Ordered accumulation of mutations in HIV protease confers resistance to ritonavir.

Analysis of the HIV protease gene from the plasma of HIV-infected patients revealed substitutions at nine different codons selected in response to monotherapy with the protease inhibitor ritonavir. Mutants at valine-82, although insufficient to confer resistance, appeared first in most patients. Significant phenotypic resistance required multiple mutations in HIV protease, which emerged subsequently in an ordered, stepwise fashion. The appearance of resistance mutations was delayed in patients with higher plasma levels of ritonavir. Early mutants retained susceptibility to structurally diverse protease inhibitors, suggesting that dual protease inhibitor therapy might increase the duration of viral suppression.

Pharmacokinetics of sertindole in healthy young and elderly male and female subjects.

OBJECTIVE: The pharmacokinetic disposition of oral sertindole, a new selective antipsychotic compound, in young and elderly male and female subjects was investigated. STUDY DESIGN: A total of 46 subjects (12 young males, 11 elderly males, 11 young females, and 12 elderly females) received 4 mg/day sertindole (once a day; days 1 through 3) for 3 consecutive days, 8 mg/day sertindole for 3 consecutive days (days 4 through 6), and 12 mg/day sertindole for 10 consecutive days (days 7 through 16). RESULTS: Age and gender did not appear to have any effect on the plasma binding of sertindole, despite a lower albumin concentration in elderly subjects. After multiple dosing of 12 mg sertindole, the mean peak plasma concentration (Cmax) values for young and elderly female subjects were 20% and 31% higher than those observed for male subjects of comparable age (p < 0.05). The mean values for area under the plasma concentration-time curve [AUC(0-24)] of female subjects were 29% higher than those observed in male subjects of similar age (p < 0.05). There were no statistically significant age-related differences in Cmax and AUC(0-24) (or apparent total plasma clearance), and there were no gender- or age-related differences for the elimination rate constant or values for apparent volume of distribution during the terminal elimination phase after the last 12 mg dose on day 16 (p > 0.05). CONCLUSIONS: There are no differences between young and elderly subjects in the absorption and elimination of sertindole. The higher Cmax and AUC values in females may be a result of a higher extent of absorption or a dependence of sertindole clearance on lean body mass.

Characterization of the pharmacokinetics and pharmacodynamics of a new oral thromboxane A2-receptor antagonist AA-2414 in normal subjects: population analysis.

The pharmacokinetics and pharmacodynamics of AA-2414 [(+-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptano+ ++ ic acid] were evaluated in 39 healthy male subjects after four different oral multiple-dosing regimens. Population pharmacokinetic analysis with NONMEM showed plasma concentration-time profiles of AA-2414 to be best characterized by a two-compartment open model with zero-order input and first-order elimination. The final estimates for oral clearance, volume of distribution, and steady-state volume of distribution were 10.7 ml/hr/kg, 92.8 ml/kg, and 280 ml/kg, respectively; the corresponding coefficients of variation for interindividual variability were 21%, 10%, and 9%. The pharmacokinetic parameters were associated only with body weight. The residual variability was 25%. The ex vivo platelet aggregation response to U-46619, a thromboxane A2 mimetic, was significantly inhibited by AA-2414. The effect was found to be linearly related to plasma concentration with population estimates of 2.3 mumol/L and 2.38 for the baseline effect and slope, respectively; the corresponding coefficients of variation for interindividual variability were 22% and 38%. The residual variability was 39%. The leukotriene B4, thromboxane B2, and anti-platelet aggregation factor activity measurements were not significantly affected by administration of AA-2414.

Population analysis of the pharmacokinetics and pharmacodynamics of seratrodast in patients with mild to moderate asthma.

