients were older (mean age 57 years) than the intentional overdose patients (38 years; P<0.001). Males predominated in the intentional overdose group (38 males, 27 females) but not in the ADR patients. The majority of intentional overdoses was caused by psychotropics. The ADRs lead to hospitalisation in a higher frequency (51%) than did the intentional overdoses (35%). In conclusion, the incidence of "certainly" or "probably" drug-related visits to the district hospital emergency room was relatively low. The ICH-10 codes on patients' files were found to be insensitive to disclose the ADRs, even when they lead to hospital admission, casting doubts on the usefulness of ICH codes alone in ADR evaluation.

Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide.

BACKGROUND AND AIMS: Gemfibrozil, and particularly its combination with itraconazole, greatly increases the area under the plasma concentration-time curve [AUC(0, infinity)] and response to the cytochrome P450 (CYP) 2C8 and 3A4 substrate repaglinide. In vitro, gemfibrozil is a more potent inhibitor of CYP2C9 than of CYP2C8. Our aim was to investigate the effects of the gemfibrozil-itraconazole combination on the pharmacokinetics and pharmacodynamics of another meglitinide analogue, nateglinide, which is metabolized by CYP2C9 and CYP3A4. METHODS: In a randomized crossover study with two phases, nine healthy subjects took 600 mg gemfibrozil and 100 mg itraconazole (first dose 200 mg) twice daily or placebo for 3 days. On day 3, they ingested a single 30-mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 12 h. RESULTS: During the gemfibrozil-itraconazole phase, the AUC(0, infinity) and C(max) of nateglinide were 47% (range 23-74%; P < 0.0001) and 30% (range - 8% to 104%; P = 0.0146) higher than during the placebo phase, respectively, but the t(max) and t1/2 of nateglinide remained unchanged. The combination of gemfibrozil and itraconazole had no effect on the formation of the M7 metabolite of nateglinide but impaired its elimination. The blood glucose response to nateglinide was not significantly changed by coadministration of gemfibrozil and itraconazole. CONCLUSIONS: The combination of gemfibrozil and itraconazole has only a limited influence on the pharmacokinetics of nateglinide. This is in marked contrast to the substantial effect of this combination on the pharmacokinetics of repaglinide. The findings suggest that in vivo gemfibrozil, probably due to its metabolites, is a much more potent inhibitor of CYP2C8 than of CYP2C9.

Orange juice substantially reduces the bioavailability of the beta-adrenergic-blocking agent celiprolol.

BACKGROUND: Grapefruit juice was recently found to decrease plasma concentrations of the beta-adrenergic receptor-blocking agent celiprolol. Our objective was to investigate the effect of orange juice on the pharmacokinetics of celiprolol in healthy subjects. METHODS: In a randomized crossover study with 2 phases and a washout of 2 weeks, 10 healthy volunteers ingested either 200 mL normal-strength orange juice or water 3 times a day for 2 days. On the morning of day 3, 1 hour after ingestion of 200 mL orange juice or water, each subject ingested 100 mg celiprolol with either 200 mL orange juice or water. In addition, 200 mL orange juice or water was ingested at 4, 10, 22, and 27 hours after celiprolol intake. The concentrations of celiprolol in plasma and its excretion into urine were measured up to 33 hours after its dosing. Systolic and diastolic blood pressures and heart rate were recorded up to 10 hours. RESULTS: Orange juice reduced the mean peak plasma concentration of celiprolol by 89% (P <.01) and the mean area under the plasma celiprolol concentration-time curve by 83% (P <.01). The time to peak concentration of celiprolol increased from 4 to 6 hours (P <.05), and the half-life was prolonged from 4.6 to 10.8 hours (P =.05) after ingestion of orange juice. Orange juice reduced the urinary excretion of celiprolol by 77% (P <.01). No significant differences were observed in the hemodynamic variables between the phases. CONCLUSIONS: Orange juice substantially reduces the bioavailability of celiprolol, but the mechanism of this interaction remains to be resolved. For example, modulation of intestinal pH and of function of transporters implicated in the absorption of celiprolol may be involved. Because of the great extent of the orange juice-celiprolol interaction and a wide use of orange juice, this interaction is likely to have clinical importance in some patients, although hemodynamic consequences were not seen in young healthy subjects.

Effect of fluconazole on the pharmacokinetics and pharmacodynamics of nateglinide.

OBJECTIVE: Our aim was to investigate the possible effects of fluconazole on the pharmacokinetics and pharmacodynamics of nateglinide, a new short-acting meglitinide analog antidiabetic drug. METHODS: In a randomized, double-blind, crossover study with 2 phases, 10 healthy volunteers took 200 mg fluconazole (400 mg on day 1) or placebo once daily for 4 days. On day 4, they ingested a single 30-mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 7 hours. RESULTS: Fluconazole raised the total area under the plasma concentration-time curve from time 0 to infinity of nateglinide by 48% (range, 20%-73%; P <.00001) and prolonged its half-life from 1.6 to 1.9 hours (P <.05), but the peak plasma nateglinide concentration remained unchanged. The peak plasma concentration of the M7 metabolite of nateglinide was reduced by 34% by fluconazole (P <.001), and its half-life was prolonged from 2.2 to 3.5 hours (P <.05). No significant differences were seen in the blood glucose response to nateglinide between the phases. CONCLUSIONS: Fluconazole raised the plasma concentrations and reduced the systemic elimination of nateglinide probably by inhibiting its cytochrome P4502C9-mediated biotransformation. Concomitant use of fluconazole with nateglinide may prolong its blood glucose-lowering effect.