Regulated Cl transport, K and Cl permeability, and exocytosis in T84 cells.

We measured stimulant-induced changes of exocytosis that are associated with increases in Cl secretion (i.e., short circuit current, ISC, in microA/cm2) and apical (ap) Cl permeability (PCl) and basolateral (bl) K permeability (PK) (both in cm/s) in T84 monolayers. PCl and PK were measured by permeabilizing the bl or ap membrane with nystatin. PCl was also measured with a fluorescent dye 6-methoxy-N-(3-sulfopropyl)quinolinium (SPQ). A noninvasive and sensitive method (release of 35SO4-labeled glycosaminoglycan [GAG], a fluid-phase marker of Golgi-derived vesicles) was used to measure exocytosis at both ap and bl membranes. At rest, ISC = 3.6, PK = 0.8 x 10(-6), PCl = 2.1 x 10(-6) with SPQ and 2.4 x 10(-6) electrically, and there was constitutive GAG secretion (i.e., exocytosis) to both ap and bl sides (bl > 2 x ap). Carbachol (C) increased: ISC (delta = 18.6), PK (6.5x), PCl (1.8-2.9x), and exocytosis to both ap (2.2-3.5x) and bl (2.0-3.0x) membranes. Forskolin (F) increased ISC (delta = 29), PCl (5.5-11x) and ap exocytosis (1.5-2x), but had no effect on PK or bl exocytosis. Synergistic effects on ISC occurred when C was added to F-treated cells but not vice versa, even though the characteristic effects of F+C on PCl, PK, and/or GAG secretion were identical to those exhibited when stimulants were added individually. Cl secretion results from coordinated activation of channels at ap and bl membranes, and exocytosis may play a role in these events.

Pharmacoimmunodynamic interactions of interleukin-10 and prednisone in healthy volunteers.

OBJECTIVE: The pharmacoimmunodynamic interactions of recombinant human interleukin-10 and prednisolone were examined in 12 normal male volunteers. METHODS: Single doses of interleukin-10 (8 microg/kg subcutaneous injection), interleukin-10 with prednisone (15 mg by mouth), placebo with prednisone, or placebo were administered. Drug concentrations yielded pharmacokinetic parameters. Response measurements included whole blood lipopolysaccharide-stimulated cytokine (tumor necrosis factor-alpha, interleukin-1beta) production, phytohemagglutinin-stimulated whole blood lymphocyte proliferation, and differential white blood cell counts (including monocytes, lymphocytes, and neutrophils). Extended indirect-response models were used to deal with diverse drug interactions in assessing single and joint effects of interleukin-10 and prednisolone. RESULTS: No pharmacokinetic alterations in interleukin-10 or prednisolone were found. Dosing with interleukin-10 produced strong inhibition of ex vivo cytokine production for the 24-hour postdosing period, whereas prednisolone, the active form of prednisone, was partly inhibitory for only 3 hours. Prednisolone significantly inhibited (P < .05) ex vivo lymphocyte proliferation for 6 hours, whereas interleukin-10 failed to alter this measure. Their joint effects on these responses were inhibitory consonant with the stronger agent. Marked changes in various leukocyte kinetics occurred. The steroid caused monocytopenia, lymphocytopenia, and neutrophilia, with IC50 or SC50 values of 10 to 20 ng/mL. Interleukin-10 elevated monocytes and neutrophils and lowered lymphocyte counts, with IC50 or SC50 values of 0.7 to 1.3 ng/mL. Dynamic modeling showed loss of prednisolone effects on monocytes and additive steroid/interleukin-10 effects on lymphocytes and neutrophils, with neutrophils exhibiting greater changes in net response. CONCLUSION: Interleukin-10 and prednisolone interacted favorably for the measured pharmacoimmunodynamic indices with no kinetic alterations but net responses that were similar to or greater than effects produced by the more strongly acting agent.

The effect of renal disease on the disposition of venlafaxine.

