No effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam

To examine the involvement of cytochrome P450 3A4 in the metabolism of estazolam, the effect of itraconazole, a potent inhibitor of this enzyme, on the single oral dose pharmacokinetics and pharmacodynamics of estazolam was studied in a double-blind randomized crossover manner. Ten healthy male volunteers received itraconazole 100 mg/day or placebo orally for 7 days, and on the 4th day they received a single oral 4-mg dose of estazolam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test, Visual Analog Scale, and Stanford Sleepiness Scale were conducted up to 72 hours after estazolam dosing. There was no significant difference between the placebo and itraconazole phases for the peak plasma concentration, apparent oral clearance, and elimination half-life. Similarly, none of the psychomotor function parameters was significantly different between the two phases. The current study showed no significant effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam, suggesting that cytochrome P450 3A4 is not involved in the metabolism of estazolam to a major extent.     

Effect of Food on the Pharmacokinetics of a New Hydroxypropyl-β-Cyclodextrin Formulation of Itraconazole

Study Objective . To compare the pharmacokinetics of a single 100-mg oral dose of itraconazole administered as 10 ml of a 10-mg/ml itraconazole solution in hydroxypropyl-β-cyclodextrin under fasting versus postprandial conditions. Design . Open-label, two-way, randomized, crossover study. Setting . Janssen Research Foundation, Belgium. Patients . Twelve healthy volunteers. Interventions . Blood samples were obtained for pharmacokinetic analyses immediately before dosing and at regular intervals up to 96 hours after each dose. Blood and urine samples were obtained for hematologic, biochemical, and urinary safety analyses at baseline and at the end of the study. Measurements and Main Results . The mean peak plasma concentrations of both itraconazole and its active metabolite hydroxy-itraconazole were significantly higher under fasting conditions than under postprandial conditions. The mean times to peak concentration for both the parent compound and its metabolite were significantly shorter under fasting than under nonfasting conditions. The mean areas under the curve (AUC_0–∞ and AUC_{0–24 hrs}) were also significantly higher under fasting than under postprandial conditions. Conclusions . Our findings suggest that the higher bioavailability of this new formulation of itraconazole may be of benefit in seriously ill patients who are not able to ingest adequate quantities of food. The fact that the solution was also well tolerated and was not associated with clinically significant changes in any laboratory value further underscores the potential utility of this dosing form.     

Pharmacokinetics of Amiloride after Inhalation and Oral Administration in Adolescents and Adults with Cystic Fibrosis

Study Objective . To compare the pharmacokinetics and systemic exposure of nebulized and oral amiloride in adolescents and adults with mild to moderate cystic fibrosis (CF). Design . Open-label, randomized, two-way crossover, single-dose pharmacokinetic study. Setting . University hospital clinical research unit. Patients . Nine adolescents and 10 adults with mild to moderate CF (forced expiratory volume in 1 sec > 50% predicted, Brasfield score ≥ 15). Interventions . Patients received amiloride solution orally (10 mg of amiloride 1-mg/ml solution) and by inhalation [4.5 ml amiloride of 1-mg/ml solution in 12% saline (∼ 3.8 mmol/L) by DeVilbiss 646 nebulizer] during two study phases separated by a 7- to 28-day washout period. Serial blood and urine samples were collected for 48 and 72 hours, respectively. Measurements and Main Results . After oral dosing, the mean ± SD maximum peak concentration (C_max) was 20.6 ± 10.0 ng/ml at 3.2 ± 1.2 hours in adults and 21.7 ± 4.88 at 2.9 ± 0.6 hours in the adolescents. Mean area under the concentration-time curve (AUC) from time zero to infinity hours was 275 ± 115 and 254 ± 60 ng•hr/ml in the adult and adolescent groups; half-life was 16.0 ± 0.7 and 13.4 ± 1.4 hours, respectively. After nebulization, 14 of 19 subjects exhibited two concentration peaks (C_max1 and C_max2) with mean values of 1.57 ± 1.67 ng/ml at 0.5 ± 0.2 hours and 1.37 ± 1.21 ng/ml at 4.0 ± 1.0 hours for adults, and 1.49 ± 0.99 ng/ml at 0.5 ± 0.1 hours and 1.52 ± 0.81 ng/ml at 3.3 ± 0.5 hours for adolescents. Estimated mean ± SD dose nebulized was 1.91 ± 0.66 and 2.28 ± 0.30 mg in the adult and adolescent groups, respectively. Mean ± SD AUC from time zero to the last measurable plasma amiloride concentration after inhalation was 14.4 ± 17.6 and 15.4 ± 10.1 ng•hr/ml in the adults and adolescents. No significant adverse events occurred during the study. Pharmacokinetic parameters were not statistically different between the adolescent and adult groups by route of administration. However significant differences in peak amiloride concentration, AUC, and urinary amiloride excretion were evident when comparing oral versus inhalation administration within each group. Conclusions . Mean amiloride plasma concentration peaks and AUC after inhalation were significantly lower than after oral dosing. In addition, the second amiloride plasma concentration peak may be due to oral ingestion of the nebulized amiloride, whereas the earlier C_max1 after inhalation may be due to pulmonary absorption of amiloride. These results suggest that single-dose amiloride inhalation in patients with mild to moderate CF results in minimal systemic exposure compared with oral dosing, and that drug disposition is similar in adolescents and adults with CF.     