BACKGROUND: Seratrodast, a potent thromboxane receptor antagonist, is approved in Japan for the treatment of asthma and currently is being developed in the United States. METHODS: This was a phase II, randomized, double-blind, parallel-group, placebo-controlled 15-center study of seratrodast in patients with mild to moderate asthma. A total of 183 patients were randomly assigned to receive daily doses of either placebo, or 80 mg seratrodast, or 120 mg seratrodast for 8 weeks. Pharmacokinetic and pharmacodynamic modeling was carried out by means of the population approach. A two-compartment model with zero-order input and first-order elimination best fitted the plasma concentration-time data. RESULTS AND CONCLUSIONS: The pharmacokinetics of seratrodast were linear after single and multiple dosing for 8 weeks. The population estimates for oral clearance and apparent volume of distribution were 8.5 ml/hr/kg and 43.3 ml/kg, respectively. All pharmacokinetic parameters (the oral central compartment clearance, the volumes of distribution of the central and peripheral compartments, and the intercompartmental clearance) were estimated with a precision of 10% or less and were found to be associated with body weight. The residual variability was 30%. The values of oral clearance estimated in this study in male patients were similar to those previously estimated in healthy male subjects. Seratrodast at a dose of 120 mg daily produced an increase in forced expiratory volume in 1 second (FEV1) from baseline that was linearly correlated with its plasma concentrations. The average slope of the concentration-effect relationship was 0.222% and 0.470% per microgram/ml after single and multiple dosing, respectively. Interpatient variability in response was mainly affected by the initial severity of the disease. A lower percentage of predicted FEV1 (i.e., more severe obstruction) was associated with higher slopes, and greater increases in FEV1.

Pharmacokinetic interaction between ritonavir and clarithromycin.

BACKGROUND: Because ritonavir, a human immunodeficiency virus (HIV) protease inhibitor, and clarithromycin, a macrolide antibiotic used in the treatment of disseminated infection caused by Mycobacterium avium complex, are likely to be administered concurrently for treatment of patients with HIV and acquired immunodeficiency syndrome (AIDS), the drug interaction potential of these 2 agents was evaluated. Both clarithromycin and ritonavir are metabolized to a significant extent through cytochrome P450-mediated biotransformation and are potential inhibitors of these enzymes. OBJECTIVE: To evaluate the pharmacokinetic effects of concomitant administration of multiple doses of ritonavir and clarithromycin. METHODS: This was an open-label, randomized, 3-period crossover study. Ritonavir alone (200 mg every 8 hours), clarithromycin alone (500 mg every 12 hours), and ritonavir and clarithromycin in combination were administered to 22 healthy volunteers. Blood samples were collected on day 4 for determination of ritonavir, clarithromycin, and its metabolite 14-(R)-hydroxyclarithromycin. RESULTS: Ritonavir practically completely inhibited the formation of 14-(R)-hydroxyclarithromycin. The mean area under the plasma concentration-time curve (AUC) for clarithromycin increased by 77% with concomitant ritonavir, and the harmonic mean terminal half-life increased from 5 hours to 14 hours. Statistically significant increases in peak plasma concentration (31%) and minimum plasma concentration (182%) were also observed. The effect of concomitant clarithromycin administration on ritonavir pharmacokinetics was statistically significant but small, with a 12.5% increase in mean AUC and a 15.3% increase in peak plasma concentration. The terminal half-life increased from 3.47 to 3.87 hours with concomitant clarithromycin. CONCLUSIONS: No adjustment of the ritonavir dose is necessary when administered with clarithromycin. In addition, no changes in clarithromycin dose are warranted in patients with normal renal function.

Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics.

BACKGROUND: Divalproex sodium has been found to be efficacious in the prophylaxis of migraine headaches and the management of the manic phase of bipolar syndrome. Because amitriptyline is also prescribed in these patient populations, data are needed on their potential for interaction. METHODS: The effect of concomitant administration of divalproex sodium on the pharmacokinetics of amitriptyline and its active metabolite, nortriptyline, was investigated in an open-label, sequential, two-period phase I study. Ten healthy male and five healthy female subjects received 50 mg amitriptyline hydrochloride on two occasions: (1) alone (period 1) and (2) 2 hours after receiving the ninth dose of 500 mg divalproex sodium (Depakote) administered once every 12 hours (period 2). RESULTS: Amitriptyline area under the curve was increased 31% from the combined effect of decreased first-pass metabolism and inhibition of systemic metabolism. The elevated nortriptyline plasma levels reflected primarily the increase in amitriptyline concentrations but also appeared to involve modest inhibition of nortriptyline elimination. For the sum of amitriptyline and nortriptyline concentrations, the peak plasma concentration mean was 19% higher with concomitant divalproex dosing. The mean area under the curve for the sum of amitriptyline and nortriptyline concentrations was 42% higher with concomitant divalproex dosing than it was for dosing with amitriptyline alone. CONCLUSION: These results suggested that a lower dose of amitriptyline might be considered when divalproex is administered concomitantly.

