Comparison of ceftibuten transport across Caco-2 cells and rat jejunum mounted on modified Ussing chambers.

Ceftibuten uptake into Caco-2 cells and intestinal brush border membrane vesicles is mediated by the dipeptide transport system (PEPT1). The apical to basolateral transport characteristics of ceftibuten across Caco-2 cells and rat jejunum mounted on a modified Ussing chamber was examined. Mannitol was used as a paracellular marker along with trans-epithelial electrical resistance (TEER) for monitoring tight junction permeability. Transport across Caco-2 cells and rat jejunum mounted on a modified Ussing chamber was linear across the concentration range 0.25-10 mM. The net flux of mannitol and ceftibuten was higher across rat jejunum compared with Caco-2 cells. At a donor concentration of 0.25 mM, ceftibuten transport across Caco-2 cells was found to be pH dependent. Glycyl proline, a dipeptide, and 2,4- dinitrophenol, an energy poison, caused a reduction in the permeability of 0.25 mM ceftibuten across Caco-2 cells. Benzoic acid and adipic acid also inhibited transcellular transport of ceftibuten. At a donor concentration of 0.25 mM, passive paracellular transport accounts for about 60% and the active carrier mediated mechanism accounts for about 40% of ceftibuten transport across Caco-2 cells. None of the inhibitors however, had a significant effect on ceftibuten transport across rat jejunum mounted on a modified Ussing chamber at a donor concentration of 0.25 mM. In the concentration range 0.25-10 mM, ceftibuten is predominantly transported by paracellular mechanisms across rat jejunum and a mixture of active and passive transport across Caco-2 cells.

Risedronate pharmacokinetics and intra- and inter-subject variability upon single-dose intravenous and oral administration.

PURPOSE: To determine the pharmacokinetics and absolute bioavailability of risedronate after single-dose oral administration of 30 mg risedronate as a tablet and an aqueous solution, and 0.3 mg risedronate as an intravenous infusion. METHODS: This study was a randomized, three-treatment, four-period, partial replicate crossover study involving 33 healthy volunteers. Treatments were administered 7 weeks apart, and the third treatment was repeated during the fourth period. Serum and urine were collected over 72 hours and 672 hours, respectively. RESULTS: Following intravenous administration, renal clearance accounted for 87% of total clearance, with 65% of the dose excreted within 24 hours and 85% of the dose excreted within four weeks. The absolute bioavailability was approximately 0.62% after both oral formulations, and the relative bioavailability of the tablet compared with the oral solution was 104%. The rate and extent of absorption from the two formulations were bioequivalent based on the range proposed for highly variable drugs. Intrasubject variability following oral administration was 50-80%, and was primarily associated with absorption. CONCLUSION: The majority of the total clearance after intravenous administration of risedronate was renal clearance, indicating that only a small percentage of a systemic dose is potentially incorporated, or "cleared," into bone. The absolute bioavailability of orally administered risedronate is approximately 0.6%, and is independent of formulation. Variability in the pharmacokinetics following oral administration is primarily associated with intrasubject variability in absorption.

Drug substitution in transplantation: a National Kidney Foundation White Paper.

Specific safeguards to guide the approval process and substitution practices for generic immunosuppressive agents are necessary for the effective delivery of patient care. Currently, the Food and Drug Administration (FDA) requires the demonstration of bioequivalence of generic drugs to innovator drugs in normal healthy subjects, a criterion that may be insufficient for critical-dose drugs. For generic equivalents of critical-dose drugs and for innovator critical-dose drugs, there should be a requirement for replicate studies measuring intrasubject variability and subject-treatment interactions to establish that bioequivalence holds true. Extensive testing of generic drugs in all target patient types is impractical and should not be required. However, when evidence suggests that the bioavailability of a critical-dose drug may vary substantially in certain subgroups, the FDA should require a demonstration of bioequivalence of generic versions to innovator products in these representative target populations. Changes in the approval process for generics should be accompanied by more consistent substitution practices. Pharmacists should notify the prescribing physician and patient whenever a critical-dose drug (generic or brand name) is dispensed in a different formulation from the one the patient has been taking. Therapeutic substitution for such drugs should not be made unless the prescribing physician has granted approval. The health care provider should consider instituting appropriate monitoring whenever patients are switched between generic formulations or between innovator drugs and generic formulations. Patients should be well informed about generic substitutes so that they can participate in treatment choices.