The pharmacokinetics of venlafaxine and its active metabolite O-desmethylvenlafaxine were studied in subjects with various degrees of renal dysfunction, including subjects requiring maintenance hemodialysis. Venlafaxine was administered as a single 50 mg dose, with blood and urine samples obtained at intervals up to 48 hours after administration for the subjects receiving dialysis or 72 hours for the subjects not receiving dialysis. Six subjects receiving dialysis also completed an intradialysis evaluation to estimate dialysis clearance. Concentrations of venlafaxine and O-desmethylvenlafaxine in plasma, urine, and dialysate fluid were determined by high-performance liquid chromatography. Apparent total clearance of venlafaxine and O-desmethylvenlafaxine were both significantly decreased by approximately 55% in the subjects receiving dialysis, and terminal disposition half-life was significantly prolonged for both compounds. Venlafaxine and O-desmethylvenlafaxine are poorly dialyzable. In conclusion, the disposition of venlafaxine and O-desmethylvenlafaxine is markedly altered in renal disease; therefore dosage adjustment is warranted for patients with creatinine clearance values below 30 ml/min.

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.

Effect of fluconazole on the pharmacokinetics of eprosartan and losartan in healthy male volunteers.

OBJECTIVE: To investigate the effect of steady-state fluconazole administration on the disposition of eprosartan, losartan, and E-3174. METHODS: Sixteen healthy male subjects received 300 mg eprosartan every 12 hours, and 16 received 100 mg losartan every 24 hours on study days 1 to 20. All 32 subjects received 200 mg fluconazole every 24 hours beginning on day 11 and continuing through day 20. Serial blood samples were collected over one dosing interval on study days 10 and 20 for measurement of plasma concentrations of eprosartan, losartan, and E-3174 (the active metabolite of losartan). RESULTS: There was no significant difference in eprosartan area under the concentration-time curve from time 0 to time of last quantifiable concentration [AUC(0-t)] or maximum concentration (Cmax) when administered alone and with fluconazole. After concomitant administration with fluconazole, losartan AUC(0-t) and Cmax were significantly increased 66% and 30%, respectively, compared with those values for losartan alone. The AUC(0-t) and Cmax for E-3174 were significantly decreased 43% and 56%, respectively, after administration of losartan with fluconazole. CONCLUSIONS: Fluconazole significantly increases the steady-state AUC of losartan and inhibits the formation of the active metabolite of losartan, E-3174. In contrast, fluconazole administration has no effect on the steady-state pharmacokinetics of eprosartan.

Pharmacokinetics of gabapentin in subjects with various degrees of renal function.

The pharmacokinetics of oral gabapentin (400 mg) was studied in normal subjects and in subjects with various degrees of renal function. Sixty subjects participated in this three-center study. None of the subjects were receiving hemodialysis. Plasma and urine samples were collected for up to 264 hours after dosing, and concentrations of gabapentin were determined by high performance liquid chromatography. Apparent oral plasma clearance (CL/F) and renal clearance (CLR) of gabapentin decreased and maximum plasma concentration, time to reach maximum concentration, and half-life values increased as renal function diminished. Gabapentin CL/F and CLR were linearly correlated with creatinine clearance. Total urinary recovery of unchanged drug was comparable in all subjects, indicating that the extent of drug absorption was unaffected by renal function. There was no evidence of gabapentin metabolism even in subjects with severe renal impairment. In summary, impaired renal function results in higher plasma gabapentin concentrations, longer elimination half-lives, and reduced CL/F and CLR values. Based on pharmacokinetic considerations, it appears that the dosing regimen of gabapentin in subjects with renal impairment may be adjusted on the basis of creatinine clearance.

Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

OBJECTIVE: To evaluate the effect of regular-strength grapefruit juice, a cytochrome P4503A4 (CYP3A4) inhibitor, on the pharmacokinetics of a commonly prescribed regimen of oral lovastatin. METHODS: In a randomized crossover study, 16 healthy subjects received a single 40 mg dose of lovastatin in the evening after each consumed an 8-ounce glass of regular-strength grapefruit juice or water with breakfast for 3 consecutive days. The effect of the same grapefruit juice and water regimen on the pharmacokinetics of midazolam (2 mg oral dose given 1 hour after the third day of grapefruit juice and water) was used as a positive control in the same subjects. Plasma concentrations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were determined by an enzyme inhibition assay, and concentrations of lovastatin, lovastatin acid, and midazolam were determined by liquid chromatography-tandem mass spectrometry. RESULTS: The area under the plasma concentration-time profiles (AUC) and maximum plasma concentrations (Cmax) of HMG-CoA reductase inhibitors increased slightly (-30% for each) after consumption of grapefruit juice. Similar effects on AUC and Cmax (approximately 40% increase for each) were noted after analysis of samples of hydrolyzed plasma (which converts inactive lactones to active hydroxy acid species). The AUC and Cmax values for lovastatin approximately doubled in the presence of grapefruit juice, whereas the same parameters for lovastatin acid increased 1.6-fold. Grapefruit juice caused the AUC for midazolam to increase by a factor of approximately 2.4. CONCLUSIONS: Daily consumption of a glass of regular-strength grapefruit juice has a minimal effect on plasma concentrations of HMG-CoA reductase inhibitors (approximately 30% to 40% increase) after a 40 mg evening dose of lovastatin.

Influence of renal function on the pharmacokinetics of lomefloxacin compared with other fluoroquinolones.

Fluoroquinolones have similar chemical structures but wide differences in their pharmacokinetic profiles. Disparity in fluoroquinolone elimination is most evident in patients with various degrees of renal insufficiency. Ofloxacin is almost exclusively eliminated by the kidney, whereas pefloxacin is predominantly cleared by the liver. The fluoroquinolones eliminated by both renal and nonrenal routes (hepatic and transintestinal) include norfloxacin, ciprofloxacin, enoxacin, fleroxacin, temafloxacin, and lomefloxacin. The primary renal mechanism of elimination for norfloxacin, ciprofloxacin, enoxacin, fleroxacin, temafloxacin, and lomefloxacin is glomerular filtration and tubular secretion. Both total clearance and renal clearance significantly correlate with creatinine clearance for these fluoroquinolones, and creatinine clearance is a useful clinical marker on which to base dosage adjustments. For some fluoroquinolones, dosage adjustments are recommended when creatinine clearances fall below 30-40 mL/min. This is especially evident for lomefloxacin, temafloxacin, norfloxacin, ciprofloxacin, enoxacin, and fleroxacin. There is very little removal of fluoroquinolones from the plasma during hemodialysis due to their extensive tissue distribution.

Bayesian forecasting of serum gentamicin concentrations in intensive care patients.

This study retrospectively evaluated the predictive performance of a 1-compartment Bayesian forecasting program in adult intensive care unit (ICU) patients with stable renal function. A comparison was made of the reliability of 3 sets of population-based parameter estimates and 2 serum concentration monitoring strategies. A larger mean error for prediction of peak gentamicin concentrations was seen with literature-derived parameters than when ICU population-based parameter estimates were used. Bias and precision improved when non-steady-state peak and trough concentrations were used to predict those at steady-state; the addition of steady-state values did not provide additional information for predictions once non-steady-state feedback concentrations were incorporated. The addition of 4 serial gentamicin concentrations obtained at both non-steady-state and steady-state did not noticeably improve the predictive performance. The results demonstrate that initial ICU pharmacokinetic parameter estimates for a 1-compartment Bayesian model provide accurate prediction of steady-state gentamicin concentrations. Prediction bias and precision showed the greatest improvement when non-steady-state gentamicin concentrations were used to determine individualised pharmacokinetic parameters.

Dose-response relationship of lansoprazole to gastric acid antisecretory effects.

