Stereoselective pharmacokinetics of chlorpheniramine and the effect of ranitidine.

This single-dose, randomized, crossover study was carried out to investigate the potential effect of ranitidine on the pharmacokinetics of chlorpheniramine. The study also afforded an opportunity to add to the limited data currently available on the stereoselective pharmacokinetics of chlorpheniramine. Healthy subjects received a single oral 4 mg dose of racemic chlorpheniramine on two separate occasions: alone, and on day 6 of dosing with ranitidine 75 mg b.i.d. for 8 days. Serum concentrations and urinary recovery of (S)-(+)- and (R)-(-)-chlorpheniramine were unaffected by administration of ranitidine, indicating no pharmacokinetic drug-drug interaction. The observed chlorpheniramine pharmacokinetic data were consistent with previous data and indicated approximately 2.5-fold higher serum concentrations of the (S)-(+) enantiomer. Previously reported high variability in chlorpheniramine pharmacokinetics was greatly reduced by well-controlled food and fluid intake.

Pharmacokinetics and pharmacodynamics of ranitidine in renal impairment.

OBJECTIVE: The pharmacodynamics and pharmacokinetics of ranitidine were examined in subjects with varying degrees of renal function to determine the effect of this condition on acid-antisecretory activity. METHODS: Subjects with creatinine clearances (Ccr) ranging from 0 to 213 m1.min-1 received single 50-mg and 25-mg i.v. doses of ranitidine. This was followed by determination of serum and urine ranitidine concentrations, and continuous gastric pH monitoring for 24 h. RESULTS: Serum ranitidine concentrations were described by a two-compartment model linked to a sigmoidal Emax model describing gastric pH. Ranitidine renal clearance, ranging from 0 to 1003 m1.min-1, correlated with CPAH (r2 = 0.707), while non-renal clearance was unaltered. Steady-state volume of distribution decreased by half in severe renal impairment. No changes in the effective concentration at half-maximal response (EC50), maximal response (Emax), or basal response (E0) were observed. Thus, renal elimination of ranitidine declined in parallel with renal function, while sensitivity to the pharmacologic effect (gastric pH elevation) was unaltered. Ranitidine was cell tolerated in these renally impaired subjects. CONCLUSION: These data indicate that the current recommendation for renal impairment dose reduction (by two-thirds when Ccr < 50 m1-min-1) might result in under-treating moderately impaired patients, and suggests a less conservative dose reduction (by half when Ccr < 10 m1.min-1) to avoid therapeutic failure while remaining within the wide margin of safety for this drug.

Pharmacokinetics of bismuth and ranitidine following single doses of ranitidine bismuth citrate.

1. The pharmacokinetics of bismuth and ranitidine derived from ranitidine bismuth citrate given in single oral doses ranging from 200 mg to 1600 mg were evaluated in healthy subjects. 2. Bismuth was only minimally absorbed (< 0.5% of the amount dosed) after administration of ranitidine bismuth citrate, and peak plasma concentrations never exceeded 33 ng ml-1 in any subject. Plasma concentrations and urinary recoveries of bismuth at doses up to and including 800 mg were relatively constant and not proportional to dose. Bismuth absorption was increased more than proportionally with the dose at 1600 mg. 3. The pharmacokinetics of ranitidine after administration of ranitidine bismuth citrate were dose-proportional and consistent with previous observations for ranitidine administered alone. 4. Ranitidine bismuth citrate was well-tolerated in single oral doses of up to 1600 mg.

Pharmacokinetics of bismuth and ranitidine following multiple doses of ranitidine bismuth citrate.

1. The pharmacokinetics of bismuth and ranitidine derived from oral doses of ranitidine bismuth citrate 800 mg given twice daily for 28 days were examined in this double-blind, placebo-controlled, parallel-group study in 27 healthy subjects. 2. Bismuth accumulation in plasma reflected its multicompartmental disposition, achieving the majority of predicted steady state within 14-28 days. Bismuth absorption from ranitidine bismuth citrate is limited (< 0.5% of the dose), and bismuth elimination is predominantly renal secretion. Peak plasma concentrations did not exceed 19 ng ml-1, remaining well below those associated with bismuth toxicity. Bismuth was measurable at low concentrations in plasma and urine for up to 5 months after the last dose. Plasma bismuth concentration-time data and urinary excretion data were best described by separate multicompartmental models, with terminal half-lives averaging 21 days and 45 days, respectively. 3. The pharmacokinetics of ranitidine derived from ranitidine bismuth citrate were similar to those of ranitidine administered alone. Ranitidine did not appreciably accumulate in plasma. 4. Ranitidine bismuth citrate was well-tolerated during 28 days of repeated dosing.

Sumatriptan absorption from different regions of the human gastrointestinal tract.