Oligonucleotide transport in rat and human intestine ussing chamber models.

Cellular and intestinal absorption of naked oligonucleotides (ONs) is limited and still remains a developmental challenge. A previous report in the literature suggests that ON absorption occurs via a paracellular mechanism. The aim of this study was to test this hypothesis using rat and human intestine in a Ussing chamber and in Caco-2 cells. Transport of a (35)S-labelled mixed backbone ON (MBO) across human or rat intestinal tissue or across Caco-2 cells was measured after a 2-h incubation in the presence or absence of increasing MBO concentrations or with uptake inhibitors and enhancers. MBO intestinal absorption was compared with an internal standard, mannitol. (35)S-MBO demonstrated very little absorption (<1%) across rat and human intestinal tissues. Transport appeared to be unsaturable up to 500 microM, and relatively insensitive to compounds that opened tight junctions or inhibited P-glycoprotein. However, preliminary studies with Caco-2 cells suggest a possible saturable mechanism at higher ON concentrations. Confocal fluorescence microscopy studies show that fluorescein isothiocyanate (FITC)-MBO was internalized into intestinal cells. Although some differences in ON transport were observed as a function of the transport model, MBO transport was mostly consistent with a transcellular, rather than a paracellular, absorption mechanism.

Comparison of methods for the assessment of central nervous system stimulant response after dextroamphetamine administration to healthy male volunteers.

The objective of this investigation was to evaluate a series of potential pharmacodynamic measures of central nervous system stimulation, including quantitative electroencephalography (EEG) and neuroendocrine, mood, and psychomotor performance measures. The reproducibility and sensitivity of the measures were compared. The study was conducted in two parts. The first part investigated the interindividual and intraindividual variability associated with a series of potential pharmacologic response measures under baseline (i.e., drug-free) conditions. It was an open-label, three-period pilot study in which healthy male volunteers underwent a series of tests (EEG, a visual continuous performance task, a finger tapping task, and self-rated mood scales) repeatedly during each study period. The second part evaluated the sensitivity of a series of potential response measures to detect the effects of dextroamphetamine, and was a double-blind, placebo-controlled, four-period crossover study in nine healthy male volunteers. Subjects received 5 mg, 10 mg, or 20 mg of dextroamphetamine or placebo orally and underwent the same series of tests as in Part I in addition to blood collection for determination of serum prolactin and dextroamphetamine levels. Peripheral response to dextroamphetamine was assessed by heart rate and blood pressure measurement. The greatest variability among days, within days, and among participants was associated with the quantitative electroencephalographic parameters studied. First-session effects were apparent for several of the tests, including EEG. Consistent response on EEG (increased alpha power) to dextroamphetamine was observed only in the three subjects who had a baseline alpha activity greater than 35%. Serum prolactin levels were inversely associated with the amount of dextroamphetamine administered, with the largest decrease in serum prolactin levels observed after the 5-mg dose, and this finding was statistically significant. Mood scales showed that three of nine participants experienced dysphoria after at least one dose level of dextroamphetamine. The effect on mood was generally greater as the dose increased. Doses could not be distinguished based on the results of the performance tests. Serum prolactin concentration was the most sensitive measure of central nervous system stimulation on EEG produced by dextroamphetamine under these study conditions. Cardiovascular measures were more sensitive measures of dextroamphetamine effects than the central nervous system measures.

Bioequivalence of two tablet formulations of nadolol using single and multiple dose data: assessment using stereospecific and nonstereospecific assays.

