Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride

OBJECTIVE: Our objective was to study the effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride, a new sulfonylurea antidiabetic drug. METHODS: In this randomized, double-blind, three-phase crossover study, 12 healthy volunteers took 200 mg of fluconazole once daily (400 mg on day 1), 100 mg of fluvoxamine once daily, or placebo once daily for 4 days. On day 4, a single oral dose of 0.5 mg of glimepiride was administered. Plasma glimepiride and blood glucose concentrations were measured up to 12 hours. RESULTS: In the fluconazole phase, the mean total area under the plasma concentration-time curve of glimepiride was 238% (P <.0001) and the peak plasma concentration was 151% (P <.0001) of the respective control value. The mean elimination half-life of glimepiride was prolonged from 2.0 to 3.3 hours (P <.0001) by fluconazole. In the fluvoxamine phase, the mean area under the plasma concentration-time curve of glimepiride was not significantly different from that in the placebo phase. However, the mean peak plasma concentration of glimepiride was 143% (P <.05) of the control and the elimination half-life was prolonged from 2.0 to 2.3 hours (P <.01) by fluvoxamine. Fluconazole and fluvoxamine did not cause statistically significant changes in the effects of glimepiride on blood glucose concentrations. CONCLUSIONS: Fluconazole considerably increased the area under the plasma concentration-time curve of glimepiride and prolonged its elimination half-life. This was probably caused by inhibition of the cytochrome P-450 2C9-mediated biotransformation of glimepiride by fluconazole. Concomitant use of fluconazole with glimepiride may increase the risk of hypoglycemia as much as would a 2- to 3-fold increase in the dose of glimepiride. Fluvoxamine moderately increased the plasma concentrations and slightly prolonged the elimination half-life of glimepiride.     

The cytochrome P4503A4 inhibitor clarithromycin increases the plasma concentrations and effects of repaglinide.

OBJECTIVE: Our objective was to study the effects of the macrolide antibiotic clarithromycin on the pharmacokinetics and pharmacodynamics of repaglinide, a novel short-acting antidiabetic drug. METHODS: In a randomized, double-blind, 2-phase crossover study, 9 healthy volunteers were treated for 4 days with 250 mg oral clarithromycin or placebo twice daily. On day 5 they received a single dose of 250 mg clarithromycin or placebo, and 1 hour later a single dose of 0.25 mg repaglinide was given orally. Plasma repaglinide, serum insulin, and blood glucose concentrations were measured up to 7 hours. RESULTS: Clarithromycin increased the mean total area under the concentration-time curve of repaglinide by 40% (P <.0001) and the peak plasma concentration by 67% (P <.005) compared with placebo. The mean elimination half-life of repaglinide was prolonged from 1.4 to 1.7 hours (P <.05) by clarithromycin. Clarithromycin increased the mean incremental area under the concentration-time curve from 0 to 3 hours of serum insulin by 51% (P <.05) and the maximum increase in the serum insulin concentration by 61% (P <.01) compared with placebo. No statistically significant differences were found in the blood glucose concentrations between the placebo and clarithromycin phases. CONCLUSIONS: Even low doses of the cytochrome P4503A4 (CYP3A4) inhibitor clarithromycin increase the plasma concentrations and effects of repaglinide. Concomitant use of clarithromycin or other potent inhibitors of CYP3A4 with repaglinide may enhance its blood glucose-lowering effect and increase the risk of hypoglycemia.     

Effects of rifampin on the pharmacokinetics and pharmacodynamics of glyburide and glipizide.