Cefsulodin kinetics in healthy subjects after intramuscular and intravenous injection.

We evaluated cefsulodin kinetics in normal subjects after 250-, 500-, and 1,000-mg, intramuscular injections and 500-, 1,000-, and 2,000-mg 30-min intravenous infusions. Twelve plasma and four urine samples were collected in the first 12 and 24 hr. Plasma samples were analyzed by a new, highly precise high-performance liquid chromatographic procedure developed in our laboratory and urine samples were analyzed microbiologically, using Pseudomonas aeruginosa as the test organism. Mean calculated peak plasma levels from the 250-, 500-, and 1,000-mg intramuscular doses were 5.46, 11.81, and 19.40 microgram/ml. After 500-, 1,000-, and 2,000-mg intravenous infusions peak levels were 32.7, 65.7, and 190.1 microgram/ml. Data from the intramuscular doses were fitted to a one-compartment open kinetic model, yielding a mean elimination half-life (t1/2) of 1.9 hr. Data from the intravenous infusions were fitted to a two-compartment open model, with a mean beta-phase t1/2 of 1.6 hr. Mean 0- to 24-hr urinary recoveries after the three intramuscular doses were 50.0%, 54.5%, and 51.2% of total dose; after the three intravenous doses they were 60.4%, 52.4%, and 54.0%. Cefsulodin kinetics were shown to be consistent and orderly.

Cefsulodin kinetics in renal impairment.

Cefsulodin kinetics were determined after a 500-mg dose to normal subjects and patients with varying degrees of renal insufficiency, including those requiring hemodialysis. Elimination kinetics were described by a two-compartment model. Steady-state volume of distribution was 0.26 l/kg regardless of renal function. When glomerular filtration rate (GFR) was more than 80 ml/min, elimination half-life (t1/2) was 1.9 hr, total body clearance (ClT) was 2.01 ml/kg/min, and renal clearance (ClR) was 1.09 ml/kg/ in. When GFR ranged from 79 to 53 ml/min, t1/2 was 2.9 hr, ClT was 1.17 ml/kg/min, and ClR was 0.65 ml/kg/min. In subjects with moderate renal failure in whom GFR was 32 to 22 ml/min, t1/2 was 5.7 hr, Clt was 0.66 ml/kg/min, and ClR was 0.26 ml/kg/min. In anuric patients t1/2 was 13.0 hr. and ClT was 0.19 ml/kg/min or 9.5% of ClT in normal subjects. There was a linear relationship between ClT and GFR such that ClT = 0.19 + 0.017 GFR (r = 0.95). During hemodialysis the average plasma flow was 122 ml/min, dialyzer plasma clearance was 50.9 ml/min, plasma drug concentration was reduced by 60%, and t1/2 fell to 2.1 hr. After dialysis the elimination rate appeared to return to that in nondialysis studies. Therefore, renal failure reduces the ClT of cefsulodin. In hemodialysis patients the maintenance dose of cefsulodin should be reduced to 10% of normal and 60% of the dose should be given after hemodialysis.

The effect of zileuton on antipyrine and indocyanine green disposition.

The effects of single and multiple oral doses of zileuton on the pharmacokinetics of antipyrine and indocyanine green were studied in 16 healthy, nonsmoking adult men by means of a double-blind, randomized, parallel placebo-controlled design. Indocyanine green disposition was not significantly altered by zileuton. Plasma antipyrine clearance declined by 20% (p < 0.0005) and 52% (p < 0.0005) after single and multiple dose zileuton exposure, respectively. Total urinary recovery of unchanged antipyrine and metabolites decreased with zileuton exposure. Selective declines from baseline of 16% (p = 0.007) and 20% (p = 0.003) after single-dose zileuton and 30% (p < 0.0005) and 43% (p < 0.0005) after multiple-dose zileuton were detected in recovery of 4-hydroxyantipyrine and 3-hydroxymethylantipyrine, respectively. Urinary recovery of the N-demethylantipyrine metabolite norantipyrine and percent of conjugation of 3-hydroxymethylantipyrine were unchanged by zileuton. In conclusion, zileuton therapy has no detectable effect on indocyanine green disposition but exerts marked effects on antipyrine plasma and urine metabolite disposition.