Short report: the absorption of fluconazole and itraconazole under conditions of low intragastric acidity

The study investigated the oral absorption of two anti-fungal agents, fluconazole and itraconazole, under conditions of low intragastric acidity. Twelve healthy male volunteers received each of 4 dosing regimens: 200 mg itraconazole alone, 200 mg itraconazole and famotidine, 100 mg fluconazole alone, and 100 mg fluconazole and famotidine. Two oral doses of 40 mg famotidine were used to induce hypochlorhydria. Serum drug concentrations were measured (by high pressure liquid chromatography) for 48 h after a single dose of each anti-fungal agent. When dosed with famotidine, there was a significant 52.9% decrease of the peak intraconazole concentration (P < 0.011), and a significant 51.1% decrease of the 48-h integrated serum intraconazole concentration (P= 0.005). Famotidine-induced hypochlorhydria did not affect the absorption of fluconazole.     

A Prospective,Open-Label Study of Single-Dose Ciprofloxacin Absorption after Chemotherapy in Patients with Malignancy

The absorption of a single oral dose of ciprofloxacin 750 mg in patients with cancer who had chemotherapy-induced Cancer and Leukemia Group B grade I or II mucositis was evaluated. Ciprofloxacin was administered after an overnight fast. Plasma samples were collected before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after the dose. Drug concentrations were determined by reverse-phase high-performance liquid chromatography with fluorescence detection. Pharmacokinetic values were characterized by noncompartmental methods. The mean ± SD for area under the curve, mean peak concentration (C_max), and time to C_max (T_max) were 18.7 ± 5.03 mg/L • hour, 4.41 ± 1.74 mg/L, and 1.81 ± 0.843 hours, respectively. The absorption of oral ciprofloxacin in patients with chemotherapy-induced grade I or II mucositis compares with that in healthy volunteers. These findings may call for further pharmacokinetic evaluation of the drug in a similar patient population.     

Effect of ranitidine on the disposition of orally and intravenously administered triazolam