OBJECTIVE: To study the effects of rifampin (INN, rifampicin) on the pharmacokinetics and pharmacodynamics of glyburide (INN, glibenclamide) and glipizide, 2 sulfonylurea antidiabetic drugs. METHODS: Two separate, randomized, 2-phase, crossover studies with an identical design were conducted. In each study, 10 healthy volunteers received 600 mg rifampin or placebo once daily for 5 days. On day 6, a single dose of 1.75 mg glyburide (study I) or 2.5 mg glipizide (study II) was administered orally. Plasma glyburide and glipizide and blood glucose concentrations were measured for 12 hours. RESULTS: In study I, rifampin decreased the area under the plasma concentration--time curve [AUC(0-infinity)] of glyburide by 39% (P <.001) and the peak plasma concentration by 22% (P =.01). The elimination half-life of glyburide was shortened from 2.0 to 1.7 hours (P <.05) by rifampin. The blood glucose decremental AUC(0-7) (net area below baseline) and the maximum decrease in the blood glucose concentration were decreased by 44% (P =.05) and 36% (P <.001), respectively, by rifampin. In study II, rifampin decreased the AUC(0-infinity) of glipizide by 22% (P <.05) and shortened its half-life from 3.0 to 1.9 hours (P =.01). No statistically significant differences in the blood glucose concentrations were found between the phases; however, 4 subjects had moderate hypoglycemia during the placebo phase but only 1 subject had moderate hypoglycemia during the rifampin phase. CONCLUSIONS: Rifampin moderately decreased the plasma concentrations and effects of glyburide but had only a slight effect on glipizide. The mechanism underlying the interaction between rifampin and glyburide is probably induction of either CYP2C9 or P-glycoprotein or both. Induction of CYP2C9 would explain the increased systemic elimination of glipizide. It is probable that the blood glucose--lowering effect of glyburide is reduced during concomitant treatment with rifampin. In some patients, the effects of glipizide may also be reduced by rifampin.     

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 gemfibrozil on the pharmacokinetics and pharmacodynamics of glimepiride.

OBJECTIVE: Our objective was to study the effects of gemfibrozil on the pharmacokinetics and pharmacodynamics of glimepiride, a new sulfonylurea antidiabetic drug and a substrate of cytochrome P4502C9 (CYP2C9). METHODS: In a randomized, 2-phase crossover study, 10 healthy volunteers were treated for 2 days with 600 mg oral gemfibrozil or placebo twice daily. On day 3, they received a single dose of 600 mg gemfibrozil or placebo and 1 hour later a single dose of 0.5 mg glimepiride orally. Plasma glimepiride, serum insulin, and blood glucose concentrations were measured up to 12 hours. RESULTS: Gemfibrozil increased the mean total area under the plasma concentration-time curve of glimepiride by 23% (range, 6%-56%; P <.005). The mean elimination half-life of glimepiride was prolonged from 2.1 to 2.3 hours (P <.05) by gemfibrozil. No statistically significant differences were found in the serum insulin or blood glucose variables between the two phases. CONCLUSIONS: Gemfibrozil modestly increases the plasma concentrations of glimepiride. This may be caused by inhibition of CYP2C9.     

Rifampin decreases the plasma concentrations and effects of repaglinide

OBJECTIVE: To study the effects of rifampin (INN, rifampicin) on the pharmacokinetics and pharmacodynamics of repaglinide, a new short-acting antidiabetic drug. METHODS: In a randomized, two-phase crossover study, nine healthy volunteers were given a 5-day pretreatment with 600 mg rifampin or matched placebo once daily. On day 6 a single 0.5-mg dose of repaglinide was administered. Plasma repaglinide and blood glucose concentrations were measured up to 7 hours. RESULTS: Rifampin decreased the total area under the concentration-time curve of repaglinide by 57% (P < .001) and the peak plasma repaglinide concentration by 41% (P = .001). The elimination half-life of repaglinide was shortened from 1.5 to 1.1 hours (P < .01). The blood glucose decremental area under the concentration-time curve from 0 to 3 hours was reduced from 0.94 to -0.23 mmol/L x h (P < .05), and the maximum decrease in blood glucose concentration from 1.6 to 1.0 mmol/L (P < .05) by rifampin. CONCLUSIONS: Rifampin considerably decreases the plasma concentrations of repaglinide and also reduces its effects. This interaction is probably caused by induction of the CYP3A4-mediated metabolism of repaglinide. It is probable that the effects of repaglinide are decreased during treatment with rifampin or other potent inducers of CYP3A4, such as carbamazepine, phenytoin, or St John's wort.     

