Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma.

Oxaliplatin-based chemotherapy is used to treat patients with esophageal adenocarcinoma (EAC), but no biomarkers are currently available for patient selection. We performed a prospective, clinical trial to identify potential biomarkers associated with clinical outcomes. Tumor tissue was obtained from 38 patients with resectable EAC before and after 2 cycles of oxaliplatin-fluorouracil chemotherapy. Pre-treatment mRNA expression of 280 DNA repair (DNAR) genes was tested for association with histopathological regression at surgery, disease-free survival (DFS) and overall survival (OS). High expression of 13 DNA damage repair genes was associated with DFS less than one year (P < 0.05); expression of 11 DNAR genes were associated with worse OS (P < 0.05). From clinical associations with outcomes, two genes, ERCC1 and EME1, were identified as candidate biomarkers. In cell lines in vitro, we showed the mechanism of action related to repair of oxaliplatin-induced DNA damage by depletion and knockout of protein binding partners of the candidate biomarkers, XPF and MUS81 respectively. In clinical samples from the clinical trial, pre-treatment XPF protein levels were associated with pathological response, and MUS81 protein was associated with 1-year DFS. XPF and MUS81 merit further validation in prospective clinical trials as biomarkers that may predict clinical response of EAC to oxaliplatin-based chemotherapy.

Efficiency of Ipratropium Bromide and Albuterol Deposition in the Lung Delivered via a Soft Mist Inhaler or Chlorofluorocarbon Metered-Dose Inhaler.

The propellant-free Combivent Respimat Soft Mist Inhaler (CVT-R) was developed to replace the chlorofluorocarbon-propelled Combivent metered-dose inhaler (CVT-MDI). This steady-state pharmacokinetic (PK) substudy evaluated drug lung-delivery efficiency, using data from two phase III safety and efficacy trials. PK parameters were obtained from well-controlled population PK analyses. Area under the plasma concentration-time curve (AUC), maximum observed plasma concentration (C(max)), and minimum observed plasma concentration (C(min)) showed systemic exposure to ipratropium bromide and albuterol delivered via the CVT-R was proportional to ex-mouthpiece delivered dose. Although the labeled dose of ipratropium bromide in the CVT-R was half that in the CVT-MDI, the systemic exposure was comparable. No PK interaction for the ipratropium bromide and albuterol Respimat drug components was demonstrated. Ipratropium bromide alone resulted in similar exposure to the combination of ipratropium bromide and albuterol. These results show that CVT-R delivers drug more efficiently to the lung than CVT-MDI.

Evaluation of steady-state pharmacokinetic interactions between ritonavir-boosted BILR 355, a non-nucleoside reverse transcriptase inhibitor, and lamivudine/zidovudine in healthy subjects.

WHAT IS KNOWN AND OBJECTIVE: BILR 355 is a second generation non-nucleoside reverse transcriptase inhibitor. It has shown promising in vitro anti-HIV-1 activities and favourable human pharmacokinetic properties after co-administration with ritonavir (RTV). Lamivudine (3TC) is a nucleoside reverse transcriptase inhibitor. It is excreted predominantly in urine by a transporter-mediated pathway. These two drugs are likely to be given together to HIV-infected patients. The objective of this study was to investigate any steady-state pharmacokinetic interactions between RTV-boosted BILR 355 and 3TC/zidovudine (ZDV). METHODS: This was a randomized, open label, prospective study. In group A, 39 healthy subjects were given 3TC/ZDV (150 mg/300 mg) twice daily (b.i.d.) for 7 days, and then BILR 355 and RTV (BILR 355/r, 150 mg/100 mg) were co-administered with this regimen for an additional 7 days. Intensive blood samples were taken on days 7 and 14 for pharmacokinetic assessments. In group B, 12 healthy subjects were given BILR 355/r (150 mg/100 mg) b.i.d. for 7 days. The pharmacokinetic data from group B were pooled with data from group B subjects in other similar studies performed in parallel (BILR 355 alone group in BILR 355 drug-drug interaction studies with tipranavir, lopinavir/RTV, and emtricitabine/tenofovir DF; BILR 355 regimen was the same). RESULTS AND DISCUSSION: After co-administration with BILR 355/r, the AUC(12,ss) and C(max,ss) of 3TC increased by 45% and 24%, respectively; the elimination half-life (t(1/2) ,ss) of 3TC was significantly increased. However, the pharmacokinetics of ZDV was unchanged. Co-administration with 3TC/ZDV resulted in a 22% decrease in AUC(12,ss) and a 20% decrease in C(max,ss) for BILR 355. The observed increase in exposure and prolongation of t(1/2,ss) of 3TC is potentially related to inhibition of OCT-mediated urinary excretion of 3TC. WHAT IS NEW AND CONCLUSION: Concomitant administration of BILR 355 with 3TC/ZDV resulted in a modest decrease in exposure to BILR 355 and a 45% increase in exposure to 3TC.