The effect of orally administered ranitidine on the pharmacokinetic properties of orally and intravenously administered triazolam was determined. Twelve healthy males with a mean age of 35 years were enrolled in this four-way, randomized, crossover study. Each subject received a total of four treatments, each separated by one week. The treatments consisted of (1) one orally administered 0.25-mg triazolam tablet after treatment with ranitidine; (2) one orally administered 0.25-mg triazolam tablet, with no ranitidine pretreatment; (3) a 0.25-mg intravenous dose of triazolam after treatment with ranitidine; and (4) a 0.25-mg intravenous dose of triazolam, with no ranitidine pretreatment. Ranitidine pretreatment consisted of five 150-mg oral doses (as the hydrochloride salt) given every 12 hours; the last dose was given two hours before triazolam was administered. Blood samples were taken at intervals up to 12 hours after triazolam treatment. Serum triazolam concentrations were measured by modified high-performance liquid chromatography, and pharmacokinetic values were calculated. Pretreatment with ranitidine had no effect on the disposition of intravenously administered triazolam but significantly increased the area under the serum drug concentration-time curve of oral triazolam. Ranitidine pretreatment had no effect on triazolam's terminal elimination rate constant or on the time to reach maximum serum triazolam concentration. Ranitidine pretreatment increased the systemic availability of triazolam by increasing its absorption.     

Effect of sucralfate on ibuprofen absorption in normal volunteers

The effect of the concurrent administration of sucralfate on the absorption of a single dose of ibuprofen was studied in nine normal volunteers using a random crossover design. Each participant received a single 600-mg dose of ibuprofen for the control phase, and a 600-mg dose of ibuprofen following 5 g of sucralfate given in 1-g divided doses for the treatment phase. Blood samples were obtained at regular intervals for 12 hours following the administration of ibuprofen, and pharmacokinetic and statistical analyses were performed. Analysis of time to peak serum concentration, maximum serum concentration, elimination rate constant, and half-life showed no significant difference between the control and treatment phases. Mean total area under the curve for ibuprofen decreased by 11.8% in the treatment phase, but this decrease was not statistically significant. The concurrent administration of sucralfate did not significantly alter the absorption of a single 600-mg dose of ibuprofen in healthy subjects.     

Effects of Terbinafine on the Pharmacokinetics of Digoxin in Healthy Volunteers

Study Objective . To assess the potential effects of terbinafine, a new synthetic allylamine antifungal agent, on the pharmacokinetics of a single 0.75-mg oral dose of digoxin. Design . Randomized, double-blind, placebo-controlled, crossover study consisting of two treatment periods. Subjects . Sixteen healthy men and women volunteers. Interventions . During treatment A, placebo was administered once/day for 12 days; during treatment B, terbinafine 250 mg was administered orally once/day for 12 days. The washout period between treatments was at least 2 weeks. A single 0.75-mg oral dose of digoxin was administered on day 8 of each period. Blood samples were collected after administration of digoxin to determine pharmacokinetics. Measurements and Main Results . Compared with placebo, terbinafine did not alter the time course of the digoxin serum levels. Although the time to maximum peak concentration with terbinafine was slightly reduced, the maximum concentration and area under the serum drug concentration-time curve from time zero to 120 hours were not significantly different with terbinafine than with placebo. No drug-related side effects were reported with either active treatment, and no clinically significant changes in vital signs, physical examination results, electrocardiograms, or clinical laboratory results were observed. Conclusions . No special dosage adjustments for digoxin appear to be necessary during concomitant therapy with terbinafine.     

Bioavailability of indomethacin tablets in men volunteers

Indomethacin bioavailability was compared in 22 healthy men who received two tablet dosage formulations and a capsule formulation of indomethacin in a three-way crossover study. In each study period, 50 mg of the indomethacin formulation (25-mg or 50-mg tablets or 50-mg capsules) was administered as a single dose to fasting subjects. Thirteen blood samples were collected at intervals over 24 hours after each dose. Urine samples were collected for 12 hours before each dose and 48 hours after each dose. Serum indomethacin concentrations were measured by a gas chromatographic procedure. The extent of indomethacin absorption for the two tablet formulations was not significantly different from that for the reference capsule. A trend toward earlier and higher peak serum concentrations with the capsule was observed. There was less than 20% difference in mean values for area under the concentration-time curve (AUC) for the three formulations. More than 75% of the subjects had serum concentrations falling between 75 and 125% of the mean serum concentrations. The extent of absorption of indomethacin from the two tablet formulations was similar to that from the capsule.     

