Absence of pharmacokinetic interaction between orally co-administered naproxen sodium and diphenhydramine hydrochloride.

The potential for a pharmacokinetic interaction between naproxen and diphenhydramine was examined in a randomized three-way crossover design with a 1-week washout between dosing. Single oral doses of 220 mg of naproxen sodium and 50 mg of diphenhydramine hydrochloride were given separately and together to 30 healthy male and female subjects. Heparinized blood samples obtained for 48 h postdose were assayed for plasma naproxen and diphenhydramine concentrations using validated high-performance liquid chromatography (HPLC) and gas chromatography (GC) assay methods, respectively. The area under the plasma concentration-time curve (AUC), maximum plasma concentrations (C(max)), time of C(max) (T(max)) and terminal exponential half-life (t(1/2,z)), were analysed for significant treatment differences by analysis of variance (ANOVA). Based on absence of significant treatment effects on AUC and C(max), single-dose oral co-administration of 220 mg of naproxen sodium with 50 mg of diphenhydramine hydrochloride does not alter the pharmacokinetics of either naproxen or diphenhydramine. Significant treatment differences seen for naproxen T(max) (0.3 h, males only) and diphenhydramine t(1/2,z) (0.8 h, females only) were minor and are unlikely to have therapeutic consequences. Thus, efficacy and safety of concomitant naproxen and diphenhydramine should not be altered due to a pharmacokinetic interaction.

Effects of oral cimetidine or ranitidine on the pharmacokinetics of intravenous enoxacin.

Enoxacin is a quinolone antibacterial agent currently being developed for oral and intravenous treatment of bacterial infections. Ten healthy subjects received a single 400-mg intravenous dose of enoxacin alone, with 300 mg (four times daily) oral cimetidine and with 150 mg (twice daily) oral ranitidine. Serial blood and urine samples were collected over a 48-hour period. Plasma and urine enoxacin concentrations were determined using a validated high-performance liquid chromatographic method. Mean enoxacin plasma concentrations were higher after administration of enoxacin with cimetidine than those measured after enoxacin alone or enoxacin with ranitidine. Cimetidine coadministration reduced enoxacin renal clearance by 26% and systemic clearance by 20%, and resulted in a 30% increase in elimination half-life. In contrast, concurrent ranitidine therapy did not significantly alter the pharmacokinetics of intravenous enoxacin.

Effect of gastric acidity on enoxacin absorption.

The effect of gastric acidity on the oral absorption of the quinolone antibiotic enoxacin was evaluated in 12 healthy volunteers. In a randomized, crossover design, single 400 mg oral enoxacin doses were administered on four occasions: alone, after 50 mg intravenous ranitidine, after 2 micrograms/kg subcutaneous pentagastrin, and after combined ranitidine and pentagastrin treatment. Gastric pH was monitored by radiotelemetry capsule for 4 hours after enoxacin administration. Ranitidine pretreatment reduced enoxacin oral bioavailability by an average of 26%. This effect was abolished when pentagastrin was used to maintain low gastric pH. Thus the ranitidine-induced decrease in enoxacin oral bioavailability probably results from a decrease in gastric acidity rather than from an interaction with ranitidine itself.

Theophylline dosage adjustment during enoxacin coadministration.