Effect of tipranavir/ritonavir combination on the pharmacokinetics of tadalafil in healthy volunteers.

This study evaluated the effects of single-dose administration and steady-state concentrations of tipranavir 500 mg and ritonavir 200 mg (TPV/r) combination on the pharmacokinetics of tadalafil 10 mg (TAD) in an open-label study. Seventeen healthy male volunteers received sequential dosing of the studied product: TAD (day 1) alone in a single dose for 7 days followed by TAD (day 8) in a single dose with TPV/r (500/200 mg twice daily, days 8-18). Pharmacokinetic parameters were determined in a noncompartmental analysis. The geometric mean ratio and 90% confidence interval were used to evaluate drug interactions. The effect of a single dose of TAD on the pharmacokinetics of TPV/r resulted in a small decrease in exposure after either first-dose or steady-state TPV/r (geometric mean ratios [90% confidence interval]: area under the concentration-time curve, 0.85 [0.74-0.97]). In contrast, coadministration of TAD exposure was increased significantly (2.33 [2.02-2.69]) when administered with the first dose of TPV/r but not when TPV/r steady state was reached (1.01 [0.83-1.21]). Antiretroviral activity may not be reduced, but the dose of TAD should be reduced at the start of TPV/r therapy and then a full dose can be resumed after steady state is reached.

A phenotype-genotype approach to predicting CYP450 and P-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir.

The effects of tipranavir/ritonavir (TPV/r) on hepatic and intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP) enzyme activity were evaluated in 23 volunteers. The subjects received oral (p.o.) caffeine, warfarin + vitamin K, omeprazole, dextromethorphan, and midazolam and digoxin (p.o. and intravenous (i.v.)) at baseline, during the first three doses of TPV/r (500 mg/200 mg b.i.d.), and at steady state. Plasma area under the curve (AUC)(0-infinity) and urinary metabolite ratios were used for quantification of protein activities. A single dose of TPV/r had no effect on the activity of CYP1A2 and CYP2C9; it weakly inhibited CYP2C19 and P-gp; and it potently inhibited CYP2D6 and CYP3A. Multiple dosing produced weak induction of CYP1A2, moderate induction of CYP2C19, potent induction of intestinal P-gp, and potent inhibition of CYP2D6 and CYP3A, with no significant effects on CYP2C9 and hepatic P-gp. Several P450/transporter single-nucleotide polymorphisms correlated with the baseline phenotype but not with the extent of inhibition or induction. Although mixed induction and inhibition are present, this approach offers an understanding of drug interaction mechanisms and ultimately assists in optimizing the clinical use of TPV/r.

Serum 25-hydroxyvitamin D levels in early and advanced breast cancer.

BACKGROUND: Laboratory and epidemiological studies have implicated vitamin D deficiency in the pathogenesis of breast cancer. 1,25-Dihydroxyvitamin D (1,25(OH)(2)D) promotes differentiation and apoptosis, and potently inhibits proliferation of malignant breast epithelial cells in culture. Serum levels of 1,25(OH)(2)D are higher in normal women than in patients with primary breast cancer. AIM: To clarify the role of vitamin D in breast cancer progression by comparing the levels of serum vitamin D in patients with early and in those with advanced breast cancer. METHODS: Circulating levels of 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH) and calcium were measured prospectively in 279 Caucasian women with invasive breast cancer, 204 women with early-stage disease and 75 women with locally advanced or metastatic disease. RESULTS: Patients with early-stage breast cancer had significantly higher circulating levels of 25(OH)D (p<0.005) and significantly lower PTH (p<0.001) levels than those with advanced disease. Calcium levels did not differ significantly (p = 0.74). CONCLUSION: Serum levels of 25(OH)D are significantly higher in patients with early-stage breast cancer than in those with locally advanced or metastatic disease.