Repeated consumption of grapefruit juice considerably increases plasma concentrations of cisapride

BACKGROUND: Grapefruit juice increases the bioavailability of several drugs that are metabolized during first pass by CYP3A4. In this study, the effect of grapefruit juice on the pharmacokinetics of orally administered cisapride was investigated. METHODS: In a randomized, two-phase crossover study, 10 healthy volunteers took either 200 mL double-strength grapefruit juice or water three times a day for 2 days. On day 3, each subject ingested 10 mg cisapride with either 200 mL grapefruit juice or water, and an additional 200 mL was ingested 1/2 hour and 1 1/2 hours after cisapride administration. Timed blood samples were collected for 32 hours after cisapride intake, and a standard 12-lead ECG was recorded before the administration of cisapride and 2, 5, 8, and 12 hours later. RESULTS: The mean peak plasma concentration of cisapride was increased by 81% (range, 38% to 138%; P < .01) and the total area under the plasma cisapride concentration-time curve by 144% (range, 65% to 244%; P < .01) by grapefruit juice. The time of the peak concentration of cisapride was prolonged from 1.5 to 2.5 hours (P < .05) and the elimination half-life from 6.8 to 8.4 hours (P < .05) by grapefruit juice. ECG tracings did not show any significant differences in the QTc interval between the grapefruit juice and control phases. CONCLUSIONS: Grapefruit juice significantly increases plasma concentrations of cisapride, probably by inhibition of the CYP3A4-mediated first-pass metabolism of cisapride in the small intestine. Concomitant use of high amounts of grapefruit juice and cisapride should be avoided, at least in patients with risk factors for cardiac arrhythmia.     

Effect of rifampin on the pharmacokinetics and pharmacodynamics of gliclazide

OBJECTIVE: Our objective was to investigate the effect of rifampin (INN, rifampicin) on the pharmacokinetics and pharmacodynamics of gliclazide, a sulfonylurea antidiabetic drug. METHOD: In a randomized 2-way crossover study with a 4-week washout period, 9 healthy Korean subjects were treated once daily for 6 days with 600 mg rifampin or with placebo. On day 7, a single dose of 80 mg gliclazide was administered orally. Plasma gliclazide, blood glucose, and insulin concentrations were measured. RESULTS: Rifampin decreased the mean area under the plasma concentration-time curve for gliclazide by 70% (P <.001) and the mean elimination half-life from 9.5 to 3.3 hours (P <.05). The apparent oral clearance of gliclazide increased about 4-fold after rifampin treatment (P <.001). A significant difference in the blood glucose response to gliclazide was observed between the placebo and rifampin phases. CONCLUSION: The effect of rifampin on the pharmacokinetics and pharmacodynamics of gliclazide suggests that rifampin affects the disposition of gliclazide in humans, possibly by the induction of cytochrome P450 2C9. Concomitant use of rifampin with gliclazide can considerably reduce the glucose-lowering effects of gliclazide.     

Plasma concentrations of inhaled budesonide and its effects on plasma cortisol are increased by the cytochrome P4503A4 inhibitor itraconazole

OBJECTIVE: Our objective was to examine the effects of itraconazole on the pharmacokinetics and cortisol-suppressant activity of budesonide administered by inhalation. METHODS: In a randomized, double-blind, 2-phase crossover study, 10 healthy subjects took 200 mg itraconazole or placebo orally once a day for 5 days. On day 5, 1 hour after the last dose of itraconazole or placebo, 1000 microg budesonide was administered by inhalation. Plasma budesonide and cortisol concentrations were measured up to 23 hours. RESULTS: Itraconazole increased the mean total area under the plasma concentration-time curve of inhaled budesonide 4.2-fold (range, 1.7-fold to 9.8-fold; P <.01) and the peak plasma concentration 1.6-fold (P <.01) compared with placebo. The mean terminal half-life of budesonide was prolonged from 1.6 to 6.2 hours (ie, 3.7-fold; range, 1.5-fold to 9.3-fold; P <.001) by itraconazole. The suppression of cortisol production after inhalation of budesonide was significantly increased by itraconazole as compared with placebo, as shown by a 43% reduction in the area under the plasma cortisol concentration-time curve from 0.5 to 10 hours (P <.001) and a 12% decrease in the cortisol concentration measured 23 hours after administration of budesonide, at 8 am (P <.05). CONCLUSIONS: Itraconazole markedly increased systemic exposure to inhaled budesonide, probably by inhibiting the cytochrome P4503A4-mediated metabolism of budesonide during both the first-pass and the elimination phases. This interaction resulted in enhanced systemic effects of budesonide, as shown by suppression of cortisol production. Long-term coadministration of budesonide and a potent CYP3A4 inhibitor may be associated with an increased risk of adverse effects of budesonide.     

Effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of s-(+)- and R-(-)-Ibuprofen

Our objective was to study the effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of S-(+)- and R-(-)-ibuprofen. Twelve healthy male volunteers took a single oral dose of 400 mg racemic ibuprofen in a randomized order either alone, after ingestion of voriconazole at 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after ingestion of fluconazole at 400 mg on the first day and 200 mg on the second day. Ibuprofen was ingested 1 h after administration of the last dose of voriconazole or fluconazole. Plasma concentrations of S-(+)- and R-(-)-ibuprofen were measured for up to 24 h. In the voriconazole phase, the mean area under the plasma concentration-time curve (AUC) of S-(+)-ibuprofen was 205% (P < 0.001) of the respective control value and the mean peak plasma concentration (C(max)) was 122% (P < 0.01) of the respective control value. The mean elimination half-life (t(1/2)) was prolonged from 2.4 to 3.2 h (P < 0.01) by voriconazole. In the fluconazole phase, the mean AUC of S-(+)-ibuprofen was 183% of the control value (P < 0.001) and its mean C(max) was 116% of the control value (P < 0.05). The mean t(1/2) of S-(+)-ibuprofen was prolonged from 2.4 to 3.1 h (P < 0.05) by fluconazole. The geometric mean S-(+)-ibuprofen AUC ratios in the voriconazole and fluconazole phases were 2.01 (90% confidence interval [CI], 1.80 to 2.22) and 1.82 (90% CI, 1.72 to 1.91), respectively, i.e., above the bioequivalence acceptance upper limit of 1.25. Voriconazole and fluconazole had only weak effects on the pharmacokinetics of R-(-)-ibuprofen. In conclusion, voriconazole and fluconazole increased the levels of exposure to S-(+)-ibuprofen 2- and 1.8-fold, respectively. This was likely caused by inhibition of the cytochrome P450 2C9-mediated metabolism of S-(+)-ibuprofen. A reduction of the ibuprofen dosage should be considered when ibuprofen is coadministered with voriconazole or fluconazole, especially when the initial ibuprofen dose is high.     

Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol

OBJECTIVES: Our objective was to evaluate the effects of itraconazole and grapefruit juice on the pharmacokinetics of the beta-adrenergic receptor-blocking agent celiprolol in healthy volunteers. METHODS: In a randomized 3-phase crossover study, 12 healthy volunteers took itraconazole 200 mg orally or placebo twice a day or 200 mL grapefruit juice 3 times a day for 2 days. On the morning of day 3, 1 hour after ingestion of itraconazole, placebo, or grapefruit juice, each subject ingested 100 mg celiprolol with 200 mL of water (placebo and itraconazole phases) or grapefruit juice. In addition, 200 mL of water or grapefruit juice was ingested 4 and 10 hours after celiprolol intake. The plasma concentrations of celiprolol, itraconazole, and hydroxyitraconazole and the excretion of celiprolol into urine were measured up to 33 hours after dosing. Systolic and diastolic blood pressures and heart rate were recorded with subjects in a sitting position before the administration of celiprolol and 2, 4, 6, and 10 hours later. RESULTS: During the itraconazole phase, the mean area under the plasma concentration-time curve from 0 to 33 hours [AUC(0-33)] of celiprolol was 80% greater (P <.05) than in the placebo phase. During the grapefruit juice phase, the mean AUC(0-33) and peak plasma concentration values of celiprolol were reduced to about 13% (P <.001) and 5% (P <.001) of the respective placebo phase values. The cumulative excretion into urine of celiprolol was increased by 59% by itraconazole (P <.05) and decreased by 85% by grapefruit juice (P <.001). Hemodynamic variables did not differ between the phases. CONCLUSIONS: Itraconazole almost doubles but grapefruit juice greatly reduces plasma concentrations of celiprolol. The itraconazole-celiprolol interaction most likely resulted from increased absorption of celiprolol possibly as a result of P-glycoprotein inhibition in the intestine. The reduced celiprolol concentrations during the grapefruit juice phase were probably caused by physicochemical factors that interfered with celiprolol absorption, although other mechanisms cannot be excluded. The grapefruit juice-celiprolol interaction is probably of clinical relevance.     

