Biomedical subjects

R F Frye

Publications and source records attributed to R F Frye.

At least 19 recordsLinked to original sources

PubMed2006

Evaluation of flurbiprofen urinary ratios as in vivo indices for CYP2C9 activity.

AIMS: We investigated flurbiprofen pharmacokinetics in 12 volunteers to develop a phenotypic trait measure that correlates with the fractional clearance to 4'-hydroxyflurbiprofen. The effect of the CYP2C9 inhibitor fluconazole on flurbiprofen metabolism was also evaluated. METHODS: Flurbiprofen pharmacokinetics were evaluated before and after the first and seventh doses of fluconazole. The urinary recovery ratio was calculated as FLRR = 4'-OHF/[4'-OHF + F(tot)] and the urinary metabolic ratio was calculated as FLMR = 4'-OHF/F(tot), where 4'-OHF and F(tot) represent total (conjugated and unconjugated) amounts recovered in urine. RESULTS: There was a statistically significant relationship between the 4'-OHF formation clearance (4OHCLf) and both the 8-h FLRR and the 8-h FLMR with and without administration of fluconazole. The flurbiprofen apparent oral clearance (CL/F) was decreased by 53% [90% confidence interval (CI) -58, -48] and 64% (90% CI -69, -59), respectively, after administration of one and seven doses of fluconazole when compared with administration of flurbiprofen alone; similarly, the 4OHCLf decreased by 69% (90% CI -74, -64) and 78% (90% CI -83, -73), the 8-h FLRR decreased by 35% (90% CI -41, -29) and 40% (90% CI -46, -35) and the 8-h FLMR decreased by 61% (90% CI -65, -58) and 67% (90% CI -70, -63). The magnitude of decrease in CL/F and 4OHCLf was greater after seven doses compared with after one dose of fluconazole (P < 0.005). CONCLUSIONS: This study provides strong evidence that both the 8-h FLRR and the 8-h FLMR are suitable phenotypic indices for CYP2C9 activity.

Administration, Oral↗

PubMed2005

The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in human liver microsomes and healthy subjects.

AIMS: Rosiglitazone, a thiazolidinedione antidiabetic medication used in the treatment of Type 2 diabetes mellitus, is predominantly metabolized by the cytochrome P450 (CYP) enzyme CYP2C8. The anti-infective drug trimethoprim has been shown in vitro to be a selective inhibitor of CYP2C8. The purpose of this study was to evaluate the effect of trimethoprim on the CYP2C8 mediated metabolism of rosiglitazone in vivo and in vitro. METHODS: The effect of trimethoprim on the metabolism of rosiglitazone in vitro was assessed in pooled human liver microsomes. The effect in vivo was determined by evaluating rosiglitazone pharmacokinetics in the presence and absence of trimethoprim. Eight healthy subjects (four men and four women) completed a randomized, cross-over study. Subjects received single dose rosiglitazone (8 mg) in the presence and absence of trimethoprim 200 mg given twice daily for 5 days. RESULTS: Trimethoprim inhibited rosiglitazone metabolism both in vitro and in vivo. Inhibition of rosiglitazone para-hydroxylation by trimethoprim in vitro was found to be competitive with apparent K(i) and IC(50) values of 29 microm and 54.5 microm, respectively. In the presence of trimethoprim, rosiglitazone plasma AUC was increased by 31% (P = 0.01) from 2774 +/- 645 microg l(-1) h to 3643 +/- 1051 microg l(-1) h (95% confidence interval (CI) for difference 189, 1549), and half-life was increased by 27% (P = 0.006) from 3.3 +/- 0.5 to 4.2 +/- 0.8 h (95% CI for difference 0.36, 1.5). Trimethoprim reduced the para-O-sulphate rosiglitazone/rosiglitazone and the N-desmethylrosiglitazone/rosiglitazone AUC(0-24) ratios by 22% and 38%, respectively. CONCLUSIONS: These results indicate that trimethoprim is a competitive inhibitor of CYP2C8-mediated rosiglitazone metabolism in vitro and that trimethoprim administration increases plasma rosiglitazone concentrations in healthy subjects.

Adult↗

PubMed2005

Pharmacokinetics of intraperitoneal cefazolin and ceftazidime coadministered to CAPD patients.