Pharmacokinetics of nevirapine and lamivudine in patients with HIV-1 infection.

The purpose of this parallel treatment group, double-blind, multicenter study was to characterize the pharmacokinetics of nevirapine and lamivudine when coadministered to patients with the HIV-1 infection. This pharmacokinetic interaction study was nested within a larger Phase III clinical trial conducted to characterize the safety and efficacy of coadministered nevirapine and lamivudine. One hundred HIV-1 infected patients with CD4+ lymphocyte counts < 200 cells/mm3and who were on a background of nucleoside (zidovudine [ZDV], didanosine [ddI], zalcitabine [ddC], stavudine [d4T]) therapy were randomly assigned to be treated with either nucleoside + lamivudine + nevirapine or nucleoside + lamivudine + placebo. Each patient underwent blood sampling at defined times for the purpose of determining the concentration of nevirapine in plasma and lamivudine in serum under steady-state conditions. Each patient was also monitored closely for concomitant administration of other drugs, including ZDV, ddI, ddC, d4T and cotrimoxazole. The pharmacokinetics of nevirapine and lamivudine were characterized using nonlinear mixed-effects modeling. There were no reported serious adverse events during the 40-day pharmacokinetic study. The results of the modeling analysis revealed that nevirapine had no effect on the pharmacokinetics of lamivudine. Estimates of the apparent clearance for nevirapine (CL/F = 3.3 L/hour; 95% confidence interval [CI] 2.9 to 3.7 L/hour) and lamivudine (CL/F 27.6 L/hour; 95% CI 22 to 33.2 L/hour) were consistent with the values reported in earlier trials. However, the results also showed that concomitant administration of lamivudine with cotrimoxazole resulted in a 31% reduction in the apparent clearance of lamivudine, resulting in a 43% increase in the average steady-state lamivudine serum concentrations. These results indicate that chronic concurrent administration of cotrimoxazole with lamivudine may significantly affect the steady-state pharmacokinetics of lamivudine.

Disposition and biotransformation of the antiretroviral drug nevirapine in humans.

The pharmacokinetics and biotransformation of the antiretroviral agent nevirapine (NVP) after autoinduction were characterized in eight healthy male volunteers. Subjects received 200-mg NVP tablets once daily for 2 weeks, followed by 200 mg twice daily for 2 weeks. Then they received a single oral dose (solution) of 50 mg containing 100 microCi of [(14)C]NVP. Biological fluids were analyzed for total radioactivity, parent compound (HPLC/UV), and metabolites (electrospray liquid chromatography/mass spectroscopy and liquid chromatography/tandem mass spectroscopy). Mean recovery of radioactivity was 91.4%, with 81.3% excreted in urine and 10.1% recovered in the feces over a period of 10 days. Circulating radioactivity was evenly distributed between whole blood and plasma. At maximum plasma concentration, parent compound accounted for approximately 75% of the circulating radioactivity. Mean plasma elimination half-lives for total radioactivity and NVP were 21.3 and 20.0 h, respectively. Several metabolites were identified in urine including 2-hydroxynevirapine glucuronide (18.6%), 3-hydroxynevirapine glucuronide (25.7%), 12-hydroxynevirapine glucuronide (23.7%), 8-hydroxynevirapine glucuronide (1.3%), 3-hydroxynevirapine (1.2%), 12-hydroxynevirapine (0.6%), and 4-carboxynevirapine (2.4%). Greater than 80% of the radioactivity in urine was made up of glucuronidated conjugates of hydroxylated metabolites of NVP. Thus, cytochrome P-450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of NVP biotransformation and elimination in humans. Only a small fraction of the dose (2.7%) was excreted in urine as parent compound.

Single dose pharmacokinetics and bioavailability of nevirapine in healthy volunteers.