Effect of antacid on the bioavailabiity of lithium carbonate

The effect of an antacid on the bioavailability of lithium carbonate was determined in six healthy men in a crossover study. The volunteers were given single 300-mg doses of lithium carbonate alone and with 30 ml of an antacid containing aluminum and magnesium hydroxides with simethicone. Blood samples were collected at various times for 0-24 hours after each dose. The plasma samples were analyzed for lithium using a spectrophotometer, and bioavailability variables were calculated from plasma lithium concentration-time curves. There were no significant differences in peak plasma lithium concentration, time to peak concentration, area under the concentration-time curve from 0 to 24 hours, first-order absorption rate constant, and first-order elimination rate constant between the two treatments. Concurrent administration of antacids and lithium carbonate should not affect lithium blood concentrations.     

Elimination profile of triamcinolone in urine following oral administration

Triamcinolone (T) is a glucocorticoid commonly used to relieve inflammation and treat arthritis, severe allergies, and asthma; however, it is banned by the World Anti‐Doping Agency in competition for athletes when administered orally, intravenously, intramuscularly, or rectally. The minimum required performance limit (MRPL) for urinary T is 30 ng/mL. However, the data about the urinary excretion of T after oral administration is limited. We investigate the elimination profile and determine whether single‐dose administration of T would cause a positive doping result. Twelve healthy volunteers received a single‐dose of 4‐mg T rally, and urine samples were collected for 24 hours. A validated liquid chromatography–tandem mass spectrometry method was used to determine urinary T levels. Non‐compartmental modeling was used to estimate the pharmacokinetic parameters. All the urinary T concentrations were much higher than the MRPL. The peak urinary T concentration was 3211.4 ± 860.3 ng/mL (mean ± SD), time to peak concentration was 1.7 ± 0.9 hours, and the estimated elimination half‐life was 4.4 ± 2.8 hours. About 27.76% of the consumed dose was eliminated via urine within 24 hours of intake. After a single‐dose oral administration, urinary T concentrations still exceeded the MRPL after 24 hours. This information could be useful for limiting the misuse of T. Athletes should be aware when using T in competition and acquire approval for a therapeutic use exemption prior to use. Moreover, the elimination profile of orally administered T may be crucial information for distinguishing different dosage routes.     

Relative Bioavailability of Ondansetron 8-mg Oral Tablets versus Two Extemporaneous 16-mg Suppositories: Formulation and Gender Differences

Study Objective . To compare the relative bioavailability of two 16-mg extemporaneously prepared suppository formulations with that of an 8-mg commercially available oral tablet. Design . Prospective, crossover bioavailability study. Setting . Inpatient clinical research center. Subjects . Sixteen young, nonsmoking, healthy volunteers. Interventions . Blood samples were obtained 24 and 48 hours after administration of an 8-mg oral ondansetron tablet and 16-mg suppository, respectively. Two 16-mg suppository formulations were compounded using commercially available Fattibase and Polybase. Measurements and Main Results . Ondansetron was well absorbed by both routes of administration. The following pharmacokinetic parameters (mean ± SEM) were obtained for the 8-mg tablet, 16-mg Fattibase suppository, and 16-mg Polybase suppository, respectively: area under the curve (AUC) in men 154.2 ± 21.77, 253.4 ± 72.3, 304.8 ± 62.2 ng·hr/ml; AUC in women 353.6 ± 32.7, 561.6 ± 103.6, and 768.7 ± 117.9 ng·hr/ml; maximum concentration (C_max) in men 45.5 ± 7.0, 40.6 ± 10.4, and 51.2 ± 6.7 ng/ml; C_max in women 51.4 ± 4.8, 47.1 ± 3.9, and 82.9 ± 6.6 ng/ml. Times to C_max (T_max; mean ± SEM) for men were 1.5 ± 0.3, 4.4 ± 0.5, and 2.9 ± 0.3 hours; T_max for women were 1.8 ± 0.3, 4.1 ± 0.4, and 4.4 ± 0.6 hours for the three formulations, respectively. Women had a consistently higher AUC for all three formulations than men (p < 0.05). Conclusion . With the exception of the 16-mg Polybase formulation in women, the two suppositories closely approximated the pharmacokinetics of the 8-mg oral tablet. These results suggest that gender may be a significant factor in ondansetron's disposition.     

Effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam

To assess the effect of itraconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4, on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam, the study was conducted in a double-blind randomized crossover manner with two phases of treatment with itraconazole-placebo or placebo-itraconazole. Ten healthy male subjects receiving itraconazole 200?mg/day or matched placebo orally for 6 days took an oral 0.8?mg dose of alprazolam on day 4 of each treatment phase. Plasma concentration of alprazolam was measured up to 48?h after alprazolam dosing, together with the assessment of psychomotor function by the Digit Symbol Substitution Test, Visual Analog Scale and Udvalg for kliniske undersøgelser side effect rating scale. Itraconazole significantly (P?相似文献   

伊曲康唑对健康志愿者体内维胺酯药代动力学影响

目的研究伊曲康唑对维胺酯的药代动力学影响,了解维胺酯在人体内的代谢途径和探索其合理联合用药。方法设计两阶段随机双盲交叉试验,8名健康男性受试者首先口服伊曲康唑200 mg或安慰剂,每天1次,连续服用5 d,在d 4,空腹口服维胺酯100 mg,利用液相色谱质谱联用法(LC-MS)测量血浆中维胺酯浓度。结果合用伊曲康唑后维胺酯平均峰浓度增加[(21.21±11.65)μg.L-1vs(27.12±13.83)μg.L-1,P<0.01],平均达峰时间差异无显著性[(2.38±0.35)hvs(2.13±0.35)h,P>0.05],平均消除半衰期延长[(2.71±0.38)hvs(4.43±0.93)h,P<0.01],平均血浆药物浓度—时间曲线下面积增大[(137.32±80.16)h.μg.L-1vs(215.19±113.01)h.μg.L-1,P<0.01],平均驻留时间延长[(4.42±0.22)hvs(6.81±0.75)h,P<0.01]。结论伊曲康唑能明显影响维胺酯的药代动力学参数,提示维胺酯可能部分经CYP3A4酶代谢。因此,在临床上两药合用治疗痤疮的同时,应注意维胺酯的给药剂量。     

Lack of pharmacokinetic interactions between argatroban and warfarin.

The potential for pharmacokinetic interactions between argatroban and warfarin was studied. In a randomized, crossover study, healthy volunteers participated in three treatment periods, each separated by a nine-day washout interval. Drug regimens consisted of a single oral 7.5-mg dose of warfarin, intravenous argatroban infused at a rate of 1.25 micrograms/kg/min for 100 hours, or both. Blood samples were collected at intervals up to 104 hours to determine clearance (CL) and the apparent first-order elimination rate constant (kel) for argatroban and the area under the concentration-versus-time curve (AUC) and maximum concentration (Cmax) for R- and S-warfarin. An interaction was defined as a > 25% difference in the magnitude of the pharmacokinetic values between administration of one drug alone and coadministration with the other agent. Twelve adult subjects were enrolled. The mean CL and lel for argatroban administered alone differed by < 7% from the mean values when the two drugs were coadministered. When warfarin was administered alone, the mean Cmax and AUC of R- and S-warfarin differed from the mean values when the two drugs were coadministered by < 10%. Prothrombin time was prolonged comparably when argatroban was administered alone and with warfarin. No deaths or serious adverse events were reported. No significant pharmacokinetic interactions were detected between i.v. argatroban 1.25 micrograms/kg/min and a single 7.5-mg oral dose of warfarin. Argatroban was well tolerated when administered alone or with warfarin.     