PURPOSE: Guidelines for empiric treatment of PD-related peritonitis published in 2000 recommend concurrent intraperitoneal (IP) cefazolin and ceftazidime. The pharmacokinetics (PK) of these agents combined have not been studied. This study was designed to determine the PK of combined IP cefazolin and ceftazidime in CAPD patients. DESIGN: Prospective PK study in seven non-infected CAPD patients. PROCEDURES: Patients had a peritoneal equilibration test (PET), then received one IP dose of cefazolin and ceftazidime (15 mg/kg each) co-administered over a 4-hour dwell, then performed three CAPD exchanges over the next 16 hours. Serum and dialysate samples collected over the 20-hour study period were assayed for drug concentrations by HPLC. OUTCOME MEASURES: PK parameters. STATISTICAL METHODS: Correlations were tested between PET and PK parameters using the Pearson-product correlation coefficient. MAIN FINDINGS: Serum cefazolin and ceftazidime levels exceeded the minimum inhibitory concentrations for susceptible organisms (8 mg/L) throughout the 20 hour study period. Mean cefazolin and ceftazidime PK parameters included: bioavailability, 71% and 63%; elimination rate constant, 0.031 and 0.045 h -1 ; total clearance, 5.8 and 16.0 ml/min; peritoneal clearance, 1.6 and 3.9 ml/min; renal clearance, 2.3 and 3.9 ml/min, respectively. Predictive equations suggest that 1000 mg IP of cefazolin and of ceftazidime every 24 hours would produce average steady-state trough serum cefazolin and ceftazidime concentrations of 70 +/- 52 mg/L and 17 +/- 7 mg/L, respectively. There was no correlation between PET and PK parameters. CONCLUSIONS: Co-administration did not adversely affect the PK of either agent. IP cefazolin and ceftazidime (15 mg/kg) produced adequate serum and dialysate concentrations in CAPD patients for 20 hours. PK predictions suggest that most patients would achieve adequate cefazolin and ceftazidime concentrations with 1000 mg IP once-daily. Anuric patients and those with significant residual renal function may require a more individualized approach.

Adult↗

PubMed2001

High-performance liquid chromatographic assay for acetaminophen glucuronide in human liver microsomes.

A rapid and specific high-performance liquid chromatographic assay was developed for the determination of acetaminophen glucuronide formed by human liver microsomes. In addition, incubation conditions were systematically evaluated. Conditions that yielded the optimal rate of acetaminophen glucuronide formation over various concentrations of acetaminophen (0.15-30 mM) consisted of the following: 0.1 M potassium phosphate buffer, 1 mM magnesium chloride, 30 microg/mg alamethicin, 4 mM uridine 5'-diphosphoglucuronic acid at a pH of 7.1. Alamethicin produced higher and more consistent APAPG formation rates compared to Brij-58. Adding saccharolactone to the incubation medium reduced the velocity of the reaction. Acetaminophen glucuronide, acetaminophen, and the internal standard (paraxanthine), were analyzed on a C18 column with UV detection at 250 nm. The mean correlation coefficient (r2) of the standard curves for acetaminophen glucuronide was >0.99 over the range of 0.1-25 nmol. The intra- and inter-day coefficients of variation were <4%. This method is suitable for in vitro studies using acetaminophen glucuronide formation as an index reaction for UGT activity.

Acetaminophen↗

PubMed2001

Cefazolin dialytic clearance by high-efficiency and high-flux hemodialyzers.

