Biomedical subjects

S D Hall

Publications and source records attributed to S D Hall.

At least 55 records · Page 3Linked to original sources

PubMed1996

Bimodal distribution of renal cytochrome P450 3A activity in humans.

It has been proposed that excessive intrarenal conversion of cortisol to 6 beta-hydroxycortisol by CYP3A may mediate increased tubular reabsorption of sodium, leading to a state of mild volume expansion and the clinical phenotype of salt-sensitive hypertension. Therefore, we characterized CYP3A activity in a bank of microsomes from human kidneys using the formation of 1'-hydroxymidazolam (1'-OHM) as a prototypical CYP3A-catalyzed reaction. Maximal rates of metabolite formation occurred at midazolam concentrations of 12.5-50 microM; higher concentrations resulted in dramatic substrate inhibition. At 12.5 microM midazolam, 4 of 27 kidneys exhibited relatively high mean +/- standard deviation 1'-OHM formation rate (184.0 +/- 14.4 pmol/hr/mg) compared with the remaining 23 samples, which had a mean formation rate of (10.1 +/- 6.4 pmol/hr/mg). Triacetyloleandomycin and anti-CYP3A antibody inhibited midazolam hydroxylation by 53% and 57%, respectively. The correlation between CYP3A5 content, determined through immunoblotting, and 1'-OHM formation rate was high (r2 = 0.84, 24 experiments). The expressions of mRNA corresponding to CYP3A3, CYP3A4, CYP3A5, and CYP3A7 were determined through polymerase chain reaction with specific oligonucleotides as primers. All kidneys examined (25 experiments) expressed CYP3A5 protein and contained the corresponding CYP3A5 mRNA. CYP3A4 mRNA was detected in 40% of the kidney samples, and 70% of those that contained detectable CYP3A4 mRNA also expressed detectable levels of the corresponding protein. Therefore, in contrast to hepatic tissue, in which CYP3A4 is universally expressed, CYP3A5 is the ubiquitously expressed member of the CYP3A family in renal tissue. The distribution of enzyme activity and protein content suggests bimodality and may represent induction of CYP3A5 in a select population and/or a genetically determined organ-specific pattern of expression.

Antibodies↗

PubMed1995

Electron microscopic visualization of RecT protein and its complexes with DNA.

Electron microscopy has been used to examine Escherichia coli RecT protein alone and in the complexes it forms with DNA substrates, with which it catalyzes strand exchange in vitro. Negative staining has revealed that the 33 kDa RecT protein monomers form open C-shaped and closed O-shaped particles. RecT protein monomers assemble into donut-shaped oligomers containing seven or eight protein monomers and rod-like structures. When bound to single-stranded DNA, RecT forms highly twisted nucleoprotein filaments that are 18 nm in diameter and have a helical pitch of 10 nm. When added to linear duplex DNA in the presence of active RecE protein (exonuclease VIII), filamentous nucleoprotein complexes are formed on the DNA ends and the DNA molecules are frequently cyclized through protein-protein interactions.

Bacterial Proteins↗

PubMed1995

Acute and chronic effects of nonsteroidal antiinflammatory drugs on glomerular filtration rate in elderly patients.

To assess the effects of nonsteroidal antiinflammatory drugs (NSAIDs) on glomerular filtration rate (GFR) in elderly patients with and without renal insufficiency, we conducted an open-label, randomized, prospective three-period cross-over study. Twenty-nine patients at least 65 years old were assigned to groups with preserved GFR (> 1.16 mL/s [70 mL/min]) or with renal insufficiency (GFR 0.50-1.16 mL/s [30-70 mL/min]). Patients received 800 mg ibuprofen three times daily, 20 mg piroxicam daily, or 200 mg sulindac twice daily for 1 month. Three-hour inulin and two-day creatinine clearances were measured before and after the first and last doses of NSAIDs. Ibuprofen, piroxicam, and sulindac decreased inulin clearance after single-doses in both groups of patients. In patients with renal insufficiency, creatinine clearance did not change after administration of ibuprofen for 1 month (0 +/- 0.06 mL/s, mean +/- standard error), but was decreased similarly with administration of either piroxicam or sulindac (-0.12 +/- 0.06 mL/s [-7.2 +/- 3.6 mL/min], P < 0.02). One patient with preserved GFR, but with other risk factors for NSAID-associated renal impairment, met our criteria for withdrawal by experiencing at least a 40 mumol/L (0.5 mg/dL) increase in serum creatinine above their baseline value. Our data indicate that NSAIDs do not adversely affect GFR in patients with preserved renal function unless they have another risk factor for NSAID-associated renal impairment. In contrast, patients with renal insufficiency may have significant chronic decrements in GFR with long-acting NSAIDs such as piroxicam and sulindac, but not with short-acting ibuprofen. Such patients should have renal function monitored while being treated with long-acting NSAIDs.