Nadolol, a nonspecific beta-blocker, is a racemate composed of equal amounts of four stereoisomers, namely, SQ-12148, SQ-12149, SQ-12150, and SQ-12151. In an open-label, randomized, four-period crossover study, the pharmacokinetics of nadolol and its stereoisomers and the bioequivalence of two formulations of nadolol were assessed in 20 healthy male subjects following a single dose (80 mg) and multiple doses (80 mg; once daily for 7 days). A standard granulated tablet and direct compressed tablet formulations, each containing 80 mg of nadolol, with different in vitro dissolution profiles that met current USP requirements were used. The four treatments were single and multiple doses of granulated tablet, and single and multiple doses of compressed tablet. There was a 7 day washout period between successive treatments. All doses of nadolol were administered after an overnight fast. Serial blood samples were collected up to 72 h following the single dose and during multiple dose treatments, following day 6 and 7 doses. Validated high-performance liquid chromatographic assays were applied to measure nadolol and its stereoisomers in the study samples. Plasma concentration data were subjected to noncompartmental pharmacokinetic analysis. Both C(max) and AUC values were significantly greater for SQ-12150 when compared to other nadolol stereoisomers obtained after a single dose or at steady state. However, T(max) and T1/2 values were similar among the four isomers. The observed steady state AUC tau values for nadolol (2278-2331 ng h/ML) or its stereoisomers (550-874 ng h/ML) were significantly greater than those predicted from the single dose AUCinf values (nadolol, 1840-1845 ng h/ML; isomers, 450-713 ng h/ML). The intrasubject variability, computed from multiple dose data, was generally greater for the stereoisomers (17-40%) than for nadolol (10-32%). The two formulations were bioequivalent for nadolol (C(max) = 0.98 [84%, 117%]; AUCinf = 1.03 [93%, 116%]) and SQ-12150 (C(max) = 1.12 [89%, 122%]; AUCinf = 0.98 [82%, 119%]) after a single dose, and only for nadolol (C(max) = 1.07 [84%, 118%]; AUCinf = 1.02 [91%, 113%]) at steady state.

Single-dose interaction study of diprafenone HCl and propranolol HCl in healthy volunteers.

Using a 3 x 3 Latin Square design, a possible interaction between diprafenone HCl a class IC antiarrhythmic drug with nonspecific beta-antagonist activity and propranolol HCl was investigated in nine young, healthy, caucasian, male volunteers. The volunteers randomly received 3 single-dose treatments: (A) 200 mg DHCl, (B) 80 mg PHCl, and (C) 200 mg DHCl and 80 mg PHCl. Scheduled blood samples were taken and plasma concentrations of both diprafenone and propranolol were measured by sensitive and specific assay methods. Lead II electrocardiogram intervals at rest, heart rate during erect bicycle ergometry, and echocardiographic variables at rest and shortly after exercise were recorded. The data analysis used compartment model independent methods. There was no evidence for a pharmacokinetic interaction between the two drugs. With DHCl, two of the nine subjects showed greatly increased areas under the plasma concentration-time curves and apparent disposition half-lives in the presence and absence of PHCl, indicating that metabolism of diprafenone may be subject to pharmacogenetic polymorphism. There was evidence for a pharmacodynamic interaction between DHCl and PHCl regarding the negative chronotropic effect at rest and during exercise. There was no difference in the pharmacodynamics and tolerability of the three treatments in suspected "poor" and "extensive metabolizers" of DHCl.

Pharmacokinetics of ceftibuten in children.

The bioavailability and pharmacokinetics of ceftibuten administered as an oral suspension were characterized by several studies in young healthy male adults (19 to 39 years old) and children ranging in age from 6 months to 17 years. Ceftibuten suspension was found to be bioequivalent and thus interchangeable with a standard 400-mg capsule. As with the capsule formulation, food slightly (< 20%) affected the rate and extent of absorption of the suspension. The recommended dose of 9.0 mg/kg was found to produce comparable plasma concentrations in children of all ages (6 months to 17 years). The range of mean values of maximum plasma concentrations (Cmax) was 12 to 16 micrograms/ml at the 9.0-mg/kg dose level. Doses of 4.5, 9.0 and 13.5 mg/kg produced Cmax and area under the plasma concentration-time curve values that were dose-proportional. The half-life (t1/2) was essentially independent of age and dose, ranging from 2 to 3 hours. The apparent clearance (Cl/F), uncorrected for the fraction of drug absorbed (F), is independent of dose but appears to increase with a decrease in age. This also occurs to a lesser degree with the volume of distribution (Vd/F), uncorrected for F. Current evidence suggests that this is more likely to be caused primarily by a decrease in F than an increase in Cl. Ceftibuten rapidly and extensively reaches the middle ear fluid in children with acute otitis media. Within 4 hours concentrations in middle ear fluid are similar to plasma concentrations and can be measured for 12 hours. The ratio of area under the concentration time curve for middle ear fluid relative to plasma was about 70%.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of isepamicin.