Based on the results of a previous study which demonstrated a 50% reduction in theophylline clearance during coadministration of 400 mg of enoxacin twice a day (b.i.d.), a sequential-design study was completed with seven nonsmoking, healthy adult female human volunteers. The subjects were given 200 mg of theophylline (Theo-Dur) orally every 12 h for 4 days. On day 5, the subjects began receiving 400 mg of enoxacin with each theophylline dose, and the dosage of theophylline was reduced to 100 mg b.i.d. This regimen was continued through day 8, after which enoxacin was discontinued. The theophylline dosage was increased to 200 mg b.i.d. on day 9, and theophylline monotherapy continued through day 12. The mean apparent theophylline clearance decreased by approximately 50% during enoxacin coadministration. No significant differences in mean theophylline maximum concentration in serum, time to maximum concentration in serum, lowest concentration observed, or area under the concentration-time curve during the steady-state dosing were observed before, during, or after enoxacin coadministration when the theophylline dosage was reduced to 100 mg b.i.d. Reduction of the theophylline dose by 50% at the onset of enoxacin dosing maintained constant theophylline concentrations in plasma. A return to the original theophylline dose immediately upon cessation of enoxacin therapy resulted in a transient 35% increase in theophylline concentrations in plasma which lasted 24 to 48 h before returning to preenoxacin values. Although a 50% reduction in the theophylline dose maintained constant mean theophylline concentrations when enoxacin was administered concomitantly, it appears that larger dose reductions (up to 75%) could be required in patients with high theophylline clearances. In addition, larger transient increases in the theophylline concentration in plasma may be observed in these patients upon cessation of enoxacin therapy if the theophylline dose is immediately returned to normal. Thus, it is recommended that theophylline concentrations in plasma be monitored when concurrent enoxacin therapy is required.

In vitro evaluation of the determinants of bactericidal activity of ampicillin dosing regimens against Escherichia coli.

An in vitro flow model was used to examine the influence of peak concentration (Cmax), the area under the antibiotic concentration-time curve (AUC), the magnitude of AUC above the MIC, and the aggregate time the antibiotic concentration exceeds the MIC (TMIC) on the bactericidal effect of ampicillin against Escherichia coli ATCC 12407. Bacteria in the log phase were exposed to therapeutically realistic drug regimens. Ampicillin concentration and bacterial density (CFU per milliliter) were measured over time. Four parameters reflecting bactericidal activity were quantitated: difference between initial and minimum and initial and final bacterial densities, area under the bacterial density-time curve, and a fourth parameter, sigma, which is a function of these three. Multiple regression analysis confirmed AUC as the major factor in predicting bactericidal activity. An AUC of greater than 70 micrograms.h/ml correlated with the lack of emergence of resistance.

Enoxacin absorption and elimination characteristics.

Enoxacin, a new fluoroquinolone antibiotic, is rapidly and extensively absorbed after oral administration and has a bioavailability independent of dose and only slightly delayed by concurrent food. Plasma concentrations are similar for both intravenous and oral administration. The t1/2 for enoxacin ranges from 4 to 6 hours, which allows effective twice-daily administration without significant accumulation. Plasma enoxacin concentrations may be slightly higher in elderly subjects, but this change does not necessitate dosage adjustment in older patients with adequate renal function. Enoxacin and ciprofloxacin decrease the clearance of coadministered theophylline, whereas ofloxacin does not appear to greatly alter methylxanthine clearance. Maalox (a magnesium-aluminium hydroxide antacid) significantly decreases the oral bioavailability of ciprofloxacin, ofloxacin and enoxacin, and use of these agents with antacids should be avoided. Enoxacin is a highly effective oral anti-infective agent with excellent bioavailability characteristics, a relatively slow rate of elimination and simple, well-defined requirements for dosage modification in patients with renal dysfunction.

The theophylline-enoxacin interaction: I. Effect of enoxacin dose size on theophylline disposition.

Theophylline interacts pharmacokinetically with a variety of other drugs. Recently enoxacin was found to change theophylline's disposition. In a four-subject, four-way crossover study enoxacin was administered every 12 hours at four levels (0, 25, 100, and 400 mg) for 14 doses. With the ninth dose of enoxacin, 200 mg theophylline was coadministered. Blood and urine samples were assayed by sensitive and specific assays for the parent drugs and their metabolites. Significant reduction in the formation of theophylline's three major metabolites occurred on coadministration of enoxacin. At the 400 mg dose level, enoxacin caused a threefold decrease in theophylline's plasma clearance, a fourfold decrease in the urinary recovery of 3-methylxanthine and 1,3-dimethylurate, and a threefold decrease in the recovery of 1-methylurate.