Cefazolin dialytic clearance has not been determined in patients undergoing hemodialysis with high-efficiency or high-flux dialyzers. The objective of this study is to determine the pharmacokinetics and dialytic clearance of cefazolin and develop dosing strategies in these patients. Twenty-five uninfected subjects undergoing chronic thrice-weekly hemodialysis were administered a single dose of intravenous cefazolin (15 mg/kg) after their standard hemodialysis session. Fifteen subjects underwent hemodialysis with high-efficiency hemodialyzers, and 10 subjects underwent hemodialysis with high-flux hemodialyzers. Blood and urine samples were collected serially over the interdialytic period, during the next intradialytic period, and immediately after the next hemodialysis session. Serum and urine concentrations of cefazolin were determined by high-performance liquid chromatography. Differential equations describing a two-compartment model were fit to the cefazolin serum concentration-time data over the study period, and pharmacokinetic parameters were determined. Mean dialytic clearance values for cefazolin were significantly greater in the high-flux group compared with the high-efficiency group (30.9 +/- 6.52 versus 18.0 +/- 6.26 mL/min, respectively; P: < 0.05). Cefazolin reduction ratios were significantly greater (0.62 +/- 0.08 versus 0.50 +/- 0.07; P: < 0.005) in the high-flux group compared with the high-efficiency group and correlated well with equilibrated urea reduction. The pharmacokinetic model developed from patient data was used to simulate cefazolin serum concentration data for high-efficiency and high-flux dialyzers. Cefazolin doses of 15 or 20 mg/kg after each hemodialysis session maintained adequate serum concentrations throughout a 2- or 3-day interdialytic period regardless of hemodialyzer type.

Adult↗

PubMed2001

Minimal in vivo activation of CYP2C9-mediated flurbiprofen metabolism by dapsone.

Dapsone has been shown to activate flurbiprofen 4'-hydroxylation by expressed CYP2C9 enzyme and in human liver microsomes. It has been suggested that this observation is due to substrate cooperativity on enzyme activity; however, the in vivo relevance of this observation is unknown. Thus, the purpose of this study was to evaluate whether dapsone can act cooperatively with flurbiprofen to activate the in vivo metabolism of flurbiprofen to 4'-hydroxyflurbiprofen. Twelve healthy subjects received single-dose flurbiprofen 50 mg on three occasions: alone (visit A); 2 h after a single dapsone 100-mg dose (visit B); and 2 h after the seventh daily dose of dapsone 100 mg (visit C). Concentrations of flurbiprofen and 4'-hydroxy flurbiprofen in plasma and urine and dapsone and N-acetyldapsone in plasma were determined by HPLC. Flurbiprofen pharmacokinetic parameters for the three visits were estimated by non-compartmental methods and compared in the absence and presence of dapsone. Flurbiprofen apparent oral clearance was increased by approximately 11% (P < 0.02) after dapsone 100 mg for 7 days. Dapsone plasma concentrations averaged 5 +/- 2 microM after a single dose and 11 +/- 4 microM after seven daily 100 mg doses. These dapsone plasma concentrations were within the range of concentrations producing activation of flurbiprofen metabolism by CYP2C9 in vitro. These results are consistent with the hypothesis that dapsone does influence flurbiprofen metabolism in vivo in a cooperative way to enhance metabolism. However, the magnitude of effect is substantially less than observed in vitro.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2001

Characterization of tubular functional capacity in humans using para-aminohippurate and famotidine.

BACKGROUND: Renal drug excretion by glomerular filtration and active tubular secretion may be altered by factors such as acute and chronic renal disease, nephrotoxins, and drug interactions. Thus, accurate and reproducible methods for quantitation of glomerular filtration rate (GFR) and tubular functional capacity are critical. METHODS: We utilized a four-step sequential infusion method to characterize anionic [para-aminohippurate (PAH)] and cationic (famotidine) tubular functional capacity in healthy volunteers. Filtration and secretion rates were quantitated from renal clearance and iothalamate-derived GFR determinations. RESULTS: Concentration-dependent renal clearance of PAH was observed at plasma concentrations> 100 mg/L; renal clearances were 442 +/- 131 (mean +/- SD), 423 +/- 94, 233 +/- 45, and 152 +/- 18 mL/min/1.73 m2 at plasma concentrations of 18 +/- 2, 92 +/- 5, 291 +/- 47 and 789 +/- 28 mg/L, respectively. The apparent affinity (Km) and maximum secretory capacity (TmPAH) were 141 +/- 70 mg/L and 71 +/- 16 mg/min/1.73 m2, respectively. The unbound renal clearance and tubular secretory clearance of famotidine were 384 +/- 70 and 329 +/- 78 mL/min/1.73 m2, respectively, and were not significantly correlated with the unbound plasma concentrations, which ranged from 126 to 2659 ng/mL. The rate of tubular secretion was linear at unbound plasma concentrations up to 2659 ng/mL. CONCLUSIONS: These data indicate that a sequential infusion method using PAH may be used to characterize the anionic secretory component of proximal tubular function. The tubular clearance of famotidine may be a suitable index of the cationic secretory capacity of the proximal tubule in humans. Saturation of the cationic secretory pathway was not observed, and further investigation into parallel pathways of cationic secretion, such as p-glycoprotein, may be warranted.