Isepamicin is a new aminoglycoside that has activity against many bacteria resistant to other aminoglycosides. The pharmacokinetics of isepamicin have been characterized in neonatal, pediatric, adult, elderly and renally impaired human populations as well as in clinical trials using the techniques of population pharmacokinetics. The pharmacokinetics of isepamicin are uncomplicated and generally similar to those of other aminoglycosides, although there is some evidence that it may have less tissue accumulation. The drug is completely absorbed following intramuscular administration. The drug is not metabolized and unchanged isepamicin accounts for all of the drug substance in plasma and urine. It is completely eliminated via the renal route; consequently dosing in patients with renal insufficiency has to be adjusted according to the degree of renal impairment. The pharmacokinetics of isepamicin are generally linear. Thus peak plasma concentrations and area under the plasma concentration curve (AUC) values are proportional to the administered dose while clearance (1.1-1.3 mL/min/kg), volume of distribution at steady state (0.23-0.29 L/kg) and half-life (2-2.5 h) are independent of dose. There is no significant accumulation of drug in the plasma with once- or twice-daily dosing. The isepamicin plasma concentration curve following a 1 g intravenous dose to healthy volunteers can be best characterized by a tri-exponential curve corresponding to a t1/2 alpha of 0.17 h, a t1/2 beta of 2.1 h, and a gamma-phase of 34 h. The t1/2 beta represents the elimination phase and changes with age and renal functions, while the gamma-phase represents the return of drug to plasma from a deep compartment including binding in renal tissue. The gamma-phase represents less than 3% of the total AUC and does not change with age. Isepamicin readily distributes to extracellular fluid and pulmonary tissue. In conclusion, isepamicin demonstrates predictable linear kinetics and is similar pharmacokinetically to other aminoglycosides. Preliminary indications of decreased tissue accumulation implied from pharmacokinetic and pharmacodynamic characteristics of isepamicin favour once-daily dosing.

A pharmacokinetic evaluation of 14C-labeled afovirsen sodium in patients with genital warts.

Afovirsen sodium is a 20-mer phosphorothioate oligonucleotide designed to be complementary to the messenger ribonucleic acid sequence for the translation initiation codon of the E2 protein vital to replication of human papillomaviruses types 6 and 11. 14C-Labeled afovirsen was given as a single-dose intradermal injection in each of four warts of five patients to determine the time-dependent changes in concentration of intact afovirsen in genital warts and to determine the systemic absorption and elimination of radiolabeled compound. Intact afovirsen in genital warts was determined by high pressure liquid chromatography analysis of protease K digested extracts. Intact afovirsen was present in wart tissue for at least 72 hours at concentrations several times in excess of the estimated minimal inhibitory concentration of 1 mumol/L. Absorption of radiolabeled afovirsen from the injection site was rapid, with a peak plasma concentration achieved within 1 hour. Clearance of afovirsen was primarily attributable to slow metabolism, with about 30% of the radiolabel eliminated as 14C-CO2 in expired air over a 6-day period after dosing. Radioactivity eliminated in urine represented metabolites of afovirsen. From the clinical pharmacokinetic data presented here and from previously published pharmacokinetic data in rats, the disposition of afovirsen in humans appears to be relatively similar to that in rats. These data suggest that once or twice weekly dosing regimen in the clinic may be appropriate.

Analysis of multiple-dose bioequivalence studies.

In multiple-dose bioequivalence studies, it is possible at steady state to take repeated measurements of pharmacokinetic variables, such as area under the curve (AUC) and the maximum concentration (CMAX) of the blood concentration-time profile, within each period of a crossover design. We develop a bivariate random effects model for such a situation in a 2 x 2 crossover design using the natural log scale for AUC and CMAX that assumes no differential carryover effects and includes components for inter- and intrasubject variability with respect to both formulations. We derive the uniformly minimum variance unbiased estimators, which also happen to be restricted maximum likelihood estimators, and we provide a sample size formula.

Differential absorption of amoxicillin from the human small and large intestine.