Correction for bacterial loss in in vitro dilution models.

A new method to correct for bacteria lost to dilution in in vitro kinetic models is presented which includes the influence of the stationary bacterial growth phase. The method imposes an upper limit on bacterial density, in contrast to previous methods.

Recent analytical methods for cephalosporins in biological fluids.

Since 1980, RP chromatography has been the principal analytical technique used for cephalosporins. This technology offers selectivity, accuracy, and ease of use. Most of the methods rely on protein precipitation and, to a lesser extent, solid-phase isolation or extraction procedures. The proper selection of a method depends on the analytical constraints imposed by the overall objective of the study. For example, pharmacokinetic datum interpretation mandates that the method be validated and provide specific and accurate results. LC is the preferred technique, since it not only meets these specifications but may also distinguish between the drug and metabolites. Those chromatographic methods which quantify several different cephalosporins are not desirable for pharmacokinetic datum interpretation, since accuracy and precision are usually compromised in order that many different drugs may be quantified in a single analysis. The proper selection of sample preparation method is dependent on the presence of potential interferences and the acceptable lower limit of quantitation. Protein precipitation methods offer ease of sample preparation but may suffer from nonselectivity. Solid-phase isolation and extraction procedures may increase selectivity and improve the limit of quantitation. Although LC provides specific and accurate results, clinical laboratories may prefer to use the less specific methods for therapeutic drug monitoring. In this case, microbiological, enzymatic, and fluorimetric methods offer improved sample throughput but less specificity. However, these methods should not be used for drugs that may have a low margin of safety or if the patient is on multiple-antibiotic therapy. Future methods may involve incorporating solid-phase isolation columns to enhance the specificity of chromatographic, microbiological, enzymatic, and fluorescence methods. Advancements in microbore column technology may allow improvements in the selectivity and sensitivity of LC methods. Many investigators prefer to use simple protein precipitation procedures for sample preparation because of sample throughput constraints. However, advances in robotic sample preparation may allow the more cumbersome solid-phase isolation or extraction techniques to be used to improved sample throughput and specificity.

The influence of food on the oral absorption of bevantolol.

The bioavailability of bevantolol was compared in 12 healthy volunteers given single doses of the drug as the HCl salt after an overnight fast, or 15 minutes before or after a standardized breakfast in a nonblind, randomized crossover design. Bevantolol was rapidly absorbed in all three treatment groups, with maximum concentrations (Cmax) observed at 1.0, 0.9, and 1.8 hours for the fasting, before breakfast, and after breakfast groups, respectively. Time to Cmax was significantly longer than fasting only when bevantolol was given after breakfast. Food ingestion did not significantly affect Cmax, total of absorbed drug, or the drug elimination rate. Since food only slightly decreases the drug absorption rate and has no measurable effect on the extent of drug absorption, the relationship of bevantolol administration to meals is not expected to influence therapeutic efficacy.

Influence of ampicillin elimination half-life on in-vitro bactericidal effect.

Escherichia coli ATCC 12407 was exposed in an in-vitro kinetic model to multiple dose ampicillin regimens differing in simulated drug elimination half-life but with equal dosage intervals and similar dose levels. Bacterial sensitivity was monitored during drug exposure. Greater bactericidal effect was observed with long half-life regimens. The development of rapid low-level resistance was not influenced by the half-life. Results suggest that in-vivo drug activity may be improved by increasing the drug elimination half-life.

Prevention of clindamycin-induced mortality in hamsters by Saccharomyces boulardii.