Age Factors↗

PubMed1995

Enantioselective effects of experimental diabetes mellitus on the metabolism of ibuprofen.

Diabetes mellitus is associated with numerous metabolic events that may influence the elimination of R- and S-ibuprofen and the inversion of R-ibuprofen. Short (3 days) and long (14 days) term experimental type I diabetes was induced in male Sprague-Dawley rats with streptozotocin, and genetically diabetic male Zucker rats were used as a model of type II diabetes. Isolated hepatocytes from long-term streptozotocin-treated rats exhibited significantly greater rate constants for ibuprofenyl-coenzyme A (CoA) formation (1.44 +/- 0.05 vs. 0.60 +/- 0.09 hr-1) and the elimination of R-ibuprofen (0.34 +/- 0.07 vs. 0.22 +/- 0.07 hr-1) relative to control (P < or = .05). These increases were consistent with significant induction of hepatic cytochrome P450 (1.14 +/- 0.45 vs. 0.54 +/- 0.10 nmol/mg protein) and an elevated hepatic free CoA content (313.4 +/- 48.5 vs. 172.9 +/- 38.6 nmol/g) relative to control (P < or = .05). In hepatocytes from type II diabetic rats there were significant reductions (P < or = .05) in the rate constants for ibuprofenyl-CoA formation (1.02 +/- 0.12 vs. 1.22 +/- 0.12 hr-1), R-ibuprofen elimination (0.21 +/- 0.06 vs. 0.34 +/- 0.10 hr-1) and S-ibuprofen elimination (0.41 +/- 0.07 vs. 0.73 +/- 0.11 hr-1) but no change in hepatic content of cytochrome P450 or CoA relative to control. The activity of ibuprofenyl-CoA synthetase in whole liver homogenate supplemented with ATP and CoA was not influenced by experimental diabetes. In both type I and type II diabetes there was a significantly greater exposure of hepatocytes to ibuprofenyl-CoA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Enantioselective disposition of ibuprofen in elderly persons with and without renal impairment.

By using stable isotope methodology, we studied the disposition of ibuprofen after the first and last dose of a 4-week regimen of 800 mg of racemic ibuprofen every 8 hr in three groups of subjects: 1) young healthy volunteers (n = 8); 2) healthy elderly volunteers (n = 14); and 3) elderly patients with creatinine clearance between 30 and 70 ml/min (n = 13). Stereoselective gas chromatography-mass spectrometry was used to quantify deuterated S- and nondeuterated R- and S-ibuprofen in serum up to 24 hr after the first and last doses. Urinary excretion of the stereoisomeric forms of carboxyibuprofen, hydroxyibuprofen and ibuprofen glucuronide were determined up to 24-hr postdose by stereoselective high-performance liquid chromatography. Stereoselective serum protein binding was determined by ultrafiltration. Both elderly groups had significantly decreased binding of S-ibuprofen compared to the young group. The S-ibuprofen pharmacokinetics were significantly different in the elderly patients with renal impairment compared to the young volunteers: the T1/2 was increased, the unbound clearance was decreased and the unbound concentration at steady state was increased. Fraction inverted was similar for all groups, but unbound clearances of glucuronidation and hydroxylation were reduced in the elderly patients with renal impairment. These results suggest that the disposition of ibuprofen enantiomers is altered in elderly persons with renal impairment; these changes may increase the risk for nonsteroidal anti-inflammatory drug-associated adverse effects in such patients.

Adult↗

PubMed1994

Characterization of dextromethorphan N-demethylation by human liver microsomes. Contribution of the cytochrome P450 3A (CYP3A) subfamily.