Adult↗

PubMed2000

Sensitive and specific high-performance liquid chromatographic assay for 4'-hydroxyflurbiprofen and flurbiprofen in human urine and plasma.

A high-performance liquid chromatographic assay has been developed for the simultaneous quantitation of flurbiprofen and its major metabolite, 4'-hydroxyflurbiprofen, in urine and plasma. No extraction procedure was necessary for analysis of these compounds, which reduced time involved in sample preparation. The analytes were separated on a Brownlee Spheri-5 C18 column with a mobile phase of acetonitrile-20 mM dibasic potassium phosphate pH 3 buffer (40:60, v/v). Fluorescence detection was utilized with an excitation wavelength of 260 nm and an emission wavelength of 320 nm, providing excellent sensitivity. The limit of quantitation for 4'-hydroxyflurbiprofen and flurbiprofen was 0.25 microg/ml in urine and 0.05 microg/ml and 0.25 microg/ml, respectively, in plasma. All components were eluted within 16 min. Intra-day, inter-day, freeze-thaw, and in process stability were tested for both compounds and the coefficient of variation was less than 14% in all cases. This method provides a sensitive and specific assay for the detection of flurbiprofen and 4'-hydoxyflurbiprofen in urine and plasma and is suitable for use in in vivo studies evaluating the regulation of CYP2C9 activity.

Aryl Hydrocarbon Hydroxylases↗

PubMed2000

In vivo modulation of CYP enzymes by quinidine and rifampin.

BACKGROUND: The metabolism of drugs and other xenobiotics is mediated by enzymes whose activities can be modulated by different compounds. The activities of these modulators have the potential to be used to optimize drug action, prevent toxicity, or identify the enzymes involved in a reaction. This approach requires that selective agents be used for specific enzymes. However, selectivity of action has been poorly characterized in vivo. METHODS: This study investigated the effect of 3 and 28 days of treatment with quinidine (200 mg daily) and rifampin (INN, rifampicin) (600 mg daily) on the activities of four cytochrome P450 enzymes and N-acetyltransferase in 28 healthy young male volunteers divided into three groups with a cocktail of drug probes used, including caffeine, mephenytoin, debrisoquin (INN, debrisoquine), and dapsone. RESULTS: Quinidine selectively and almost completely inhibited the activity of CYP2D6 from day 3 through day 28 without affecting any other enzymes. Rifampin showed evidence of time-dependent induction of the activities of all measured oxidative routes of metabolism but decreased the acetylation ratio in fast acetylators. The quinidine/rifampin combination resulted in selective CYP2D6 inhibition and induction of all other enzymes evaluated over this time period, suggesting that predictable complex interactions occur with the drug combination. CONCLUSIONS: These observations illustrate the value of simultaneous assessment of the effect of modulators on the activities of multiple specific enzymes with the drug cocktail approach.

Acetylation↗

PubMed2000

Effect of ceftazidime on systemic cytokine concentrations in rats.

The effect of a single dose of ceftazidime on circulating concentrations of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) in a rat model of sepsis was studied. IL-6 concentrations were significantly elevated (100 to 200 times the baseline) 6 h after ceftazidime administration in both septic and nonseptic (control) rats. TNF-alpha concentrations increased significantly in nonseptic (approximately 40 times the baseline) rats but not septic (approximately 2 to 3 times the baseline) rats. Ceftazidime administration was not associated with an increase in endotoxin concentrations. These findings suggest that ceftazidime modulation of proinflammatory cytokine concentrations may be independent of its antimicrobial properties.

Animals↗

PubMed2000

Determinants of ceftazidime clearance by continuous venovenous hemofiltration and continuous venovenous hemodialysis.