Saccharomyces boulardii, a yeast used in a number of countries for general and antibiotic-associated gastrointestinal illnesses, was examined for possible application in the prevention of clindamycin-induced mortality in the hamster colitis model. Hamsters were given free access to an aqueous 5% suspension of lyophilized yeast for 3 days before and 10 days after administration of a single oral clindamycin dose of from 0.2 to 0.8 mg/kg. Mortality was recorded in groups of 7 to 20 animals every 24 h for 10 to 30 days. Mean cecal concentrations of S. boulardii were greater than 10(6) CFU/ml throughout the yeast administration period. Yeast treatment significantly decreased cumulative percent mortality by an average of 29%. Death onset was not affected by yeast treatment. Cecitis was present in 86% of moribund animals (N = 95) and was absent in all surviving animals examined (N = 27). Toxigenic Clostridium difficile was isolated from 13 of 14 moribund hamsters examined. No adverse effects of the yeast treatment were observed in animals receiving S. boulardii without clindamycin. The results suggest that S. boulardii warrants further evaluation for the prevention of antibiotic-associated colitis.

Experimental meningitis in the rat: Haemophilus influenzae.

Leptomeningitis due to type b Haemophilus influenzae can be produced in infant rats (up to three weeks of age) by intranasal inoculation, and in animals up to three months of age by intraperitoneal inoculation. In infant animals, the pathogenesis appears to mimic the disease in human infants. Immunologic experiments indicate that antibody directed against the type b capsule (actively or passively acquired) will protect against bacteremia (by any route of inoculation) and the subsequent development of meningitis. However, antibody directed against other surface structures of H. influenzae b (alone or with anticapsular antibody) will protect against sustained bacteremia after any route of inoculation. Evaluation of antibiotic activity against this infection in rats is unreliable due to a marked age-dependent increase in antibiotic clearance. A means of mimicking human pharmacokinetics in rats is proposed. The rat model is useful for the study of H. influenzae meningitis provided certain limitations are recognized.

Effect of dose size on the pharmacokinetics of oral hydrocortisone suspension.

The pharmacokinetics of hydrocortisone were examined following single doses of 5-, 10-, 20-, and 40-mg hydrocortisone suspensions to healthy male volunteers. Endogenous hydrocortisone was suppressed by giving 2 mg of dexamethasone the night before hydrocortisone administration. Plasma samples obtained serially for 12 hr after hydrocortisone administration were assayed by reversed-phase high-pressure liquid chromatography using a fixed-wavelength (254 nm) UV absorbance detector. Drug absorption was rapid, with mean maximum plasma hydrocortisone concentrations occurring within 60 min of dosing. Subsequent drug elimination was monophasic with mean elimination half-lives increasing from 1.2 hr for the 5-mg dose to 1.7 hr for the 40-mg dose. Increase in AUC and Cmax with increasing dose were linear but not directly proportional to dose size. This was attributed to dose-dependent absorption or to loss of drug the first-pass through the liver.

An in vitro model for the study of antibacterial dosage regimen design.

A model was developed that is capable of simulating antibacterial agent concentration versus time profiles commonly observed following intravenous and intramuscular bolus injections, intravenous infusions, and oral doses, administered as single or multiple doses. The model consisted of two physical compartments separated by a membrane of a commercial hemodialyzer. The 1.08 m2 membrane surface area allowed rapid transmembrane passage of drugs and other small molecules, while membrane pore size prevented bacterial passage. These characteristics allowed bacteria in one of the two compartments of the model to be exposed to time-variant drug concentrations without affecting the number or concentration of bacteria. The model was used to study the effects of a multiple intravenous bolus dosage regimen of ampicillin on Escherichia coli ATCC 12407.

Oral hydrocortisone pharmacokinetics: a comparison of fluorescence and ultraviolet high-pressure liquid chromatographic assays for hydrocortisone in plasma.