BACKGROUND: Proton pump inhibitors have been found to be effective in numerous studies in patients with peptic ulcer disease, particularly associated with Helicobacter pylori and gastro-oesophogeal reflux disorders. Optimal healing rates of antisecretory therapy for peptic acid disease is dependent upon the degree and duration of acid suppression and the length of treatment. OBJECTIVE: To evaluate the extent and duration of gastric acid suppression of several lansoprazole regimens, administered for 5 consecutive days in 32 healthy adult male subjects. METHODS: Intragastric 24-h pH monitoring was performed in 32 healthy subjects in a randomized, double-blind, four-way crossover study. Sixteen subjects (Group 1) received lansoprazole 30 mg o.d. (once daily), 15 mg b.d. (twice daily), 30 mg b.d. and 30 mg t.d.s. (three times a day) for 5 days; and 16 subjects (Group 2) received lansoprazole 30 mg o.d., 60 mg o.d., 60 mg b.d. and 60 mg t.d.s. for 5 days. RESULTS: Mean 24-h intragastric pH values for lansoprazole 30 mg o.d., 15 mg b.d., 30 mg b.d. and 30 mg t.d.s. were 4.47, 4.57, 5.07 and 5.63, respectively. Multiple-dose regimens of lansoprazole 30 mg b.d. and t.d.s. produced greater acid suppression compared to lansoprazole 30 mg o.d. and 15 mg b.d. There was no significant difference in acid suppression between lansoprazole 30 mg o.d. and 15 mg b.d. Mean 24-h intragastric pH values for lansoprazole 30 mg o.d., 60 mg o.d., 60 mg b.d. and 60 mg t.d.s. were 4.13, 4.45, 5.19 and 5.13, respectively. Multiple-dose regimens of lansoprazole 60 mg b.d. and t.d.s. produced significantly greater acid suppression compared to lansoprazole 30 mg o.d. and 60 mg o.d. There was no significant difference in acid suppression between lansoprazole 30 mg o.d. and 60 mg o.d. Lansoprazole 30 mg t.d.s., 60 mg b.d. and 60 mg t.d.s. produced significantly greater percentage time above pH 3, 4, 5 and 6 than did lansoprazole 30 mg o.d. Post-regimen serum gastrin values increased by 50-130% from pre-study mean values but remained within normal range and returned to pre-study values 7-14 days post-dosing. CONCLUSIONS: Multiple-dose regimens of lansoprazole (> or =30 mg b.d. for 5 days) produce significantly increased intragastric pH and significantly longer duration of increased intragastric pH than does lansoprazole 30 mg administered once daily.

Predictive performance of Sawchuk-Zaske and Bayesian dosing methods for tobramycin.

We evaluated the reliability of pharmacokinetic parameter estimations determined by the Sawchuk-Zaske method and by a Bayesian method for predicting steady-state tobramycin concentrations on day 4 and day 10 of therapy in 30 patients treated for gram-negative infections. We also assessed the effect of using only trough tobramycin concentrations on the predictive performance of the Bayesian method. The mean estimation of tobramycin volume of distribution was significantly different for the Bayesian methods compared with the Sawchuk-Zaske methods when the same number of L/kg). Comparing the Bayesian and Sawchuk-Zaske methods when the same number of serum concentrations was available, the Bayesian method overpredicted peak concentrations on day 4 of therapy. When only trough concentration data were used, the Bayesian method significantly overpredicted peak concentrations compared with the Sawchuk-Zaske method on days 4 and 10 of therapy. Each method predicted steady-state trough concentrations without significant differences in bias or accuracy. The Bayesian method may be useful in providing aminoglycoside dosing recommendations.

Evaluation of the renal protective effect of misoprostol in elderly, osteoarthritic patients at risk for nonsteroidal anti-inflammatory drug-induced renal dysfunction.