Pharmacokinetic interactions between two human immunodeficiency virus protease inhibitors, ritonavir and saquinavir.

OBJECTIVE: To assess the pharmacokinetic interaction between ritonavir and saquinavir. METHODS: Ritonavir and saquinavir were administered in single doses to six groups of healthy volunteers in a two-way (saquinavir alone and ritonavir plus saquinavir for groups I through V) and a three-way (ritonavir alone, saquinavir alone, and ritonavir plus saquinavir for group VI) crossover manner with the following doses: group I, 200 mg saquinavir and 300 mg ritonavir; group II, 200 mg saquinavir and 600 mg ritonavir; group III, 400 mg saquinavir and 300 mg ritonavir; group IV, 400 mg saquinavir and 600 mg ritonavir; group V; 600 mg saquinavir and 200 mg ritonavir; group VI, 600 mg saquinavir and 600 mg ritonavir. RESULTS: Coadministration of ritonavir markedly increased the area under the plasma concentration-time curve (AUC) and peak concentration of saquinavir (> 50-fold and 22-fold, respectively). For a constant ritonavir dose, the pharmacokinetics of saquinavir were relatively proportional to dose. For a constant saquinavir dose, the increase in saquinavir concentration tended to be less than proportional to ritonavir dose. Ritonavir reduced intersubject variability in the saquinavir AUC from 60% to 28%. The in vivo inhibition constant was 0.025 +/- 0.020 micrograms/ml with noncompartmental estimation and 0.0164 +/- 0.0004 micrograms/ml with nonlinear mixed-effects model compartmental analysis. Saquinavir showed no clinically significant effect on the pharmacokinetics of ritonavir (+6.4% in AUC). The regimens were well tolerated. CONCLUSIONS: The large effect of ritonavir on the pharmacokinetics of saquinavir is consistent with a large reduction of saquinavir first-pass metabolism and postabsorptive clearance. Given the limited bioavailability of saquinavir given in the hard gelatin capsule formulation, this drug interaction is expected to have implications in the use of protease inhibitors in the management of human immunodeficiency virus infection.

A single-dose study to define tiagabine pharmacokinetics in pediatric patients with complex partial seizures.

We report an open-label study of 25 children with complex partial seizures that assessed the pharmacokinetics and safety of a single dose of approximately 0.1 mg/kg tiagabine. The children received their usual individualized regimen of one concomitant antiepilepsy drug (AED) throughout the study. Seventeen children were receiving an inducing AED (carbamazepine or phenytoin); eight were receiving valproate. Tiagabine was well tolerated. Dose-normalized Cmax was higher in children taking valproate (18.2 +/- 5.0 ng/mL/mg) than in the induced children (14.8 +/- 6.9 ng/mL/mg), but the difference was not statistically significant. Dose-normalized area under the plasma concentration-time curve from time zero to infinite time was significantly higher (p = 0.002) in children taking valproate (176.5 +/- 54.7 ng.hr/mL/mg) than in induced children (92.4 +/- 56.7 ng.hr/mL/mg). Similarly, oral clearance in the children taking valproate (96 +/- 39 mL/min) was half that of the induced children (207 +/- 91 mL/min). Half-life in children taking valproate (5.7 hr) was almost twice that for the induced children (3.2 hr), and the elimination rate constant was significantly lower (p < 0.02) for the children taking valproate than for the induced children. Volume of distribution was similar in the children taking valproate (52 +/- 9 L) and the induced children (59 +/- 29 L). This is consistent with observations in adults taking tiagabine with inducing AEDs or valproate. Exploratory regressions on these data in children and previous data in adults showed fairly strong relationships between body size and tiagabine clearance and volume of distribution, with body size explaining about 40 to 50% of the variability. When adjusted per kg body weight, clearance and volume were greater in children than adults. When adjusted per m2 body surface area, clearance and volume were more similar in adults and children.

The influence of age on the pharmacokinetics of temafloxacin.