Three fasted, male subjects received single 10-, 30-, and 50-mg oral doses of hydrocortisone tablets on separate occasions. Endogenous hydrocortisone was suppressed by giving 2 mg of dexamethasone 9 hr prior to dosing. Plasma samples obtained serially for 8 hr after hydrocortisone dosing were assayed by reversed-phase high-pressure liquid chromatography (HPLC) with UV detection and by normal-phase HPLC with fluorescence detection of the dansylhydrazine derivative of hydrocortisone. The two assay methods yielded equivalent plasma hydrocortisone concentrations. Metabolite interference was absent in both assay methods. Drug concentrations in plasma from all three doses of hydrocortisone were described by one-compartment open-model kinetics, with first-order absorption and elimination, and an absorption lag time. Mean Cmax values of 199, 393, and 419 ng/ml were obtained at 1.0, 1.0, and 1.7 hr following the 10-, 30-, and 50-mg doses, respectively. Hydrocortisone was cleared from plasma with an elimination half-life of approximately 1.5 hr. Within the dosage range studied, plasma levels of hydrocortisone were related, but not directly proportional, to dose size. This apparent lack of proportionality may be due to reduced drug availability or altered distribution with increasing dose.

Effect of dose size on the pharmacokinetics of intravenous hydrocortisone during endogenous hydrocortisone suppression.

The pharmacokinetics of hydrocortisone were examined following single intravenous doses of 5, 10, 20, and 40 mg hydrocortisone, as the sodium succinate salt, to healthy male volunteers. Endogenous hydrocortisone was suppressed by administration of 2 mg dexamethasone the night before hydrocortisone injection. Plasma samples obtained serially during 8 h after hydrocortisone injection were assayed by reverse-phase HPLC using a fixed wavelength (254 nm) ultraviolet detector. Initial concentrations of hydrocortisone in plasma were proportional to dose size. The subsequent decline in hydrocortisone concentrations was biphasic, and individual data sets were adequately described in terms of the pharmacokinetic two-compartment open model. Values of pharmacokinetic parameters were similar from the 5, 10, and 20 mg doses. Following the 40 mg dose, the overall elimination rate constant decreased, while the distribution volume, Vdss, and plasma clearance increased, in comparison with the values obtained from lower doses. Changes in the pharmacokinetics of hydrocortisone at high doses may be related to drug concentration-dependent changes in the binding of hydrocortisone to plasma proteins. Previously reported dose-dependent changes in some pharmacokinetic parameters following oral hydrocortisone are attributed to absorption rather than distribution or elimination effects.

Pharmacokinetics of cefuroxime in normal and impaired renal function: comparison of high-pressure liquid chromatography and microbiological assays.

The pharmacokinetics of cefuroxime were studied after a single dose of 750 mg was given intravenously to each of 21 male volunteers grouped according to their creatinine clearances; these clearances were 60 to 120, 20 to 59, and less than 20 ml/min per 1.73 m,2 respectively, for groups 1 (12 subjects), 2 (4 subjects), and 3 (5 subjects). Cefuroxime obeyed two-compartment model kinetics in all three groups. Initial serum levels of cefuroxime were approximately 130 microgram/ml in group 1 and 2 and 80 microgram/ml in group 3. the levels then declined rapidly for 0.5 to 1 h after injection. After that time, cefuroxime levels declined more slowly, and the elimination rate became monoexponential. The mean serum half-lives for cefuroxime in groups 2, 2, and 3 were 1.7, 2.4, and 17.6 h, respectively. Mean cefuroxime levels in serum were greater than 8 microgram/ml for 3 h in group 1, for 6 h in group 2, and for 30 h in group 3. Cumulative 24-h urinary excretion accounted for essentially 100% of the dose in group 1 and 2, and for 40% in group 3. Urine levels exceeded the minimal inhibitory concentration for susceptible organisms for more than 12 h in all groups. Cefuroxime distribution characteristics were independent of renal function. In patients with creatinine clearances less than 20 ml/min per 1.73 m2, doses of cefuroxime needs to be reduced. A microbiological disk diffusion assay and a high-pressure liquid chromatography assay for cefuroxime yielded statistically identical results, except for serum levels in uremic patients (group 3).