The cytochrome P450 3A4 inhibitor itraconazole markedly increases the plasma concentrations of dexamethasone and enhances its adrenal-suppressant effect

OBJECTIVE: To examine the possible interaction of itraconazole with orally and intravenously administered dexamethasone. METHODS: In a randomized, double-blind, placebo-controlled crossover study with four phases, eight healthy subjects took either 200 mg itraconazole (in two phases) or placebo (in two phases) orally once daily for 4 days. On day 4 each subject received an oral dose of 4.5 mg dexamethasone or an intravenous dose of 5.0 mg dexamethasone sodium phosphate during both itraconazole and placebo phases. Plasma dexamethasone and cortisol concentrations were determined by HPLC up to 71 hours, itraconazole and hydroxyitraconazole up to 23 hours. RESULTS: Itraconazole decreased the systemic clearance of intravenously administered dexamethasone by 68% (P < .001), increased the total area under the plasma dexamethasone concentration-time curve [AUC(0-infinity)] 3.3-fold (P < .001), and prolonged the elimination half-life of dexamethasone 3.2-fold (P < .001). The AUC(0-infinity) of oral dexamethasone was increased 3.7-fold (P < .001), the peak plasma concentration 1.7-fold (P < .001), and the elimination half-life 2.8-fold (P < .001) by itraconazole. The morning plasma cortisol concentrations measured 47 and 71 hours after administration of dexamethasone were substantially lower after exposure to itraconazole than to placebo (P < .001). Accordingly, the adrenal-suppressant effect of dexamethasone was greatly enhanced during the itraconazole phases. CONCLUSIONS: Itraconazole markedly increases the systemic exposure to and effects of dexamethasone. A careful follow-up is recommended when itraconazole or other potent inhibitors of the cytochrome P450 3A4 are added to the drug regimen of patients receiving dexamethasone.     

Enhanced stimulant and metabolic effects of combined ephedrine and caffeine

OBJECTIVE: Herbal weight loss and athletic performance-enhancing supplements that contain ephedrine and caffeine have been associated with serious adverse health events. We sought to determine whether ephedrine and caffeine have clinically significant pharmacologic interactions that explain these toxicities. METHODS: Sixteen healthy adults ingested 25 mg ephedrine, 200 mg caffeine, or both drugs in a randomized, double-blind, placebo-controlled crossover study. Plasma and urine samples were collected over a 24-hour period and analyzed by liquid chromatography-tandem mass spectrometry for ephedrine and caffeine concentrations. Heart rate, blood pressure, and subjective responses were recorded. Serum hormonal and metabolic markers were serially measured during a 3-hour fasting period. RESULTS: Ephedrine plus caffeine increased systolic blood pressure (peak difference, 11.7 +/- 9.4 mm Hg; compared with placebo, P =.0005) and heart rate (peak difference, 5.9 +/- 8.8 beats/min; compared with placebo, P =.001) and raised fasting glucose, insulin, free fatty acid, and lactate concentrations. Ephedrine alone increased heart rate and glucose and insulin concentrations but did not affect systolic blood pressure. Caffeine increased systolic blood pressure and plasma free fatty acid and urinary epinephrine concentrations but did not increase heart rate. Compared with ephedrine, caffeine produced more subjective stimulant effects. Clinically significant pharmacokinetic interactions between ephedrine and caffeine were not observed. Women taking oral contraceptives had prolonged caffeine elimination (mean elimination half-life, 9.7 hours versus 5.0 hours in men; P =.05), but sex differences in pharmacodynamic responses were not seen. CONCLUSIONS: The individual effects of ephedrine and caffeine were modest, but the drugs in combination produced significant cardiovascular, metabolic, and hormonal responses. These enhanced effects appear to be a result of pharmacodynamic rather than pharmacokinetic interactions.     