In an effort to identify the human cytochromes P450 involved in the N-demethylation of dextromethorphan, the kinetics of 3-methoxymorphinan formation were studied in microsomal enzyme systems. Under initial rate conditions, 3-methoxymorphinan formation demonstrated single enzyme Michaelis-Menten kinetics using microsomes obtained from three human livers (Km: 0.52-0.71 mM; Vmax: 375-812 pmol/mg protein/min). B-lymphoblastoid cells expressing CYP3A4 incubated with 0.4 mM dextromethorphan catalyzed the formation of 3-methoxymorphinan at a rate of 22 pmol product/mg protein/min. Midazolam, a prototypic substrate for CYP3A4 and CYP3A5, competitively inhibited dextromethorphan N-demethylation by two human liver microsomal samples with Ki values of 46 +/- 10 and 63 +/- 8 microM. At a dextromethorphan concentration of 0.4 mM, gestodene (100 microM) inhibited 3-methoxymorphinan formation by approximately 50%. Immunoinhibition of dextromethorphan N-demethylation using rabbit anti-CYP3A4 antibodies resulted in a 60% decrease in 3-methoxymorphinan formation at a dextromethorphan concentration of 0.4 mM. Additional inhibition studies using furafylline, coumarin, sulfaphenazole, mephenytoin, quinidine, and diethyldithiocarbamic acid, which are selective inhibitors of CYP1A2, CYP2A6, CYP2C8/9, CYP2Cmp, CYP2D6, and CYP2E1, respectively, demonstrated no substantial inhibition of dextromethorphan N-demethylation. Correlation analysis was performed using the rate of 3-methoxymorphinan formation at a concentration of 1 mM dextromethorphan and immunoquantified levels of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 and their associated characteristic catalytic activities. A significant correlation was observed between dextromethorphan N-demethylase activity and midazolam 1'- and 4-hydroxylase activity (r2 = 0.77 and 0.69 respectively, N = 19, P < 0.01); the exclusion of those samples containing both CYP3A4 and CYP3A5 increased the correlation significantly (r2 = 0.87 and 0.91 respectively, N = 12, P < 0.01). In the absence of CYP3A5, a significant correlation was observed between 3-methoxymorphinan formation and the sample's erythromycin N-demethylase activity (r2 = 0.94, N = 12, P < 0.01), testosterone 6 beta-hydroxylase activity (r2 = 0.96, N = 7, P < 0.01) and relative immunoquantified levels of CYP3A4 (r2 = 0.96, N = 12, P < 0.01). Inclusion of those samples expressing CYP3A5 in addition to CYP3A4 reduced the magnitude of the observed correlation. No significant correlation between 3-methoxymorphinan formation and the sample's relative immunoquantified levels of or form-selective activity associated with CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19 (or CYP2Cmp), CYP2D6, and CYP2E1 was observed. In conclusion, dextromethorphan N-demethylation appears to be catalyzed primarily by CYP3A4 and to a lesser extent by CYP3A5 in vitro in humans.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1994

Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily.

The capabilities of cytochrome P4503A4 (CYP3A4), CYP3A5, and fetal hepatic microsomes containing CYP3A7 to metabolize midazolam were investigated using human hepatic microsomes and purified CYP3A4 and CYP3A5. Under initial rate conditions and high substrate concentration (400 microM midazolam), variability among eighteen human liver microsomal samples was 30- and 16- fold for 1'- and 4-hydroxylation of midazolam, respectively. Exclusion of two samples isolated from patients previously administered barbiturates reduced the inter-individual variability to 10.5- and 6.0-fold for 1'- and 4-hydroxylation, respectively. Six fetal hepatic microsomal samples showed 10-fold variation in both 1'-hydroxymidazolam and 4-hydroxymidazolam formation rates. The rates of formation of 4-hydroxymidazolam and 1'-hydroxymidazolam from midazolam by adult samples containing only CYP3A4 and by fetal liver samples were highly correlated (r2 = 0.99 and 0.97, P < 0.01, respectively). The rates of formation of 1'-hydroxymidazolam and 4-hydroxymidazolam from midazolam (400 microM) by adult samples that contained only CYP3A4 were correlated significantly (P < 0.01) with the ability of the samples to N-demethylate erythromycin (r2 = 0.95 and 0.92, respectively). 6 beta-hydroxylate testosterone (r2 = 0.96 and 0.96, respectively), and the CYP3A4 content of the samples (r2 = 0.89 and 0.86, respectively). Microsomal samples containing CYP3A5 in addition to CYP3A4 exhibited a significantly greater ratio of 1'-hydroxymidazolam to 4-hydroxymidazolam compared with samples containing only CYP3A4 or CYP3A7 (P < 0.001). Purified CYP3A5 in a reconstituted system, consisting of dilauroylphosphatidylcholine, cytochrome b5, and NADPH-cytochrome P450 reductase, and an NADPH-regenerating system displayed a 2-fold greater rate of 1'-hydroxymidazolam formation and a similar rate of 4-hydroxymidazolam formation compared with a reconstituted system with CYP3A4. In conclusion, CYP3A4, CYP3A5, and fetal microsomes containing CYP3A7 catalyze 1'- and 4-hydroxylation of midazolam with the ratio of these metabolites indicative of the CYP3A form.