Differences in extent of amoxicillin absorption from various regions of the gastrointestinal tract were determined and compared with the same dose administered orally. Nine healthy men were intubated at a proximal (duodenum or jejunum) or distal (ileum or colon) site with use of a 15-foot double lumen nasointestinal tube. Amoxicillin solutions (375 mg in 120 ml water) were delivered on 2 successive days as a bolus or a 4-hour infusion. Subjects were reintubated at another site and amoxicillin administration was repeated. Subjects with colonic intubation received only infusions. Finally, all subjects received an oral dose of amoxicillin solution. Plasma samples were obtained at 16 time points over a 10-hour period and assayed for amoxicillin by use of an HPLC method. Area under the concentration-time curve and the maximum plasma concentration were computed to evaluate amoxicillin absorption. Amoxicillin absorption was rate and site dependent in the gastrointestinal tract. The drug was well absorbed in the duodenum and jejunum, with no significant differences in absorption when administered as a bolus or 4-hour infusion, but absorption was decreased and rate dependent in the ileum, where more drug was absorbed as an infusion compared with a bolus. Amoxicillin was unabsorbed when infused in all colonic regions.

Site-differential gastrointestinal absorption of benazepril hydrochloride in healthy volunteers.

The absorption of benazepril-HCl (BZPH), an orally active angiotensin-converting enzyme (ACE) inhibitor, in various regions of the gastrointestinal (GI) tract was investigated using an intestinal intubation technique. Thirteen subjects completed this single-dose, three-phase sequential crossover study. The drug (20 mg) was administered either as a 4-hr colonic infusion (COLON) or as a small intestinal infusion (SI) in the first two phases and as an oral bolus solution (ORAL) in the third phase, with a 2-week washout between each treatment. Serial plasma and urine samples were collected for up to 4 days after dosing. BZPH and its active metabolite benazeprilat (BZPL) were determined using a gas chromatography/mass spectrometry method. BZPH was absorbed rapidly into the bloodstream (Tmax = 0.5 hr after ORAL). Absorption was also rapid for SI, with a postinfusion half-life (0.57 hr) nearly identical to that for ORAL (0.59 hr). The absorption rate after COLON was much slower (lower Cmax and longer Tmax) compared to that after SI, and the apparent half-life (1.7 hr) was prolonged. SI delivered 90%, whereas COLON delivered 23%, of the drug into the systematic circulation as compared to ORAL. BZPL was rapidly formed upon drug absorption. The metabolite-to-drug AUC ratios were comparable for SI and ORAL (8.9 vs 9.7), indicating that first-pass metabolism of BZPH was neither saturable nor input rate dependent. The metabolite-to-drug AUC ratio was reduced for COLON (5.0), indicating that the mechanism of absorption of BZPH in the colon may be different than that after SI and ORAL. Urinary recovery data were consistent with plasma data.(ABSTRACT TRUNCATED AT 250 WORDS)

Single-dose bioavailability of two extended-release lithium carbonate products.

The single-dose bioavailabilities of two extended-release lithium carbonate products and an immediate-release product were compared. Nonsmoking healthy volunteers ages 20-31 (n = 12) were randomly assigned to one of three groups and given three treatments, each separated by a one-week period. The treatments, which were given to each group in a different sequence, consisted of three 300-mg immediate-release lithium carbonate tablets (Lithotab), two 450-mg extended-release lithium carbonate tablets (Eskalith CR), and three 300-mg extended-release lithium carbonate tablets (Lithobid). Blood samples were collected just before drug administration and at intervals up to 48 hours afterward. Urine was collected for 96 hours. Plasma and urine lithium concentrations were determined by flame-emission spectrophotometry, and lithium pharmacokinetic values and the cumulative urinary excretion of lithium were computed. Mean maximum plasma lithium concentration (Cmax) differed significantly among all three lithium carbonate products. Eskalith CR produced a 40% lower Cmax and Lithobid a 25% lower Cmax than Lithotab; Lithobid produced a 23% higher Cmax than Eskalith CR. Lithotab had a significantly shorter mean time to maximum plasma lithium concentration than either extended-release product. Mean cumulative urinary excretion of lithium did not differ significantly among the three products. Two extended-release lithium carbonate products were not bioequivalent when given in single doses to healthy volunteers.