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R J Guttendorf

Publications and source records attributed to R J Guttendorf.

9 recordsLinked to original sources
PubMed1999

Pharmacokinetics of clinafloxacin enantiomers in humans.

The pharmacokinetics of R-clinafloxacin and S-clinafloxacin enantiomers of the broad-spectrum fluoroquinolone antibiotic, clinafloxacin, were characterized in selected volunteer subjects and patients after the administration of oral and intravenous doses of racemic drug. The absorption of each enantiomer was rapid and nearly complete after a single, oral 400 mg racemic dose. The mean (+/- SD) bioavailability of R-clinafloxacin was 87.5% +/- 4.8% compared to 86.2% +/- 5.8% for S-clinafloxacin. The mean Cmax of each enantiomer was 1.19 micrograms/mL, with plasma concentrations of each enantiomer remaining above 0.1 microgram/mL for at least 12 hours. No notable differences in the disposition of R-clinafloxacin and S-clinafloxacin were observed. After a single 400 mg intravenous dose of racemic drug, mean (+/- SD) t1/2 was 5.6 +/- 0.3 hours and 5.7 +/- 0.4 hours, plasma Cl was 329 +/- 49 mL/min and 314 +/- 45 mL/min, and Vdss was 138 +/- 18 L and 134 +/- 16 L for R- and S-clinafloxacin, respectively. Two healthy volunteers each received a single 400 mg oral dose of racemic clinafloxacin (alone) and with oral administration of 1 gm probenecid separated by a 1-week washout period between treatments. With probenecid coadministration, the increase in AUC0-infinity was 75% and 83% for R-clinafloxacin and was 71% and 75% for S-clinafloxacin in each subject, respectively. Probenecid increased the total exposure (AUC) of both R-clinafloxacin and S-clinafloxacin, although it had no stereo-selective effects on the disposition of either enantiomer. The antimicrobial potency of the isomers was also evaluated. In vitro susceptibility testing showed that the two compounds were comparable in their inhibitory activities, as all MICs were within twofold for each organism tested. These results demonstrate that in addition to their similar antimicrobial potency, R- and S-clinafloxacin have nearly identical disposition characteristics and are eliminated by similar mechanisms that display no apparent enantioselectivity in man.

Adult↗
PubMed1997

High-performance liquid chromatographic assay for CI-1004, a dual-inhibitor antiinflammatory agent, in rat, rabbit, dog, monkey and human plasma.

CI-1004 and PD 138389 (internal standard, I.S.), were isolated from rat, rabbit, dog, monkey and human plasma by solid-phase extraction with Bond-Elut C18 cartridges. Liquid chromatographic separation was achieved isocratically on a Zorbax Rx-C8 analytical column (250 mm x 4.6 mm I.D). The mobile phase consisted of acetonitrile-20 mM ammonium acetate (65:35, v/v), (pH 4.0). Column temperature was either 40 degrees C (human assay) or 45 degrees C and column effluent was monitored spectrophotometrically at 360 nm. Specificity, chromatographic performance parameters, system repeatability, recovery from matrix, linearity, precision, accuracy and stability were evaluated. Mean retention times (+/-S.D.) of CI-1004 and I.S. were 7.8+/-0.1 and 10.9+/-0.2 at 40 degrees C and 7.7+/-0.2 min and 10.7+/-0.2 min at 45 degrees C. No interfering peaks were observed at the retention time of CI-1004 throughout the validation process. Peak height ratios were proportional to CI-1004 over the concentration range of 7.5-5000 ng/ml in rat, rabbit and monkey plasma and 2.5-5000 ng/ml in dog and human plasma. Recovery of low, medium and high standards of CI-1004 ranged from 82.8-107% from all animal species and recovery of I.S. from rat, rabbit, dog and monkey plasma ranged from 77.5-82.0% and from human plasma was 111%. Assay precision for CI-1004 based on quality control samples was less than or equal to 8.5% C.V. with an accuracy (percentage relative error) of +/-4.7% for all species. Minimum quantitation limit of CI-1004 was 7.5 ng/ml for 0.2 ml rat, rabbit and monkey plasma samples and 2.5 ng/ml for 0.5 ml dog and human plasma samples. The method is suitable for studying the preclinical and clinical pharmacokinetics of CI-1004.

Animals↗
PubMed1996

Nonpeptidic HIV protease inhibitors: 4-hydroxy-pyran-2-one inhibitors with functional tethers to P1 phenyl ring to reach S3 pocket of the enzyme.

A systematic study of tethering various groups on 6-phenyl ring of 4-hydroxy-6-phenyl-3-[(2-isopropylphenyl)thio]pyran-2-one was performed to increase the binding affinity with HIV protease. This tethering approach was aimed to fill S3 pocket of the enzyme. Thus, tethering hydrophilic groups resulted in more potent inhibitors. Similarly, various aromatic hydrophobic rings as well as heterocyclic rings were explored as tethering substituents to alter the physical properties as well as to enhance the binding affinity with HIV protease. Inhibitor 24, 4-hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-(3-pyridinylmethoxy+ ++ ) phenyl]-2H-pyran-2-one, was evaluated as a prototypic lead structure to study various physical as well as pharmacological properties of this class of HIV protease inhibitors.

Cell Line↗
PubMed1990

Rapid screening for polymorphisms in dextromethorphan and mephenytoin metabolism.