Biotransformation↗

PubMed1994

Homologous pairing and strand exchange promoted by the Escherichia coli RecT protein.

RecT protein of Escherichia coli promotes the formation of joint molecules between homologous linear double-stranded M13mp19 replicative-form bacteriophage DNA and circular single-stranded M13mp19 DNA in the presence of exonuclease VIII, the recE gene product. The joint molecules were formed by a mechanism involving the pairing of the complementary strand of the linear double-stranded DNA substrate with the circular single-stranded DNA substrate coupled with the displacement of the noncomplementary strand. When the homologous linear double-stranded DNA substrate had homologous 3' or 5' single-stranded tails, then RecT promoted homologous pairing and strand exchange in the absence of exonuclease VIII. Histone H1 could substitute for RecT protein; however, joint molecules formed in the presence of histone H1 did not undergo strand exchange. These results indicate that under the reaction conditions used, the observed strand exchange reaction is promoted by RecT and is not the result of spontaneous branch migration. These results are consistent with the observation that expression of RecE (exonuclease VIII) and RecT substitutes for RecA in some recombination reactions in E. coli.

Bacterial Proteins↗

PubMed1994

The role of coenzyme A in the biotransformation of 2-arylpropionic acids.

A number of 2-arylpropionic acid non-steroidal anti-inflammatory drugs ('profens') undergo highly enantioselective inversion from the (R)- to (S)-enantiomer. The mechanism of this inversion reaction involves the initial enantioselective formation of a coenzyme A thioester followed by epimerization and finally hydrolysis to regenerate free acids. Long-chain fatty acyl-CoA synthetase appears to mediate the initial thioester formation and an epimerase of an unknown physiologic function effects the second step. The hydrolases mediating the final step are poorly defined. Available evidence suggests that the liver is quantitatively the most important tissue site of inversion but local tissue inversion may influence the pharmacological and toxicological response of a given organ. Data from isolated rat hepatocytes indicate that other xenobiotics can modulate the formation and hydrolysis of ibuprofenyl-CoA by influencing inversion pathways, non-inversion pathways or both. Interactions between xenobiotics may therefore accentuate inter-individual variability in response to 2-aryl-propionic acids. The formation of 2-arylpropionyl-CoA thioesters in vivo has the potential to disrupt numerous biochemical pathways in addition to enhancing individual exposure to the potent anti-inflammatory (S)-enantiomers.

Acyl Coenzyme A↗

PubMed1994

The pharmacokinetics of piroxicam in elderly persons with and without renal impairment.

1. Piroxicam pharmacokinetics were assessed in three groups of subjects: (1) young healthy volunteers, (2) healthy elderly subjects (mean +/- s.d. creatinine clearance 88 +/- 13 ml min-1), and (3) elderly patients with renal insufficiency (creatinine clearance 60 +/- 10 ml min-1) following the administration of piroxicam 20 mg as a single dose and after chronic dosing of 20 mg once daily for 4 weeks. 2. Piroxicam and 5'-hydroxypiroxicam concentrations were measured by h.p.l.c. in serum and urine samples collected for 96 h after the single dose and for 144 h after chronic dosing. Unbound concentrations of piroxicam were determined by ultrafiltration. 3. Elimination half-lives, steady state concentrations of piroxicam and 5'-hydroxypiroxicam, clearances of total and unbound piroxicam, volumes of distribution normalized for body weight, and urinary recovery of 5'-hydroxypiroxicam were not influenced by age or renal function. Volumes of distribution after the single dose were significantly lower in women compared with men (mean +/- s.d. 10.0 +/- 2.9 l vs 12.9 +/- 5.0 l; 95% confidence interval of the difference 0.1 to 5.6). 4. Percent unbound piroxicam values were 1.46 +/- 0.3% after the single dose and 1.45 +/- 0.2% at steady state. There were significant reductions in clearance and clearance of unbound piroxicam between single and chronic doses. The half-lives of 5'-hydroxypiroxicam (80.9 +/- 44 h) were significantly longer than those of piroxicam (54.9 +/- 26 h) after chronic dosing.