Although several dosage adjustment regimens have been proposed, there is little quantitative information to guide the initiation of ceftazidime therapy in patients who are receiving continuous renal replacement therapy. To determine the clearance of ceftazidime by continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD), we performed controlled clearance studies with stable hemodialysis patients with three hemofilters: a 0.6-m(2) acrylonitrile copolymer (AN69; Hospal) filter, a 2.1-m(2) polymethylmethacrylate filter (PMMA; Toray) filter and a 0.65-m(2) polysulfone (PS; Fresenius) filter. Subjects received 1,000 mg of ceftazidime intravenously prior to the start of a clearance study. The concentration of ceftazidime in multiple plasma and dialysate or ultrafiltrate samples was determined by high-performance liquid chromatography. The diffusional clearances (CI(diffusion)) and sieving coefficients of ceftazidime were compared by a mixed-model repeated-measures analysis of variance with filter and blood, dialysate inflow, or ultrafiltration rate as the main effect and the patient as a random effect. The fraction of ceftazidime bound to plasma proteins was 17%+/-7% (range, 10 to 25%). The clearances of ceftazidime, urea, and creatinine by CVVHD were essentially constant at blood flow rates of 75 to 250 ml/min for all three filters. Significant linear relationships (P<0.0001) were observed between CI(diffusion) of ceftazidime and clearance of urea for all three filters: AN69 (slope = 0.83), PMMA (slope = 0.89), and PS (slope = 1.03). Ceftazidime clearance was membrane independent during CVVH and CVVHD. CVVH and CVVHD can significantly augment the clearance of ceftazidime. Dosing strategies for initiation of ceftazidime therapy in patients receiving CVVH and CVVHD are proposed.

Adolescent↗

PubMed2000

Evaluation of the influence of diabetes mellitus on antipyrine metabolism and CYP1A2 and CYP2D6 activity.

STUDY OBJECTIVE: To evaluate the metabolism of antipyrine, a general metabolic probe, caffeine, a probe for cytochrome P450 (CYP) 1A2 and N-acetyltransferase activity, and dextromethorphan, a specific probe for CYP2D6 activity in patients with type 1 or 2 diabetes mellitus. DESIGN: Prospective, controlled study. SETTING: Research facility. Patients. Fifteen patients with type 1 and 16 with type 2 diabetes, and 16 healthy controls. INTERVENTION: Each subject simultaneously received antipyrine 10 mg/kg, caffeine 100 mg, and dextromethorphan 30 mg. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of antipyrine and its primary metabolites were determined from saliva and urine samples. Type 1 diabetes had marked effects on antipyrine metabolism whereas type 2 disease did not alter the metabolism of any of the probe drugs. The apparent oral clearance of antipyrine was increased 72% in patients with type 1 disease compared with controls (p=0.0001). In addition, formation clearances of 4-hydroxyantipyrine and 3-hydroxymethylantipyrine were increased by 74% and 137% in those patients relative to controls. The caffeine metabolic index (paraxanthine/caffeine) was increased 34% (p=0.11), and N-acetylation and CYP2D6 phenotype were not altered. CONCLUSION: The metabolism of antipyrine is increased in patients with type 1 diabetes. Based on in vitro reports of antipyrine metabolism and current caffeine metabolic index data, the predominant effect of type 1 diabetes appears to be an increase in CYP1A2 activity. Assessment of the effect of the disease on other specific CYP metabolic pathways is warranted.

Acetylation↗

PubMed2000

Determinants of ceftriaxone clearance by continuous venovenous hemofiltration and hemodialysis.