Improved prandial glucose control with lower risk of hypoglycemia with nateglinide than with glibenclamide in patients with maturity-onset diabetes of the young type 3

OBJECTIVE: To study the effect of the short-acting insulin secretagogue nateglinide in patients with maturity-onset diabetes of the young type 3 (MODY3), which is characterized by a defective insulin response to glucose and hypersensitivity to sulfonylureas. RESEARCH DESIGN AND METHODS: We compared the acute effect of nateglinide, glibenclamide, and placebo on prandial plasma glucose and serum insulin, C-peptide, and glucagon excursions in 15 patients with MODY3. After an overnight fast, they received on three randomized occasions placebo, 1.25 mg glibenclamide, or 30 mg nateglinide before a standard 450-kcal test meal and light bicycle exercise for 30 min starting 140 min after the ingestion of the first test drug. RESULTS: Insulin peaked earlier after nateglinide than after glibenclamide or placebo (median [interquartile range] time 70 [50] vs. 110 [20] vs. 110 [30] min, P = 0.0002 and P = 0.0025, respectively). Consequently, compared with glibenclamide and placebo, the peak plasma glucose (P = 0.031 and P < 0.0001) and incremental glucose areas under curve during the first 140 min of the test (P = 0.041 and P < 0.0001) remained lower after nateglinide. The improved prandial glucose control with nateglinide was achieved with a lower peak insulin concentration than after glibenclamide (47.0 [26.0] vs. 80.4 [71.7] mU/l; P = 0.023). Exercise did not induce hypoglycemia after nateglinide or placebo, but after glibenclamide six patients experienced symptomatic hypoglycemia and three had to interrupt the test. CONCLUSIONS: A low dose of nateglinide prevents the acute postprandial rise in glucose more efficiently than glibenclamide and with less stimulation of peak insulin concentrations and less hypoglycemic symptoms.     

Effect of nateglinide on the size of LDL particles in patients with type 2 diabetes

The objective of the present study was to evaluate the efficacy of nateglinide in controlling blood glucose levels and regulating lipid metabolism in patients with type 2 diabetes by focusing attention particularly on low-density lipoprotein (LDL) particle size. The subjects were 23 patients with type 2 diabetes who were given nateglinide, 90 to 270 mg/d. Laboratory studies were conducted at treatment initiation and 3 mo later. Despite a decline that occurred in the level of fasting plasma glucose before and after administration of nateglinide, no significant difference was recognized. Hemoglobin A1c decreased significantly from 6.37±0.75% to 5.91±0.64% (P<.001). A significant decline was also seen in the fasting level of immunoreactive insulin, from 9.82±5.69 μU/mL to 8.59±4.05 μU/mL (P<.05), and in the homeostasis model assessment for insulin resistance, from 3.0±1.83 to 2.55±1.26 (P<.05). Regarding lipids, triglycerides significantly decreased from 140.7±61.8 mg/dL to 117.3±34.7 mg/dL (P<.05). The significant reduction in migration index value, which was used as an index to LDL particle size, from 0.374±0.034 to 0.357±0.035 (P<.05), confirmed that LDL particle size had increased. The results of the present study show that nateglinide is effective in controlling blood glucose and improving insulin resistance, hypertriglyceridemia, and LDL particle size in patients with mild type 2 diabetes. These effects suggest that nateglinide may effectively control coronary artery disease in this population.     

Randomized dose ranging study of the reduction of fasting and postprandial glucose in type 2 diabetes by nateglinide (A-4166).