Adult↗

PubMed1994

Homologous pairing proteins encoded by the Escherichia coli recE and recT genes.

Early genetic analysis of alternate recombination pathways in Escherichia coli identified the RecE recombination pathway and the required exonuclease VIII encoded by the recE gene. Observations that not all recombination events promoted by the RecE pathway require recA suggest the existence of an additional homologous pairing protein besides RecA in E. coli. Genetic and biochemical analysis of the recE gene region indicates there are two partially overlapping genes, recE and recT, encoding at least two proteins: exoVIII and the RecT protein. Biochemical analysis has shown that the RecT protein, in combination with exoVIII, promotes homologous pairing and strand exchange in reactions containing linear duplex DNA and homologous, circular, singlestranded DNA as substrates. This reaction occurs in the absence of any high-energy cofactor. These two proteins, RecT and exoVIII, appear to be members of a second class of homologous pairing proteins that are required in genetic recombination and differ from the class of homologous pairing proteins that includes RecA. Members of this second class of proteins appear to include both bacteriophage-encoded proteins and proteins from eukaryotes and their viruses.

Amino Acid Sequence↗

PubMed1993

Lack of presystemic inversion of (R)- to (S)-ibuprofen in humans.

Presystemic inversion of (R)- to (S)-ibuprofen has been proposed but not directly examined in humans. We investigated the bioavailability of the enantiomers of ibuprofen in 10 healthy volunteers. Low-dose racemic ibuprofen (400 mg) was administered orally and intravenously (60-minute infusion), in random order. There were no significant differences between oral and intravenous doses for the area under the curve values, terminal rate constants, clearances, metabolite formation clearances, and serum protein binding for (R)- and (S)-ibuprofen. The bioavailabilities of (R)-ibuprofen and total ibuprofen were 0.92 +/- 0.11 and 0.95 +/- 0.08, respectively. The fractional inversion of (R)-ibuprofen was determined by two methods (stable isotope method and from the stereochemical composition of the urinary metabolites) that gave similar estimates of inversion for oral dosing (0.56 +/- 0.12 and 0.60 +/- 0.07, respectively) and intravenous dosing (0.56 +/- 0.09 and 0.60 +/- 0.06, respectively). We conclude that the bioavailability of both enantiomers of ibuprofen is complete and find no evidence of significant presystemic inversion.

Administration, Oral↗

PubMed1993

Identification and characterization of the Escherichia coli RecT protein, a protein encoded by the recE region that promotes renaturation of homologous single-stranded DNA.

Recombination of plasmid DNAs and recombination of bacteriophage lambda red mutants in recB recC sbcA Escherichia coli mutants, in which the recE region is expressed, do not require recA. The recE gene is known to encode exonuclease VIII (exoVIII), which is an ATP-independent exonuclease involved in the RecE pathway of recombination. A 33,000-molecular-weight (MW) protein was observed to be coexpressed with both exoVIII and a truncated version of exoVIII, pRac3 exo, when they were overproduced under the control of strong promoters. We have purified this 33,000-MW protein (p33) and demonstrated by protein sequence analysis that it is encoded by the same coding sequence that encodes the C-terminal 33,000-MW portion of exoVIII. p33 is expressed independently of exoVIII but is probably translated from the same mRNA. p33 was found to bind to single-stranded DNA and also to promote the renaturation of complementary single-stranded DNA. It appears that p33 is functionally analogous to the bacteriophage lambda beta protein, which may explain why RecE pathway recombination does not require recA.

Amino Acid Sequence↗

PubMed1993

Modulation of enantioselective metabolism and inversion of ibuprofen by xenobiotics in isolated rat hepatocytes.