An age greater than 60 and diuretic use have been implicated as risk factors for nonsteroidal anti-inflammatory drug (NSAID)-induced decreases in renal function. Misoprostol, a prostaglandin E1 analog, was studied in nine elderly osteoarthritic patients at risk for NSAID-induced renal dysfunction to determine whether it could prevent NSAID-induced renal dysfunction. Subjects received ibuprofen 2400 mg/day and either misoprostol 800 mcg/day or placebo for 14 days in a randomized, double-blinded, crossover trial. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) studies using inulin and PAH plasma clearance, urinary prostaglandin E2 (PGE2) and protein excretion, and serum electrolytes were obtained at baseline, after the first dose, and on day 7 and 14 of each treatment period. Prostaglandin E2 excretion was significantly reduced after the first dose of ibuprofen and throughout the 14 days in both the misoprostol and placebo treatment groups. No statistically significant differences in GFR, ERPF, protein excretion, serum potassium, or serum sodium were detected between misoprostol and placebo treatment during the 14 days of ibuprofen treatment. However, a subset of two patients who exhibited a decrease of greater than 20% in GFR during placebo treatment, appeared to demonstrate an attenuation of this decline when treated with misoprostol. Effect of time, independent of treatment group, indicated that ERPF was significantly decreased from baseline after the first dose of ibuprofen (P < or = 0.05), whereas GFR was notably diminished from baseline on day 14 only (P < or = 0.05). Misoprostol does not influence GFR and ERPF in unselected subjects purportedly at risk for NSAID-induced renal dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacodynamic modeling of lansoprazole using an indirect irreversible response model.

A mechanism-based pharmacokinetic/pharmacodynamic model was used to assess lansoprazole effects on gastric pH. The irreversible inactivation of the H+/K+-ATPase enzyme by lansoprazole controls the secretion rate of H+ ions and gastric pH values. The basal circadian rhythm of gastric acid production was taken into account as well as the effects of food intake. A model was applied to multiple-dose data from a crossover study of four dosage regimens of lansoprazole in two groups of normal male subjects. Model parameters were estimated by nonlinear regression and were compared to historical values reported in the literature. The predicted mean gastric ion concentration was 23.2 mM (pH 1.6) with the peak time at 12.6 hours (8:30 p.m.), and the half-time for H+ removal from the stomach averaged 1.7 hours. The estimated half-life of gastric food removal was 0.8 hours. The rate constant for normal H+/K+-ATPase degradation was 0.045 h(-1). The pharmacodynamic parameter describing lansoprazole action on gastric acid secretion was the second-order enzyme inactivation constant, which averaged 0.16 microg(-1) x L x h(-1). The parameters obtained for both the baseline and drug treatment data were consistent with the literature and physiologically relevant with the exception of effective food volume, which was large presumably due to buffer effects. The model successfully incorporated the physiological regulation of gastric acid production, the effects of food on gastric acid, and the effects of multiple-dosing regimens of lansoprazole on gastric acid production to give reasonable profiles of gastric pH.

Pharmacokinetic and adrenal interactions of IL-10 and prednisone in healthy volunteers.

The pharmacokinetic and adrenal interactions of recombinant human interleukin-10 and prednisolone were examined in this open-label, randomized, four-way crossover study in 12 healthy adult male volunteers. Single doses of IL-10 (8 micrograms/kg s.c.), IL-10 with prednisone (15 mg p.o.), placebo with prednisone, or placebo were administered on four separate occasions with at least 3-week interceding washout periods. Measurements included plasma prednisone, prednisolone and cortisol, unbound prednisolone, and serum IL-10 concentrations. Pharmacokinetic parameters were determined using noncompartmental and model-fitting analysis, while area analysis and an indirect response model were used to assess cortisol dynamics. IL-10 exhibited prolonged serum concentrations owing to dual-absorption processes that were largely unaffected by prednisone. The Cmax values were about 3 ng/mL, while the tmax occurred at 7 to 9 hours. Prednisolone exhibited rapid systemic kinetics with a Cmax of 235 ng/mL, tmax at 1.11 hours, and t1/2 of 2.54 hours with no significant alterations owing to IL-10. Both prednisolone and prednisolone/IL-10 caused marked suppression of cortisol concentrations with similar magnitude and IC50 values; however, IL-10 alone significantly increased the 24-hour AUC of cortisol by 20%. Thus, IL-10 and prednisolone do not interact in disposition or adrenal suppression to a clinically significant degree.

Prednisolone pharmacokinetics and pharmacodynamics in relation to sex and race.