STUDY OBJECTIVE: To guide individual ceftriaxone dosages in patients receiving continuous renal replacement therapy. DESIGN: Prospective, outpatient study. SETTING: University-affiliated general clinical research center. PATIENTS: Eight patients receiving hemodialysis. INTERVENTION: We performed controlled clearance studies with three hemofilters: an acrylonitrile copolymer 0.6 m2 (AN69), polymethylmethacrylate 2.1 m2 (PMMA), and polysulfone 0.65 m2 (PS). MEASUREMENTS AND MAIN RESULTS: Subjects received ceftriaxone 1000 mg intravenously before the start of a clearance study. The concentration of ceftriaxone in multiple plasma and dialysate-ultrafiltrate samples was determined by high-performance liquid chromatography. The diffusional clearances (Cl(diffusion)) and sieving coefficients (SC) of ceftriaxone, urea, and creatinine were compared by a mixed-model repeated-measures analysis of variance with filter and blood, dialysate inflow, or ultrafiltration rate as the main effect and patient as a random effect. The fraction of ceftriaxone bound to plasma proteins was 43 +/- 15% (range 13-92%). Concentration dependence was evident in all three groups. The fraction unbound to plasma proteins (f(up)) at the time that SCs were determined was significantly lower in the PS group (0.16 +/- 0.07) than the AN69 group (0.30 +/- 0.17, p<0.01), but similar to that in the PMMA group (0.27 +/- 0.12). Despite the higher f(up), the SC of unbound ceftriaxone with the AN69 filter (0.48 +/- 0.13) was significantly lower than values for the PMMA (0.86 +/- 0.33) and PS (0.82 +/- 0.22) groups (p<0.05). Continuous venovenous hemofiltration clearance of urea and unbound ceftriaxone increased significantly only for the PMMA (p=0.006) and PS (p=0.015) filters when the ultrafiltration rate was increased. Significant linear relationships (p<0.0001) were observed between Cl(diffusion) of unbound ceftriaxone and clearance of urea for all three filters: AN69 slope = 0.57, PMMA slope = 0.90, and PS slope = 1.02. The slope of this relationship for the AN69 filter was significantly lower than for the other two filters. CONCLUSION: Ceftriaxone clearance was significantly increased and membrane dependent during continuous venovenous hemofiltration and continuous venovenous hemodialysis. Thus individual ceftriaxone dosages for patients receiving continuous renal replacement therapies should incorporate extracorporeal clearance.

Adult↗

PubMed2000

Nalmefene to prevent epidural narcotic side effects in pediatric patients: a pharmacokinetic and safety study.

STUDY OBJECTIVE: To determine the pharmacokinetics and preliminary efficacy of nalmefene in children in preventing epidural-induced narcotic side effects. DESIGN: Double-blind, placebo-controlled study. SETTING: University-affiliated children's hospital. PATIENTS: Thirty-four children (aged 2-12 yrs) undergoing cardiothoracic surgery with epidural anesthesia. INTERVENTIONS: Patients were randomized to receive intravenous bolus nalmefene 1 microg/kg or placebo. MEASUREMENTS AND MAIN RESULTS: Six blood samples (one before nalmefene administration and five from 13 randomly designated time points) from each patient were assayed to determine plasma nalmefene concentrations. Patients were assessed for pain, nausea, vomiting, and urinary retention for 24 hours after administration. Concentration-time data were analyzed by a limited sampling strategy with adult pharmacokinetic parameters used as Bayesian priors. A two-compartment, first-order model was fitted to the data using ADAPT II. Pharmacokinetic parameter estimates in these patients were similar to values reported in adults. The initial disposition half-life (t(1/2alpha)) was 0.36+/-0.11 hour, the terminal elimination half-life (t(1/2beta)) 8.7+/-2.3 hours, clearance 0.729+/-0.172 L/kg/hr, and steady-state volume of distribution 7.21+/-2.49 L/kg. Ability to prevent epidural narcotic-induced side effects could not be documented at the 1-microg/kg dose. No statistically significant differences were noted between study and placebo groups with regard to pain, nausea, vomiting, or urinary retention. CONCLUSION: Nalmefene has similar pharmacokinetics in children as in adults. It was administered safely to these patients and did not produce unmanageable pain.

Analgesia, Epidural↗

PubMed2000

Sex differences in the pharmacokinetics of dehydroepiandrosterone (DHEA) after single- and multiple-dose administration in healthy older adults.

The pharmacokinetics of exogenously administered DHEA have not been well characterized despite its increasing use in therapeutic and research investigations. The purpose of this study was to evaluate the pharmacokinetics of DHEA and its sulfated metabolite (DHEA-S) after single- and multiple-dose oral administration of DHEA 200 mg. Healthy older adult volunteers (7 women, 6 men) ages 65 to 79 years were studied on five visits separated by 1 week. Subjects received daily administration of placebo (days 1 to 7), DHEA 200 mg (days 8 to 22), and placebo (days 23 to 29). Blood samples were collected over 24 hours on days 1, 8, 15, 22, and 29 for DHEA and DHEA-S determinations by RIA. Pharmacokinetic parameter estimates were calculated by noncompartmental methods. Administration of DHEA 200 mg resulted in higher DHEA Cmax, AUC, and overall concentrations in women than in men (p < 0.03); DHEA-S parameter estimates were similar between men and women. Following a single dose of DHEA 200 mg, DHEA concentrations increased 5- to 6-fold in both men and women, and DHEA-S concentrations increased 5-fold in men and 21-fold in women relative to endogenous concentrations. The results of this study indicate that the pharmacokinetics of DHEA differ between older men and women.