Sumatriptan exhibits low oral bioavailability partly due to presystemic metabolism, which may vary with regional differences in metabolic activity throughout the gastrointestinal tract. This study evaluated sumatriptan absorption in humans after administration orally and by oroenteric tube into the jejunum and cecum. Because the site of cecal administration varied, pharmacokinetic parameters for sumatriptan and its major metabolite were compared statistically only after oral and jejunal administration. One-half of the oral dose was recovered in the urine as parent (3%) and metabolite (46%). Sumatriptan was absorbed throughout the gastrointestinal tract; absorption was similar after oral and jejunal administration, and less after cecal administration. The metabolite AUC and the AUC ratio (metabolite/parent) were significantly lower after jejunal compared to oral administration; the AUC ratio was two-fold lower after cecal administration. Results suggest that presystemic metabolism of sumatriptan varies throughout the gastrointestinal tract and/or regional differences exist in the absorption of metabolite formed within the gastrointestinal tract.

Quantification of GR90291 in human blood by high resolution gas chromatography-mass selective detection (HRGC-MSD).

A specific and sensitive high resolution gas chromatography-mass spectrometry method for the determination of GR90291 in human blood is described. The extraction of GR90291 from blood required a polar organic solvent mixture. The crude extract was further purified by successive liquid-liquid partitioning prior to esterification with an HCl-n-butanol solution. This derivative was analysed using a deuterium-labelled internal standard by selected ion monitoring mass spectrometry. The calibration curve ranged from 1 to 100 ng ml-1. The method is reliable for the determination of GR90291 pharmacokinetics in human subjects.

Determination of remifentanil in human blood by liquid-liquid extraction and capillary GC-HRMS-SIM using a deuterated internal standard.

Remifentanil (G187084) is a phenylaminopiperidine derivative of the fentanyl type with potent analgesic activity. The compound has an N-substituted labile methyl ester which is highly susceptible to chemical and enzymatic hydrolysis resulting in a short half-life for the drug. A sensitive capillary GC-HRMS-SIM method for the determination of remifentanil in blood has been developed and progressively revalidated in response to pharmacokinetic needs. The method relies on immediate precipitation of blood proteins with acetonitrile to stabilize the drug, followed by liquid-liquid extraction with methylene chloride. Collection tubes are pre-spiked with tetra-deuterated remifentanil as an internal standard to correct for variations in recovery and stability between samples. An initial method was developed on a Hewlett-Packard GC-MSD and had a validated range of 1-100 ng ml-1. Due to sensitivity requirements established during the first clinical study, the analysis was transferred to a VG 70S high resolution mass spectrometer and revalidated. The quantitation range of the current assay is 0.1-250 ng ml-1. To date, the method has been used to analyse several thousand blood samples from remifentanil clinical studies.

Pharmacokinetics of cefuroxime axetil and cefaclor: relationship of concentrations in serum to MICs for common respiratory pathogens.

The pharmacokinetics of single doses of cefaclor at 250 and 375 mg and cefuroxime axetil at 250 mg administered under optimal conditions (i.e., cefuroxime axetil after food and cefaclor in the fasted state) were studied in 24 healthy male volunteers. Drug concentrations in serum were related to MICs for common respiratory tract pathogens by using data generated from a recently completed national survey. The time the concentrations in serum exceeded the MICs for Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella (formerly Branhamella) catarrhalis were significantly greater (P less than 0.05) for cefuroxime axetil at 250 mg than for cefaclor at 250 or 375 mg. With the recommended dosing regimens (cefuroxime axetil at 250 mg and cefaclor at 375 mg twice daily or cefaclor at 250 mg three times daily), cefuroxime concentrations exceed the MIC for 90% of the strains tested for a greater time period than cefaclor concentrations with either regimen. The reasons for this difference are (i) the greater potency and slower clearance of cefuroxime compared with those of cefaclor and (ii) the greater sensitivity of these pathogens to cefuroxime.

X-ray absorption spectroscopic studies of high valent iron porphyrins. Horseradish peroxidase compounds I and II and synthetic models.

X-ray absorption edge and extended x-ray absorption fine structure studies have been undertaken on resting (ferric) horseradish peroxidase, HRP compound I (HRP-I), HRP compound II (HRP-II), and several highly oxidized synthetic iron porphyrins that may have relevance as models for the iron site in horseradish peroxidase. The energies of the absorption edges are consistent with an Fe(IV) formulation for the highly oxidized species. The shapes of the absorption edges further support the assignment of HRP-I and one of the model compounds as Fe(IV)-porphyrin pi-cations. The edge shapes also demonstrate that the iron sites in the model porphyrins are not identical to the iron sites in the enzyme. Preliminary curve fitting analysis of the extended x-ray absorption fine structure clearly indicates the presence of two different nearest neighbor distances for the iron, both in HRP-I and HRP-II, as well as in two of the highly oxidized model porphyrins. These distances are interpreted as an iron-porphyrin nitrogen distance and as a short (approximately 1.6 A) iron-oxygen distance.