The pharmacokinetics of temafloxacin were assessed in 12 healthy young and 12 healthy elderly volunteers after oral administration of a single 600 mg dose. Groups were balanced with respect to gender distribution. Plasma and urine temafloxacin concentrations were determined using high-performance liquid chromatography. Compared with the young group, mean peak plasma concentration in the elderly was 45% higher, the area under the plasma concentration versus time curve was 70% higher, the terminal elimination half-life was 18% higher, and the apparent beta-phase volume of distribution was 30% lower in the elderly group. Gender differences were small and largely disappeared when data were normalized to body surface area. As the difference in elimination half-life was small, alteration of the usual twice-daily dosage regimen is not necessary in the elderly. However, elderly patients with decreased renal function (creatinine clearance less than 40 mL/min) will need dosage reduction, similar to that recommended for younger patients.

Pharmacokinetics of temafloxacin after multiple oral administration.

Four multiple dose studies involving 102 healthy volunteers were reviewed to determine the sources of intersubject variability in the pharmacokinetics of temafloxacin. As a result of the preferential distribution of temafloxacin into muscle, liver and kidney compared with adipose tissue, the best anthropometric explanatory variable was found to be lean body mass, rather than total body mass or body surface area. Single dose studies have confirmed that the distribution volume of temafloxacin is smaller in subjects in whom the lean body mass:total body mass ratio is low, notably in females, the elderly, and those with hepatic impairment. Average creatinine clearance for the volunteers included in this analysis was normal (109 +/- 29 ml/min), and renal function was only a marginally significant covariate; however, renal clearance accounts for 60 to 70% of total clearance (CLT) and has been shown to be a major factor in the elderly, as well as in patients with renal or hepatic impairment. Since temafloxacin is partially reabsorbed renally, urine flow rate was found to be a potentially important secondary factor. Overall, the pharmacokinetics of temafloxacin are essentially linear, with steady-state plasma concentrations at trough (Cssmin) and 2h postdose (Css2h) averaging slightly more than 0.5 and 1.0 mg/L per 100mg administered every (q) 12h. For example, mean Cssmin and peak steady-state plasma concentration (Cssmax) values after administration of temafloxacin 600mg q12h were 3.3 +/- 1.1 and 6.2 +/- 1.8 mg/L, respectively. Total apparent clearance (CLT/F) and the terminal elimination half-life (t1/2) averaged 11 L/h (184 ml/min) per 55kg lean body mass and 8.4h, respectively. Considering that the data reviewed came from 4 studies with doses ranging from 100 to 800mg q12h, the intersubject coefficients of variation were low for an orally administered drug, ranging from 15.4% for t1/2, 20.6% for Css2h, 21.2% for CLT/F and 25% for Cssmin.

The effect of food on the bioavailability of temafloxacin. A review of 3 studies.

Temafloxacin is a new fluoroquinolone antibacterial agent. Previous pharmacokinetic studies have shown that the extent of absorption of temafloxacin is independent of dose and that the dispositional pharmacokinetics are linear. The pharmacokinetics of 3 tablet formulations of temafloxacin were investigated in phase I studies in healthy adult volunteers, to determine whether the bioavailability is altered by the presence of food. Results of these studies indicate that the absorption of temafloxacin is slightly enhanced by concomitant administration of food. Thus, special coordination of temafloxacin administration and meals appears to be unnecessary.

Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions.

This article reviews the information available to assist pharmacokineticists in the prediction of metabolic drug interactions. Significant advances in this area have been made in the last decade, permitting the identification in early drug development of dominant cytochrome P450 (CYP) isoform(s) metabolising a particular drug as well as the ability of a drug to inhibit a specific CYP isoform. The major isoforms involved in human drug metabolism are CYP3A, CYP2D6, CYP2C, CYP1A2 and CYP2E1. Often patients are taking multiple concurrent medications, and thus an assessment of potential drug-drug interactions is imperative. A database containing information about the clearance routes for over 300 drugs from multiple therapeutic classes, including analgesics, anti-infectives, psychotropics, anticonvulsants, cancer chemotherapeutics, gastrointestinal agents, cardiovascular agents and others, was constructed to assist in the semiquantitative prediction of the magnitude of potential interactions with drugs under development. With knowledge of the in vitro inhibition constant of a drug (Ki) for a particular CYP isoform, it is theoretically possible to assess the likelihood of interactions for a drug cleared through CYP-mediated metabolism. For many agents, the CYP isoform involved in metabolism has not been identified and there is substantial uncertainty given the current knowledge base. The mathematical concepts for prediction based on competitive enzyme inhibition are reviewed in this article. These relationships become more complex if the inhibition is of a mixed competitive/noncompetitive nature. Sources of uncertainty and inaccuracy in predicting the magnitude of in vivo inhibition includes the nature and design of in vitro experiments to determine Ki, inhibitor concentration in the hepatic cytosol compared with that in plasma, prehepatic metabolism, presence of active metabolites and enzyme induction. The accurate prospective prediction of drug interactions requires rigorous attention to the details of the in vitro results, and detailed information about the pharmacokinetics and metabolism of the inhibitor and inhibited drug. With the discussion of principles and accompanying tabulation of literature data concerning the clearance of various drugs, a framework for reasonable semiquantitative predictions is offered in this article.

Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents.

Ritonavir is 1 of the 4 potent synthetic HIV protease inhibitors, approved by the US Food and Drug Administration (FDA) between 1995 and 1997, that have revolutionised HIV therapy. The extent of oral absorption is high and is not affected by food. Within the clinical concentration range, ritonavir is approximately 98 to 99% bound to plasma proteins, including albumin and alpha 1-acid glycoprotein. Cerebrospinal fluid (CSF) drug concentrations are low in relation to total plasma concentration. However, parallel decreases in the viral burden have been observed in the plasma, CSF and other tissues. Ritonavir is primarily metabolised by cytochrome P450 (CYP) 3A isozymes and, to a lesser extent, by CYP2D6. Four major oxidative metabolites have been identified in humans, but are unlikely to contribute to the antiviral effect. About 34% and 3.5% of a 600 mg dose is excreted as unchanged drug in the faeces and urine, respectively. The clinically relevant t1/2 beta is about 3 to 5 hours. Because of autoinduction, plasma concentrations generally reach steady state 2 weeks after the start of administration. The pharmacokinetics of ritonavir are relatively linear after multiple doses, with apparent oral clearance averaging 7 to 9 L/h. In vitro, ritonavir is a potent inhibitor of CYP3A. In vivo, ritonavir significantly increases the AUC of drugs primarily eliminated by CYP3A metabolism (e.g. clarithromycin, ketoconazole, rifabutin, and other HIV protease inhibitors, including indinavir, saquinavir and nelfinavir) with effects ranging from an increase of 77% to 20-fold in humans. It also inhibits CYP2D6-mediated metabolism, but to a significantly lesser extent (145% increase in desipramine AUC). Since ritonavir is also an inducer of several metabolising enzymes [CYP1A4, glucuronosyl transferase (GT), and possibly CYP2C9 and CYP2C19], the magnitude of drug interactions is difficult to predict, particularly for drugs that are metabolised by multiple enzymes or have low intrinsic clearance by CYP3A. For example, the AUC of CYP3A substrate methadone was slightly decreased and alprazolam was unaffected. Ritonavir is minimally affected by other CYP3A inhibitors, including ketoconazole. Rifampicin (rifampin), a potent CYP3A inducer, decreased the AUC of ritonavir by only 35%. The degree and duration of suppression of HIV replication is significantly correlated with the plasma concentrations. Thus, the large increase in the plasma concentrations of other protease inhibitors when coadministered with ritonavir forms the basis of rational dual protease inhibitor regimens, providing patients with 2 potent drugs at significantly reduced doses and less frequent dosage intervals. Combination treatment of ritonavir with saquinavir and indinavir results in potent and sustained clinical activity. Other important factors with combination regimens include reduced interpatient variability for high clearance agents, and elimination of the food effect on the bioavailibility of indinavir.

Effect of cimetidine on the pharmacokinetics of temafloxacin.