OBJECTIVE: This randomized crossover double-blind placebo-controlled study aimed to assess the efficacy of nateglinide (A-4166), a novel phenylalanine-derived insulin secretagogue, in type 2 diabetic subjects while fasting and 5 min before a standard meal. RESEARCH DESIGN AND METHODS: A single dose of nateglinide (60, 120, or 180 mg) or placebo was given to eight diet-treated overnight-fasted type 2 diabetic patients and to seven patients 5 min before a standard breakfast. Plasma glucose, radioimmunoassay insulin, and nateglinide were measured at baseline and for a further 180 min. RESULTS: The time-averaged 180-min postdose mean decrease in fasting plasma glucose concentration was greater after nateglinide (1.8 mmol/l; 95% CI 1.5-2.0) than after placebo (0.7 mmol/l; 95% CI 0.3-1.2) (P < 0.001). Hypoglycemia did not develop in any of the subjects. Insulin concentrations increased 1.5-, 1.8-, and 1.9-fold with the 60-, 120-, and 180-mg doses, respectively (P < 0.001), peaking approximately 30 min after the dose. Nateglinide concentrations peaked after approximately 30 min, decreasing to 21% of peak by 180 min. In the meal test, the mean increase (2.9 mmol/l, 2.3-3.6) in plasma glucose over 180 min after placebo was reduced by 1.8 mmol/l (P < 0.001) with the two higher doses of nateglinide. CONCLUSIONS: A single dose of nateglinide administered to diet-treated type 2 diabetic patients with fasting hyperglycemia increased insulin secretion and reduced fasting glucose without hypoglycemia. Administered 5 min before a meal, nateglinide reduced the postprandial glucose excursion by 64%. With its rapid onset and short duration of action, nateglinide is a promising oral prandial therapy in type 2 diabetes.     

Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam.

OBJECTIVE: To assess the effect of human immunodeficiency virus protease inhibitor saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. METHODS: In a double-blind, randomized, two-phase crossover study, 12 healthy volunteers (six men and six women; age range, 21 to 32 years) received oral doses of either 1200 mg saquinavir (Fortovase soft-gel capsule formulation) or placebo three times a day for 5 days. On day 3, six subjects were given 7.5 mg oral midazolam and the other six subjects received 0.05 mg/kg intravenous midazolam. On day 5, the subjects who had received oral midazolam on day 3 received intravenously midazolam and vice versa. Plasma concentrations of midazolam, alpha-hydroxymidazolam, and saquinavir were determined for 18 hours after midazolam administration, and midazolam effects were measured up to 7 hours by six psychomotor tests. RESULTS: Saquinavir increased the bioavailability of oral midazolam from 41% to 90% (P < .005), the peak midazolam plasma concentration more than twofold, and the area under plasma concentration-time curve more than fivefold (P < .001). During saquinavir treatment, five of the six psychomotor tests revealed impaired skills and increased sedative effects after midazolam ingestion (P < .05). Saquinavir decreased the clearance of intravenous midazolam by 56% (P < .001) and increased its elimination half-life from 4.1 to 9.5 hours (P < .01). After intravenous midazolam, only the subjective feeling of drug effect was increased significantly (P < .05) by saquinavir. CONCLUSION: The dose of oral midazolam should be greatly reduced or avoided with saquinavir, but bolus doses of intravenous midazolam can probably be used quite safely. During a prolonged midazolam infusion, an initial dose reduction of 50% followed by careful titration is recommended to counteract the reduced clearance caused by saquinavir.     

Mibefradil but not isradipine substantially elevates the plasma concentrations of the CYP3A4 substrate triazolam.