Prednisolone pharmacokinetics (PK) and pharmacodynamics (PD) were investigated in relation to sex and race in white males, black males, white females, and black females (n = 8/group) after a single oral dose (0.27 mg/kg) of prednisone. The study consisted of baseline and prednisone phases with 32-hour sampling in each phase. Women were studied during the luteal phase of their menstrual cycle. Total and free plasma prednisolone concentrations were assayed by HPLC and ultrafiltration, and pharmacokinetic data were analyzed by compartmental fitting using WinNonlin. Plasma cortisol concentrations were assayed by HPLC; T-helper, T-suppressor lymphocyte, and neutrophil cell counts were determined by FACS and hemocytometry, and these pharmacodynamic data were evaluated by basic and extended indirect response models using ADAPT II. Total body weight-normalized free prednisolone oral clearance and apparent volume of distribution were higher in men compared with women, regardless of race (by 22% in whites and 40% in blacks for oral clearance, p < 0.01; by32% in whites and 38% in blacks for apparent volume of distribution, p < 0.01). The 50% inhibitory concentration (IC50) values for T-suppressor cell-trafficking inhibition were higher in whites than in blacks, regardless of sex (by 125% in men and 208% in women, p < 0.01). The IC50 or SC50 values for effects of prednisolone on cortisol secretion and T-helper lymphocyte or neutrophil trafficking were not statistically different between men and women, blacks and whites. The findings of this study suggest that there are some prednisolone PK/PD differences related to sex and race. However, these differences do not suggest the need for dosage adjustments, and additional experiments with repeat dosing are needed to fully evaluate the clinical implication of these findings.

Effects of oral prasterone (dehydroepiandrosterone) on single-dose pharmacokinetics of oral prednisone and cortisol suppression in normal women.

This study sought to determine effects of multiple dosing of prasterone (DHEA, dehydroepiandrosterone) on the pharmacokinetics of prednisolone and endogenous cortisol secretion. These drugs are likely to be coadministered to patients with systemic lupus erythematosus. Fourteen normal women (ages 30.1 +/- 5.4 years) received single-dose oral prednisone (20 mg) before and after 200 mg/day of oral prasterone for one menstrual cycle (approximately 28 days). Identical assessments, timed to onset of menses, were conducted pretreatment (baseline) and at days 28 and 29 of prasterone treatment and included serum total and free prednisolone, prednisone, DHEA, DHEA-S (dehydroepiandrosterone sulfate), ACTH-stimulated cortisol, and sex hormones and 24-hour urine free cortisol. Pharmacokinetic parameters of prednisolone as assessed by Cmax, t 1/2, AUC, or serum protein binding were not affected by prasterone. The ACTH-stimulated plasma cortisol concentrations were mildly reduced, but 24-hour urinefree cortisol excretion was unchanged during prasterone administration. Serum androstenedione and testosterone increased, while no changes in serum estradiol or estrone occurred. The administration of 200 mg oral prasterone produced serum concentrations of DHEA and DHEA-S significantly greater than endogenous levels. Chronic dosing with 200 mg/day of prasterone did not alter either prednisolone pharmacokinetics or inhibition of cortisol secretion by prednisolone.

Pharmacokinetics of quinapril and its active metabolite, quinaprilat, in patients on chronic hemodialysis.

The pharmacokinetics of quinapril and its active metabolite, quinaprilat, were evaluated in 12 patients with end-stage renal disease (ESRD) on chronic hemodialysis. Each subject received a single 20-mg oral dose of quinapril 4 hours before a 4-hour hemodialysis treatment. Serial dialysate and blood samples were obtained over 4 and 96 hours, respectively. Samples were analyzed for quinapril and quinaprilat concentrations by gas chromatography. Mean tmax and Cmax values for quinapril were 1.2 hours and 129 ng/mL, respectively. Only one patient had detectable quinapril dialysate concentrations which accounted for 2.8% of the quinapril dose. Mean apparent plasma clearance for quinapril was 1275 mL/min with a mean half-life of 1.7 hours. Quinapril was extensively de-esterified to its diacid metabolite, quinaprilat. Mean tmax and Cmax for quinaprilat were 4.5 hours and 671 ng/mL, respectively. Mean apparent plasma clearance for quinaprilat was 24.0 mL/min with a mean half-life of 17.5 hours. As with quinapril, quinaprilat was not readily dialyzable. Only 5.4% of the administered quinapril dose was recovered as quinaprilat during a single hemodialysis treatment. In view of these results, supplemental quinapril doses need not be routinely given to patients following hemodialysis. Overall, quinapril and quinaprilat pharmacokinetics in patients with ESRD on chronic hemodialysis were not markedly different from those previously observed in patients with moderate to severe renal dysfunction (CLcr less than 29 mL/min) not yet requiring hemodialysis (RDND).