Pharmacokinetics and side-effects of clonidine

Summary A single oral dose of clonidine 300 µg was administered to 8 healthy, normotensive subjects and the time course of its plasma concentrations was followed for 24 h. The plasma concentration of clonidine rose to a peak of 1.17±0.12 ng/ml at about 2 h: the absorption half-life was 0.6±0.2 h. Elimination followed first order kinetics with a half-life of 7.7±2.0 h. The correlation between the two most common side-effects of clonidine, sedation and dryness of the mouth, with the time course of its plasma concentrations was highly significant, p<0.01. All the subjects complained of severe sedation. During continuous administration of clonidine (75 µg t.i.d.) for one week a steady state serum level of 0.30–0.35 ng/ml was achieved. One 75 µg tablet of clonidine raised the serum level to about 0.69±0.13 ng/ml in two hours. After cessation of dosing, the serum level declined with a half-life of 7.5±1.5 h. The urinary excretion of unchanged clonidine was found to be about onethird of the administered dose in 24 h during continuous administration and in the first 24 h after the single oral dose.     

Absence of a pharmacokinetic interaction between etanercept and warfarin

Etanercept, a soluble recombinant human tumor necrosis factor receptor (TNFr) fusion protein, is effective and well tolerated in the treatment of rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). The primary objective of this study was to investigate the potential pharmacokinetic and pharmacodynamic interaction between a single dose of R- and S-enantiomers of warfarin and multiple doses of etanercept after administration of warfarin and etanercept alone and together. In a nonrandomized, three-period study, 12 healthy male subjects received a single oral 25-mg dose of warfarin after an overnight fast, followed by twice-weekly 25-mg subcutaneous doses of etanercept for seven doses. The last dose of etanercept was administered concurrently with a second dose of warfarin. Serial blood samples for plasma warfarin concentration measurement and international normalized ratio (INR) assessment were collected before and up to 144 hours after dose administration. Serial blood samples for serum etanercept concentration measurement were collected before and up to 60 hours after the sixth dose and 264 hours after the seventh dose. Etanercept did not affect the pharmacokinetics and pharmacodynamics of warfarin. All ratios of maximum serum concentration (C(max)) and area under the serum concentration versus time curve (AUC) for pharmacokinetics (R- and S-enantiomers of warfarin) and INR fell within the confidence interval of 0.8 to 1.25. Warfarin also did not cause a clinically significant alteration in the pharmacokinetics of etanercept. In conclusion, coadministration of etanercept and warfarin would not be expected to change the pharmacokinetics of either medication; therefore, no dosage adjustment is needed in cases in which warfarin and etanercept are coadministered.     

Relative bioavailability of ketoprofen 20% in a poloxamer-lecithin organogel.

PURPOSE: The bioavailability of a single, topically applied, 200-mg dose of ketoprofen (delivered in a ketoprofen 20% gel) relative to a single 50-mg oral dose in healthy volunteers was studied. METHODS: This was an open-label crossover study. The subjects were randomized to receive an oral 50-mg ketoprofen capsule or a single topical dose of ketoprofen 20% in a poloxamer-lecithin organogel (PLO). Treatment was followed by a one-week washout period. Blood samples were collected at intervals up to 10 hours after administration, and plasma ketoprofen concentrations were determined by high-performance liquid chromatography with ultraviolet or mass spectrometry detection. Noncompartmental pharmacokinetic values were obtained after each dose, and relative bioavailability was calculated. RESULTS: Eight healthy volunteers enrolled in and completed the study. Topical absorption of ketoprofen was highly variable among the subjects over the 10-hour sampling period. The median oral maximum plasma concentration (Cmax) exceeded the topical Cmax by nearly 200-fold (4.15 versus 0.021 microg/mL) (p = 0.001). The median relative bioavailability of topical ketoprofen was 0.48%, with individual subjects' values ranging from 0.18% to 2.1%. CONCLUSION: The relative bioavailability of ketoprofen was low and highly variable when the drug was administered as a single dose in a PLO-based ketoprofen 20% gel.     