Aged↗

PubMed1999

Determination of famotidine in human plasma and urine by high-performance liquid chromatography.

An improved, rapid and specific high-performance liquid chromatographic assay was developed for the determination of famotidine in human plasma and urine. Plasma samples were alkalinized and the analyte and internal standard (cimetidine) extracted with water-saturated ethyl acetate. The extracts were reconstituted in mobile phase, and injected onto a C18 reversed-phase column; UV detection was set at 267 nm. Urine samples were diluted with nine volumes of a mobile phase-internal standard mixture prior to injection. The lower limits of quantification in plasma and urine were 75 ng/ml and 1.0 microg/ml, respectively; intra- and inter-day coefficients of variation were < or =10.5%. This method is currently being used to support renal function studies assessing the use of intravenously administered famotidine to characterize cationic tubular secretion in man.

Calibration↗

PubMed1999

Pharmacokinetics of intermittent intraperitoneal ceftazidime.

Ceftazidime is currently recommended as an alternative first-line agent in the treatment of peritonitis and for Pseudomonas peritonitis. The pharmacokinetics of intermittent intraperitoneal (i.p.) ceftazidime have been poorly characterized. This study was designed to characterize the pharmacokinetic disposition of a single dose of ceftazidime in anuric and non-anuric CAPD patients, over 48 hours. This was a prospective, open label, pharmacokinetic study. The study was conducted in an independent, outpatient dialysis center. Ten volunteer continuous ambulatory peritoneal dialysis (CAPD) patients with and without residual renal function, no peritonitis or antibiotics in the previous 4 weeks, and on CAPD for at least 2 months were recruited. Patients received a single dose of i.p. ceftazidime (15 mg/kg) in the first daytime exchange over a 6-hour dwell, after an overnight dwell. Serum, urine, and dialysate were collected over a 48-hour period. A high-pressure liquid chromatography (HPLC) assay was used to analyze ceftazidime in these samples. Pharmacokinetic parameters were calculated. Six of the 10 patients were non-anuric with a mean residual renal creatinine clearance of 2.9 +/- 1.6 mL/min. The mean +/- SD bioavailability was 72% +/- 14%, and the volume of distribution was 0.34 +/- 0.08 L/kg. The mean serum elimination half-life of 22 +/- 5 hours. The peritoneal clearance was 5.74 +/- 1.6 mL/min. No difference was detected between anuric and nonanuric patients. Mean plasma and dialysate concentrations at 24 hours were 24 +/- 6 microg/mL and 18 +/- 7 microg/mL, respectively, and were 12.0 +/- 3.6 microg/mL and 7.4 +/- 3.1 microg/mL at 48 hours, respectively. Once-daily i.p. dosing of ceftazidime achieves serum and dialysate levels greater than the MIC of sensitive organisms over 48 hours.

Adult↗

PubMed1999

DHEA and DHEA-S: a review.

Dehydroepiandrosterone (DHEA) and its sulfated metabolite DHEA-S are endogenous hormones secreted by the adrenal cortex in response to adrenocorticotrophin (ACTH). Much has been published regarding potential effects on various systems. Despite the identification of DHEA and DHEA-S more than 50 years ago, there is still considerable controversy as to their biological significance. This article reviews the metabolism and physiology of DHEA and DHEA-S, the influence of age and gender on concentrations, and changes in endogenous concentrations associated with disease states and other factors, including diet and exercise. This article is unique in that it also summarizes the influence of drugs on DHEA and DHEA-S concentrations, as well as concentrations of DHEA and DHEA-S observed after the administration of DHEA by various routes. Sections of the article specifically address DHEA and DHEA-S concentrations as they relate to stress, central nervous system function and psychiatric disorders, insulin sensitivity, immunological function, and cardiovascular disorders.

Age Factors↗