The results of two randomized, single-dose, crossover bioavailability studies are presented which describe the pharmacokinetics and oral bioavailability of nevirapine, a novel nonnucleoside antiretroviral drug. In the first study 12 healthy male volunteers received nevirapine 15 mg via short-term i.v. infusion or orally as a 50 mg tablet or reference solution (50 mg/200 mL). Following the i.v. dose, nevirapine had a low systemic clearance (Mean +/- S.D., Cl = 1.4 +/- 0.3 L/h) and a prolonged elimination phase (t(1/2beta) = 52.8 +/- 14.8 h; MRT = 81.4 +/- 22.4 h). Nevirapine absolute bioavailability was 93 +/- 9% and 91 +/- 8% for the tablet and oral solution, respectively. In the second study, 24 healthy male volunteers were administered nevirapine as a 200 mg production-line tablet or oral reference solution (200 mg/200 mL). There was no significant difference in bioavailability between the tablet and reference solution. Overall, comparison of the pharmacokinetic parameters between the 50 and 200 mg doses indicates that nevirapine is well absorbed at clinically relevant doses. The absorption profiles using deconvolution revealed no evidence of differential enzyme induction between the two doses or routes of administration following a single dose.

Product characteristics and pharmacokinetics of intranasal ipratropium bromide.

The in vivo absorption potential of ipratropium bromide nasal spray was evaluated in studies involving healthy volunteers (0.03%, 0.06%, and 0.12% dosage strengths) and patients with perennial rhinitis (0.03% and 0.06%) and the common cold (0.06%). The dose used was two sprays per nostril, corresponding to a total dose of 84 micrograms, 168 micrograms, and 336 micrograms for the three dosage strengths. These studies indicate that 10% or less of active drug is absorbed systemically after nasal administration based on the amount of unchanged drug excreted in urine in a 24-hour interval. In most instances, the plasma drug concentrations were undetectable. In none of these studies did plasma ipratropium concentrations reach a level where systemic anticholinergic effects are known to occur.

Argon Assisted CO2 Laser Laparoscopy

The use of a small amount of Argon gas to purge the operating channel of the CO2 laser laparoscope eliminates the thermal lensing (blooming) that has plagued CO2 laser laparoscopy. By eliminating the blooming, the power density and transmission of laser power is increased. Overall, the efficacy of the CO2 laser/laparoscope system is dramatically improved. This simple procedure allows even older CO2 lasers to equal the efficiency of the newer generation shifted wave length CO2 isotope lasers. This technique is superior to others which require special equipment to achieve extremely high insufflation/evacuation flow rates in order to control thermal blooming.

The murine gene for cellular retinoic acid-binding protein type II. Genomic organization, chromosomal localization, and post-transcriptional regulation by retinoic acid.

The cellular retinoic acid-binding protein type II (CRABP-II) is a member of the serum and cytoplasmic retinoid-binding protein family. It is expressed during embryonic development and in adult skin and is upregulated by retinoic acid (RA) in F9 teratocarcinoma cells. We have determined the genomic organization of the murine CRABP-II gene and performed a detailed analysis of its transcriptional unit. The CRABP-II gene, located on mouse chromosome 2, is approximately 4.6 kilobases long and divided into four exons in a structure common to other members of the family of serum and cellular retinoid-binding proteins. Primer extension analysis and S1 nuclease protection assay were used to identify the transcription initiation site which is located 27 base pairs downstream of a typical TATAA box. Sequence analysis of the promoter also revealed a GC-rich region with overlapping putative SP1-binding sites at nucleotides -61 and AP-1 and AP-2-binding sites at nucleotides -518 and -544, respectively. The 3'-untranslated region contains two copies of the pentanucleotide AUUUA shown to be involved in messenger RNA destabilization. Consensus sequence for retinoic acid response elements were not detected in the promoter region of the CRABP-II gene. Results of nuclear run on experiments show that the CRABP-II gene is not transcriptionally activated by RA in F9 teratocarcinoma cells. These results suggest that the up-regulation of CRABP-II mRNA levels by RA is mainly controlled by a post-transcriptional mechanism.

In vitro protein binding behavior of dipyridamole.

The in vitro protein binding behavior of dipyridamole in plasma and buffered protein solutions was investigated by equilibrium dialysis. The drug was highly protein bound (approximately 98%) in heparinized human plasma, and the extent of protein binding remained constant for drug concentrations over the range of therapeutic interest of 0.1-10 micrograms/mL. Comparable binding results were obtained with a mixture of 80 mg % of alpha 1-acid glycoprotein and 40 g/L of human serum albumin in pH 7.4 phosphate buffer solution. Pure alpha 1-acid glycoprotein (80-400 mg %) or pure human serum albumin (40 g/L) in phosphate buffer gave significantly (p less than 0.05) lower binding results, indicating that both proteins are responsible for the high binding of dipyridamole in plasma. Addition of alpha 1-acid glycoprotein to heparinized human plasma, to simulate an acute phase increase in the protein, had no effect on the fraction of free drug in plasma. Binding of dipyridamole to heparinized human plasma or human serum albumin in buffer was concentration independent through 40 micrograms/mL. The free fraction of dipyridamole increases with concentrations exceeding 40 micrograms/mL.