Cimetidine, a widely prescribed histamine H2-receptor antagonist, is known to interact with a variety of drugs; consequently, it is important to determine its potential for interaction with any new drug. The interaction between cimetidine and a new quinolone, temafloxacin, has been examined in an open randomised 2-period crossover study in 12 healthy adults. Half the volunteers received cimetidine 400mg 3 times daily for 8 days. On day 5, a single temafloxacin 400mg dose was administered. No other drugs were allowed during this period. The other volunteers did not receive cimetidine (or any other drugs) for an 8-day period except for temafloxacin 400mg on day 5. Blood and urine were sampled serially after temafloxacin administration and daily thereafter until the last day of the study. A 2-week washout period preceded crossover. Pharmacokinetic analyses showed that cimetidine did not affect the rate or extent of temafloxacin absorption, as evidenced by unchanged peak plasma concentration, time to peak plasma concentration, and terminal-phase volume of distribution. However, renal and total clearance values for temafloxacin were reduced by 19%, and elimination half-life and area under the concentration vs time curve were increased in the presence of cimetidine. The most likely mechanism underlying these effects is inhibition by cimetidine of tubular secretion of temafloxacin in the kidney. The lack of clinically significant adverse effects and the small magnitude of the reduction in temafloxacin clearance suggest that the interaction is of little clinical consequence.

Effect of antacid medication on the pharmacokinetics of temafloxacin.

The effect of an antacid drug (Maalox 70) on the pharmacokinetics of temafloxacin was studied in 12 healthy young volunteers. The study was designed as a randomised open 2-period crossover trial in which temafloxacin was administered alone and with Maalox 70. In both treatments, temafloxacin was administered as a single oral 400mg dose on the morning of day 2. In the antacid regimen, 8 doses of Maalox 70 were administered every 2h on day 1, starting at 8am and ending with the last dose at 10pm; 5 doses were given on day 2, at 2.5 and 1h before administration of temafloxacin and 1, 3 and 5h after the temafloxacin dose. With coadministration of Maalox 70, peak plasma temafloxacin concentrations (Cmax) were reduced to 44.6% (+/- 24.5), and AUC(0-infinity) was reduced to 39.8% (+/- 17.4) of the corresponding values obtained when temafloxacin was given alone. Urinary excretion of temafloxacin was reduced to 46.0% (+/- 13.7) of that observed when temafloxacin was administered alone. Time to peak plasma concentration (tmax = 1.8h) was not affected by antacid administration. Comparable or greater antacid-associated reductions in relative bioavailability have been reported for other quinolones. As with other quinolones, the concurrent administration of temafloxacin and antacids should be avoided.

Determination of a new 5-lipoxygenase inhibitor, zileuton, and its inactive N-dehydroxylated metabolite in plasma by high performance liquid chromatography.

A rapid and sensitive assay was developed for the measurement of plasma concentrations of zileuton racemate, a potent inhibitor of 5-lipoxygenase. Zileuton and its inactive N-dehydroxylated metabolite were extracted from human, monkey, and rat plasma by use of a solid-phase extraction column (Analytichem Bond Elut). The compounds were then separated by reverse-phase high performance liquid chromatography (HPLC) on a Supelcosil LC-18 column and quantified on the basis of ultraviolet absorption at 260nm relative to an internal standard. The extraction recovery of zileuton, as determined by HPLC assay, was 77.9 +/- 1.7%. Recovery of the metabolite was 85.8 +/- 0.7%. Calibration curves for both compounds were linear over the zileuton concentration range 0.01 to 10.0 mg/L (correlation coefficients > 0.987), while the intra- and interassay coefficients of variation were < 15.6%. In practice, > 97% of blinded daily spiked control samples for zileuton and > 90% of those for the metabolite were within 10% of their target concentrations.

Lack of pharmacokinetic interaction between zileuton and phenytoin in humans.

A randomised double-blind crossover study was undertaken in 20 healthy adult male volunteers to assess the effects of multiple oral dose administration of zileuton (600mg every 6 hours for 8 days) on the single dose pharmacokinetics of phenytoin 300mg. Serial blood samples were collected up to 72 hours after phenytoin administration and plasma concentrations were determined by high performance liquid chromatography. Pharmacokinetic data were analysed utilising noncompartmental and Michaelis-Menten-based population pharmacokinetic analysis. Zileuton did not significantly alter the peak plasma concentration, time to peak plasma concentration, and area under the plasma concentration-time curve of phenytoin. Moreover, population analysis revealed no significant effect of zileuton on the Michaelis-Menten parameters of phenytoin. Thus, coadministration of multiple doses of zileuton (2.4 g/day) did not significantly affect the single dose pharmacokinetics of phenytoin.