The comparative effects of lansoprazole, omeprazole, and ranitidine in suppressing gastric acid secretion.

The effects on 24-hour intragastric pH levels of once-daily doses of lansoprazole 15 mg and lansoprazole 30 mg were compared with the effects of omeprazole 20 mg QD and ranitidine 150 mg QID in a phase I, randomized, double-masked, four-way crossover study conducted in 29 healthy male volunteers. Subjects received each treatment regimen for 5 consecutive days with at least a 2-week washout between treatment periods. Ambulatory 24-hour intragastric pH values were monitored in each subject at baseline (2 days before crossover period 1) and again before dosing on day 5 of each of the four crossover treatment periods. Gastric pH values increased during all four regimens, with significantly higher mean 24-hour pH values noted in subjects receiving lansoprazole 30 mg QD (4.53 +/- 0.16) compared with those receiving lansoprazole 15 mg QD (3.97 +/- 0.16), omeprazole 20 mg QD (4.02 +/- 0.16), or ranitidine 150 mg QID (3.59 +/- 0.16). Lansoprazole 30 mg produced significantly greater mean percentages of time that the gastric pH was above 3.0 and 4.0 (75% and 63%, respectively) compared with the other treatment regimens. The mean percentages of time during which gastric pH was above 3.0 and 4.0, respectively, for the other treatments were lansoprazole 15 mg, 64% and 48%; omeprazole 20 mg, 63% and 51%; and ranitidine 150 mg, 52% and 38%. All treatment regimens were well tolerated, with no clinically significant differences between the regimens. Multiple-dose lansoprazole 30 mg QD produced a significantly increased intragastric pH level and significantly longer durations of increased intragastric pH level compared with lansoprazole 15 mg QD, omeprazole 20 mg QD, and ranitidine 150 mg QID.

Mathematic modeling of drug disposition and postdialysis rebound in patients requiring hemodialysis.

We developed a model to describe intradialysis and postdialysis serum concentration changes and, in concert with nonlinear regression, to estimate drug removal during hemodialysis. A Lotus-based computer simulation program was developed that describes drug disposition in this therapy. The hemodialysis removal rate constant and beta were two important factors identified that influence postdialysis rebound. Also, a nonlinear regression routine using PCNONLIN was developed that enables simultaneous fitting of predialysis, intradialysis, and postdialysis drug concentration data. Data from four patients who received intravenous sulbactam were analyzed using this model. The mean measured amount of sulbactam removed by hemodialysis was 446 +/- 32 mg versus predicted amounts of 456 +/- 92 mg from model estimates, and 449 +/- 33 mg when dialysate recovery of drug was included in the input. This program will be useful in characterizing pharmacokinetic constants and predicting hemodialysis drug removal.

A review of eprosartan pharmacokinetic and pharmacodynamic drug interaction studies.

A series of clinical pharmacology studies was conducted to characterize potential interactions between eprosartan and other commonly prescribed drugs. Separate studies assessed the effect of eprosartan on the pharmacokinetics of digoxin and hydrochlorothiazide (HCTZ) and the pharmacodynamics of warfarin and glyburide (glibenclamide), as well as the effects of ranitidine, HCTZ, fluconazole, and ketoconazole on eprosartan pharmacokinetics. Eprosartan had no significant effect on the pharmacokinetics of digoxin and HCTZ and the pharmacodynamics of warfarin and glyburide. Thus, no dosing adjustments are necessary during concomitant therapy with these agents. Ranitidine, HCTZ, ketoconazole, and fluconazole had no effect on eprosartan pharmacokinetics. Single or multiple oral doses of eprosartan were safe and well tolerated when coadministered with these agents.