CO2 laser used through the operating channel of laser laparoscopes: in vitro study of power and power density losses.

The purpose of this study was to measure the effects of several variables on energy transmission and power density through the CO2 laser laparoscope. The factors studied included the laser beam diameter, coupler optics, laparoscope lumen size, and absorption of the laser wavelength by the insufflation gas. The addition of CO2 insufflating gas to the operating channel at higher power settings not only reduced the energy transmitted to tissue by 35-58% with a 7.2-mm laparoscopic operating channel and by as much as 61% with a 5-mm operating channel, but also increased the spot size. This "blooming" of the laser beam definitely reduced power density at tissue and eliminated the pinpoint spot size needed for microdissection. Even under optimal conditions regarding lumen size and beam diameter, our data indicate a point of diminishing returns for power density above 40 W for the systems tested. Power densities obtainable at laparotomy were not possible. Clinically, this effect resulted in optimal cutting (vaporization) at low power settings and coagulation accompanying cutting at higher settings.

Efficacy of oral mexiletine therapy at a 12-h dosage interval.

The antiarrhythmic effectiveness and safety of 12-h oral administration of mexiletine were evaluated in adult outpatients with a baseline hourly rate of PVCs of 30 or higher who had initially shown at least a 50 percent reduction of this rate when treated with mexiletine at an 8-h dosage interval. Doses were titrated on the basis of 24-h Holter monitoring for both 8- and 12-h intervals. Seventeen of 26 patients showed PVC reductions after 8-h treatment. Fifteen of these 17 patients reached the goal reduction of greater than or equal to 50 percent in the hourly PCV rate with 12-h dosing. Hour-by-hour analysis disclosed a consistent degree of PVC suppression throughout both 8- and 12-h dose intervals. No increase in the incidence of adverse effects was associated with conversion to the 12-h regimen.

Oral pharmacokinetics of pirenzepine in patients with chronic renal insufficiency, failure, and maintenance haemodialysis.

The pharmacokinetic properties of pirenzepine following administration of a single, 50 mg oral dose were evaluated in three groups of subjects: group I, end stage renal disease requiring maintenance haemodialysis (CLCR 0 to 10 ml.min-1); group II, moderate renal insufficiency (CLCR 10 to 30 ml.min-1); and group III, mild renal dysfunction (CLCR 30 to 70 ml.min-1). Additionally, subjects in group I received a 50 mg dose on a non-dialysis day and at least one week later, a 50 mg dose during haemodialysis. There was a linear relationship (r = 0.97) between pirenzepine renal clearance and renal function as measured by creatinine clearance. The harmonic mean terminal half-life for pirenzepine was 17.3 h in subjects with end stage renal disease, 18.0 h in subjects with moderate renal insufficiency and 14.7 h in subjects with mild renal dysfunction. Haemodialysis reduced the level of circulating pirenzepine by approximately 25%. The mean arterial to venous plasma pirenzepine ratio during hemodialysis was 1.29 (range 1.02-1.56). Based on subjective reporting of adverse experiences and clinical observation, pirenzepine appeared to have had a wide margin of safety in these patients. Dry mouth was the most frequently reported adverse experience attributable to pirenzepine administration. A reduction in dose or dosing frequency may be warranted only in end state renal disease (CLCR 0 to 10 ml.min-1).

Clinical pharmacokinetics of clonidine.