1. The phenotyping parameters for dextromethorphan and mephenytoin were assessed in 48 normal male volunteers following administration of each metabolic probe drug on separate occasions and together according to a randomized 3-way crossover design. 2. Neither the urinary S-/R-mephenytoin ratio nor the dextromethorphan metabolic ratio were altered significantly by coadministration of the probe drugs. 3. Five-hundred and nineteen subjects were screened for expression of mephenytoin 4-hydroxylase and dextromethorphan O-demethylase activity following the coadministration of mephenytoin and dextromethorphan. The activity was determined in each case by methods not requiring any quantitative measurements. 4. Nineteen (3.7%) of the subjects were identified as poor metabolizers (PMs) of mephenytoin and 35 subjects (6.7%) as PMs of dextromethorphan. 5. All PMs of dextromethorphan were confirmed by more rigorous evaluation of the metabolic ratio.

Adolescent↗
PubMed1989

Quantification of propranolol enantiomers in small blood samples from rats by reversed-phase high-performance liquid chromatography after chiral derivatization.

A high-performance liquid chromatographic (HPLC) technique is described for quantification of R(+)- and S(-)-propranolol from 100-microliters rat blood samples. The procedure involves chiral derivatization with tert.-butoxycarbonyl-L-leucine anhydride to form diastereomeric propranolol-L-leucine derivatives which are separated on a reversed-phase HPLC column. The method as previously reported has been modified for assaying serial blood microsamples obtained from the rat for pharmacokinetic studies. An internal standard, cyclopentyldesisopropylpropranolol, has been incorporated into the assay and several derivatization parameters have been altered. Standard curves for both enantiomers were linear over a 60-fold concentration range in 100-microliters samples of whole rat blood (12.5-750 ng/ml; r = 0.9992 for each enantiomer). Inter- and intra-assay variability was less than 12% for each enantiomer at 25 ng/ml. No enantiomeric interference or racemization was observed as a result of the derivatization. No analytical interference was noted from endogenous components in rat blood samples. Preliminary data from two male Sprague-Dawley rats given a 2.0 mg/kg intravenous dose of racemic propranolol revealed differential disposition of the two enantiomers. R(+)-Propranolol achieved higher initial concentration but was eliminated more rapidly than S(-)-propranolol. Terminal half-lives of R(+)- and S(-)-propranolol were 19.23 and 51.95 min, respectively, in one rat, and 14.50 and 52.07 min, respectively, in the other.

Animals↗
PubMed1988

Simplified phenotyping with dextromethorphan by thin-layer chromatography: application to clinical laboratory screening for deficiencies in oxidative drug metabolism.

Identifying individuals with a deficient capacity for oxidative drug metabolism is of increasing clinical importance. Dextromethorphan (DM) is gaining wide acceptance as a probe drug to characterize individual expression of a specific cytochrome P-450 isozyme. The thin-layer chromatography (TLC) technique described in the present study is a rapid and inexpensive alternative to the methods currently available for assessing the urinary metabolic profile of DM. Sixty-five healthy volunteers participated in the study by ingesting 213 mmol DM and collecting all urine for the ensuing 8 h. Urine samples were analyzed by TLC and high-performance liquid chromatography (HPLC) after treatment with beta-glucuronidase. Based on the relative color intensities of DM and its O-demethylated metabolite, dextrorphan, the TLC analysis provided an accurate phenotype assessment. A greater intensity of the parent drug relative to the metabolite indicates a poor metabolizer phenotype whereas a reversed relative intensity indicates the extensive metabolizer phenotype. The phenotype assignments made by TLC were verified by comparison with the quantitative results (based on metabolic ratios) obtained from HPLC analysis. Complete agreement was found between the two methods. The routine implementation of phenotype determination into clinical protocols can be realized with this facile TLC technique.

Adolescent↗
PubMedDate not supplied

Stereoselective differences in propranolol disposition in female Sprague-Dawley and Dark Agouti rats.

Although genetic constitution is recognized as an important factor in drug elimination, there is still only a modest amount of information about its impact on stereoselective drug disposition. To examine how strain differences in cytochrome P-450 expression may affect stereoselective drug elimination, the disposition of R- and S-propranolol was examined in female Sprague-Dawley (SD) and Dark Agouti (DA) rats. The half-life of R-propranolol was increased and its apparent oral clearance decreased significantly in DA rats relative to the SD strain [85 +/- 41 min (DA) vs. 26 +/- 10 min (SD) and 0.020 +/- 0.014 liter/min/kg (DA) vs. 0.31 +/- 0.14 liter/min/kg (SD)], respectively. Strain differences in S-propranolol half-life and apparent oral clearance also were observed, but were not as marked [97 +/- 36 min (DA) vs. 52 +/- 35 min (SD) and 0.20 +/- 0.13 liter/min/kg (DA) vs. 0.70 +/- 0.68 liter/min/kg (SD)], respectively. Due to a more pronounced effect of rat strain on the disposition of R-propranolol, the stereoselective S-/R- oral clearance ratio for propranolol was also strain-dependent [10 +/- 3 (DA) vs. 2.1 +/- 0.9 (SD)]. These differences could not be accounted for by propranolol stereoselective plasma protein binding or by a difference in the blood/plasma ratio for R- or S-propranolol in these separate strains. This represents one of the few examples where an increase in stereoselective drug disposition has been observed due to strain differences that diminish drug elimination.

Animals↗