Pharmacokinetics of ritanserin in patients undergoing hemodialysis

The pharmacokinetics of ritanserin were studied in five patients with chronic renal insufficiency and who were undergoing periodic hemodialysis. Immediately after breakfast, a single 10-mg ritanserin tablet was administered to each patient on a day that they did not undergo dialysis. Plasma ritanserin levels were measured by a specific high-performance liquid chromatographic assay sensitive to 2 ng/mL plasma. After the oral 10-mg dose, the average time to reach the peak plasma concentration, Tmax, was 4.4 +/- 2.2 hours in these uremic patients, with a range of 2 to 8 hours. The average peak plasma concentration was 73.6 +/- 26.9 ng/mL (range: 54.6-120.0 ng/mL). Compared with a previous study in healthy volunteers, the uremic patients had a slower absorption profile, with a 39% reduction in peak plasma concentration and mean delay of 2.5 hours in Tmax. The mean area under the plasma concentration-time curve for ritanserin (2031 +/- 636 ng.hr/mL) was 47% lower compared with that in healthy volunteers (3867 +/- 1413 ng.hr/mL). The observed delayed and lower ritanserin absorption in these uremic patients may be caused by the chronic use of antacids such as aluminum hydroxide and calcium carbonate in all patients and/or by concurrent pathologic changes in the gastrointestinal mucosa of these patients. The regular hemodialysis sessions every 2-3 days did not affect the elimination rate of ritanserin, as the terminal half-life in these patients (39 +/- 23 hr) is similar to that in healthy volunteers (41 +/- 14 hr).     

The Influence of Multiple Dosing and Age on the Pharmacokinetics and Pharmacodynamics of Glipizide in Patients with Type II Diabetes Mellitus

Study Objectives . To determine the pharmacokinetics and pharmacodynamics of glipizide after a single dose and 12 weeks of dosing in patients with type II diabetes mellitus, and evaluate the influence of aging. Design . Comparison of single and multiple doses of glipizide. Setting . University-affiliated outpatient internal medicine clinic and diabetes care unit. Patients . Twenty patients (11 men, 9 women, mean age 55.2 ± 9.9 yrs) with type II diabetes mellitus who were currently receiving oral hypoglycemic agents or were hyperglycemic with diet. Interventions . A 24-hour pharmacokinetic evaluation of glipizide was assessed after a 5-mg dose at the start of therapy and after 12 weeks of therapy. Pharmacokinetic parameters were assessed using compartmental population analysis techniques. Glipizide pharmacodynamic evaluation was assessed by serum glucose, insulin, and C-peptide responses during a 4-hour Sustacal tolerance test performed at baseline before instituting glipizide therapy, with the first 5-mg dose, and at week 12 of therapy. Glipizide dosages were titrated to a targeted goal of fasting plasma glucose of 7.8 mmol/L or less or to reach maximum daily doses of 40 mg. Measurements and Main Results . No significant differences in time to peak concentration, apparent volumes of distribution for the central and peripheral compartments, apparent oral clearance from the central compartment, distributional clearance between the central and peripheral compartments, or terminal elimination half-life were observed with a single dose and long-term dosing. The mean ± SD terminal elimination half-lives were 9.67 ± 5.6 and 9.35 ± 4.6 hours after a single dose and 12 weeks, respectively. Fasting plasma glucose concentrations decreased from 12.3 ± 3.6 mmol/L before the first dose of glipizide to 9.2 ± 1.7 mmol/L after 12 weeks of treatment. The values for area under the serum concentration-time curve from zero to 4 hours for glucose (AUC_{0–4.glucose}) were significantly reduced at week 12 (baseline 49.8 ± 15.6, week 12 37.8 ± 9.8 mmol/L/hr). Glipizide provoked an increase in serum insulin and C-peptide concentrations (AUC_{0–4.insulin}: baseline 698 ± 327, single dose 954 ± 461, long-term dosing 945 ± 600 pmol/L/hr). No significant change in insulin response was observed between single and multiple doses. No age-related differences in the pharmacokinetic parameters or the pharmacodynamic responses of glipizide were observed. Conclusions . Long-term dosing and aging have little effect on the pharmacokinetic profile of glipizide. In addition, glipizide stimulates insulin secretion to a similar extent following glucose challenge after a single dose and long-term administration.