Clonidine is a centrally active antihypertensive agent effective in the treatment of mild, moderate and severe hypertension, alone or in combination with other drugs. Use of oral clonidine has often been limited by side effects which include dry mouth and drowsiness. Transdermal clonidine was therefore developed as an alternative to oral therapy. Ideally, a drug administered at a constant rate into the systemic circulation should attain steady-state concentrations with less peak-to-trough fluctuation than that associated with intermittent oral dosing. In theory, transdermal administration should thus minimise the adverse effects associated with peak plasma drug concentration, while avoiding the potential for decreased efficacy associated with trough levels. Clonidine has been incorporated into a small, pliable adhesive cutaneous delivery device designed to provide therapeutically effective doses of drug at a constant rate for at least 7 days. The transdermal therapeutic system is a laminate consisting of an external film impermeable to moisture and to the drug, a thin layer of active drug dispersed within a highly drug-permeable matrix, a membrane with a controlled intrinsic permeability regulating the rate of delivery of drug to the skin, and an adhesive coating that attaches the system to the skin surface. The permeation of drug through the skin occurs primarily by diffusion. Application of the clonidine transdermal system to both normotensive and hypertensive subjects has consistently reduced systolic and diastolic blood pressures. Maximum reduction in blood pressure occurs 2 to 3 days after initial application, and is maintained for at least 7 days or until the system is removed. The rate at which clonidine is presented to the skin surface is controlled by the microporous membrane: this rate is the same for all strengths of transdermal clonidine, the amount of clonidine released being proportional to its surface area. Thus, the daily dose is regulated by the area of skin covered. Typically, steady-state plasma concentrations are reached on the fourth day after initial transdermal system application. The lack of dose dependency in half-life and renal clearance estimates emphasise that the transdermal absorption of clonidine is linear. The plasma clonidine concentration produced by a particular transdermal dose varies considerably between individuals as a result of interindividual variation in renal clearance. For this reason, it is recommended that dosages be titrated up from the smallest system (3.5 cm2) until the desired pharmacological effect has been obtained.(ABSTRACT TRUNCATED AT 400 WORDS)

Relative bioavailability of metaproterenol in humans utilizing a single dose, stable isotope approach.

The relative bioavailability of metaproterenol (3,5-dihydroxy-alpha-[(isopropylamino)methyl]benzyl alcohol) following a single dose (10-mg metaproterenol sulfate tablet) was studied in six normal male volunteers using coadministration of a solution of a deuterated analogue (metaproterenol-d7 sulfate). The bioavailability of the tablet formulation relative to that of the oral solution was 92 +/- 9%, with excellent power at the 5% significance level. Comparison of the coadministration of the labeled and unlabeled metaproterenol sulfate solutions in two subjects after a one-week washout demonstrated the absence of an isotope effect on either absorption or elimination. A GC-MS assay for metaproterenol was developed to measure plasma concentrations resulting from oral administration. The assay was linear over the range of 0.5-8 ng/mL, corresponding to typical plasma metaproterenol concentrations obtained after a single 10-mg oral dose. Accuracy and precision data were obtained at metaproterenol concentrations of 1.0 and 2.0 ng/mL plasma to demonstrate the applicability of the assay for bioavailability studies. Following oral administration, metaproterenol showed peak plasma concentrations of 2.2 to 13 ng/mL at 0.75 to 3.0 h, with a terminal harmonic mean half-life of 2.1 h over the plasma concentration range studied. The renal clearance of 133-158 mL/min for metaproterenol slightly exceeds the glomerular filtration rate in humans.

Relative bioavailability of chlorthalidone in humans after single oral doses.

The relative bioavailability of chlorthalidone from rapidly dissolving, stabilized, amorphous 15- and 25-mg formulations was compared in 24 normal adult male volunteers to the 25-mg market standard tablet and a 25-mg oral reference solution. When adjusted for dose, the experimental formulations were 116 and 104% of the calculated mean area under the curve for chlorthalidone reference solution compared to 81% for the tablet of the innovator. Likewise, the dose-adjusted mean peak blood levels for the 15- and 25-mg experimental tablets and the 25-mg tablet of the innovator were 112, 105 and 78% of the reference solution, respectively. Mean times-to-peak blood concentrations were 8.4 h for the 25-mg and 9.1 h for the 15-mg amorphous formulations compared to 9.2 h for the oral reference solution and 11.8 h for the market standard tablet. Drug concentrations declined monoexponentially with harmonic mean half-lives ranging from 47 to 55 h and intrinsic clearances ranging from 0.13 to 0.18 L/h regardless of formulation. The dose-adjusted relative bioavailability for the experimental formulations was not significantly different from the oral reference solution, whereas the market standard tablet was significantly (p less than 0.0001) lower than the reference solution. The urinary excretion of chlorthalidone was generally greater following the stabilized amorphous formulations than either the tablet of the innovator or the reference solution. The results of this research show that a rapidly dissolving chlorthalidone tablet can be formulated that shows complete relative bioavailability in humans.