BACKGROUND: The calcium channel blockers mibefradil and isradipine inhibit CYP3A4 in vitro. However, their in vivo inhibitory effects on CYP3A4 are not known in detail, although mibefradil was recently withdrawn from the market because of serious drug interactions. METHODS: The effects of mibefradil and isradipine on the pharmacokinetics and pharmacodynamics of oral triazolam, a model substrate of CYP3A4, were studied in a randomized, double-blind crossover study with three phases. Nine healthy subjects took 50 mg mibefradil, 5 mg isradipine, or placebo orally once a day for 3 days. On day 3, each subject received a single 0.25 mg oral dose of triazolam. Thereafter, blood samples were collected up to 18 hours, and pharmacodynamic effects of triazolam were measured up to 8 hours. RESULTS: Mibefradil increased the total area under the plasma triazolam concentration-time curve [AUC(0 - infinity)] 9-fold compared with placebo (P < .001). The peak plasma concentration of triazolam was increased 1.8-fold (3.4+/-0.1 ng/mL versus 1.8+/-0.2 ng/mL [mean +/- SEM]; P < .001), and the elimination half-life (t 1/2) was increased 4.9-fold (18.5+/-1.9 hours versus 4.0+/-0.5 hours; P < .001) by mibefradil. In addition, mibefradil was associated with increased pharmacodynamic effects of triazolam. In contrast to mibefradil, isradipine reduced the AUC(0 - infinity) and t 1/2 of triazolam by about 20% (P < .05) and had no significant effects on the pharmacodynamics of triazolam. CONCLUSION: Mibefradil but not isradipine markedly increases the plasma concentrations of triazolam and thereby enhances and prolongs its pharmacodynamic effects, consistent with potent inhibition of CYP3A4.     

Effect of fluconazole on the disposition of phenytoin

In a randomized, placebo-controlled, parallel study, phenytoin was given in the presence and absence of fluconazole. Twenty healthy male subjects received phenytoin, 200 mg orally, on study days 1 to 3 and 18 to 20 and 250 mg intravenously on study days 4 and 21. Ten subjects received fluconazole, 200 mg orally, and 10 received placebo daily on study days 8 to 21. Serial blood samples were collected during a 24-hour period after the intravenous phenytoin dose. Fluconazole trough concentrations were determined on days 14, 18, and 21. Serum phenytoin area under the concentration-time curve from 0 to 24 hours increased 75% and minimum plasma drug concentration increased 128% after administration of fluconazole, 200 mg/day, for 14 days. These values were significantly greater than the 5% increase in area under the concentration-time curve from 0 to 24 hours and 11.6% increase in minimum plasma drug concentration in the placebo group. Fluconazole trough concentrations remained unchanged during the coadministration of phenytoin. The increased phenytoin concentrations in the presence of fluconazole suggest that fluconazole inhibits phenytoin metabolism. Serum concentration monitoring with a reduction in phenytoin dosage is clinically warranted in patients receiving phenytoin and concomitant fluconazole therapy.     

Improved control of mealtime glucose excursions with coadministration of nateglinide and metformin

OBJECTIVE: Nateglinide, a new short-acting D-phenylalanine derivative for treating type 2 diabetes, reduces mealtime blood glucose excursions by physiologic regulation of insulin secretion. This study evaluated the pharmacokinetic and pharmacodynamic interactions of nateglinide and metformin in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 12 type 2 diabetic subjects with the following baseline characteristics were enrolled: age, 56 +/- 13 years; BMI, 28.7 +/- 4.5 kg/m2; HbA1c, 8.4 +/- 1.3%; and fasting plasma glucose 13 +/- 2.8 mmol/l. All subjects had been previously treated with glyburide and were switched to metformin monotherapy for 3 weeks before study start. Subjects then randomly received, in combination with 500 mg metformin, either 120 mg nateglinide or placebo before meals for 1 day, followed by the alternate treatment 7 days later. After 1 week of washout from both drugs, subjects received 1 day of open-label nateglinide treatment. Plasma concentrations of glucose, insulin, nateglinide, and metformin were assessed frequently during inpatient periods. RESULTS: Postmeal plasma glucose levels were significantly lower in subjects treated with nateglinide plus metformin than in those treated with either drug alone (P < 0.001), especially after lunch and dinner. Coadministration of nateglinide and metformin did not affect the pharmacokinetics of either drug. All treatments were safe and well tolerated. CONCLUSIONS: Combination therapy with nateglinide and metformin was more effective than either treatment alone and did not result in any pharmacokinetic interactions. Coadministration of nateglinide and metformin appears to be an excellent option for treating patients with type 2 diabetes not controlled with monotherapy.