R-ibuprofen undergoes chiral inversion by the formation of a coenzyme A (CoA) thioester and subsequent epimerization and hydrolysis. Using isolated rat hepatocytes, the interaction of xenobiotics with the inversion and oxidation pathways of ibuprofen enantiomers was determined from the time course of R- and S-ibuprofen and ibuprofenyl-CoA during 4-hr incubations with R- or S-ibuprofen (25 microM). By fitting a first-order model, the rate constants of the formation of ibuprofenyl-CoA (K12), oxidation of R-ibuprofen (K10), hydrolysis of ibuprofenyl-CoA (K21) and oxidation of S-ibuprofen (K30) were 1.306, 0.284, 6.858 and 0.496 hr-1, respectively. The fractional inversion of R-ibuprofen was 0.75 and the area under the curve for ibuprofenyl-CoA was 203.8 microM min. Coincubation with 50 microM of the cytochrome P450 inhibitors metyrapone and proadifen resulted in significant reductions of K10 and K30; the fractional inversion of R-ibuprofen increased to 116% and 127% and the area under the curve of ibuprofenyl-CoA to 145% and 144% of controls, respectively. Valproic acid and pivalic acid at 50 microM significantly reduced the K12 and increased the K21; the fractional inversion was unchanged but the area under the curve of ibuprofenyl-CoA was significantly reduced to 57% and 28% of controls, respectively. Valproic acid also significantly reduced K10 and K30. p-nitrobenzoic acid at 50 microM significantly increased K21 and reduced the area under the curve of ibuprofenyl-CoA to 44% of control but did not influence the fractional inversion. Selective inhibitors of ibuprofen oxidation were found to enhance significantly hepatocellular exposure to the potentially reactive ibuprofenyl-CoA intermediate.

Animals↗

PubMed1992

Pulmonary inversion of 2-arylpropionic acids: influence of protein binding.

The possible contribution of pulmonary metabolism to the putative first-pass metabolism of 2-arylpropionic acid nonsteroidal antiinflammatory drugs has not been documented. Isolated perfused rabbit lungs, perfused with 4.5% bovine serum albumin or 5% dextran, were used to study the pulmonary elimination of (R)- and rac-ibuprofen, fenoprofen, and flurbiprofen. In the absence of protein binding, ibuprofen was metabolized via inversion and other pathways, whereas fenoprofen metabolism was essentially restricted to inversion of the (R)-enantiomer; fraction inverted (+/- SE) was 0.37 +/- 0.05 for (R)-ibuprofen and 0.85 +/- 0.03 for (R)-fenoprofen. In the presence of protein, neither ibuprofen nor fenoprofen was metabolized. Flurbiprofen did not undergo pulmonary elimination under any condition studied. This study illustrates that even though a tissue is capable of metabolism, particularly inversion of 2-arylpropionics, the quantitative importance of such elimination pathways may be minimal in the presence of the high degree of protein binding that is characteristic of these drugs.

Animals↗

PubMed1992

The effects of a salicylate, ibuprofen, and naproxen on the disposition of methotrexate in patients with rheumatoid arthritis.

We have studied the pharmacokinetics of methotrexate in patients with rheumatoid arthritis concurrently treated with choline magnesium trisalicylate, ibuprofen, naproxen, or a non-NSAID analgesic (control treatment). The apparent systemic clearance of methotrexate was significantly reduced by all three treatments. Trisalicylate and ibuprofen both significantly reduced methotrexate renal clearance, but only the trisalicylate significantly displaced methotrexate from protein, increasing the fraction unbound by 28%. These data show that NSAIDs can affect the disposition of methotrexate, possibly increasing the potential for toxicity and necessitating dosage adjustments. However, large inter-subject variability precludes specific dosage recommendations.

Adult↗

PubMed1992

Variability in the disposition of ibuprofen enantiomers in osteoarthritis patients.

The pharmacokinetics of the enantiomers of ibuprofen have been investigated following oral administration of 300 or 600 mg of racemic ibuprofen four times daily to 45 patients with osteoarthritis. Fifteen of these patients also received single doses of 300 or 600 mg of racemic ibuprofen. Serum concentrations of R- and S-ibuprofen and urine concentrations of the stereoisomers of ibuprofen and its metabolites were measured by high-performance liquid chromatography. The fraction inverted (F(inv)) of the inactive R- to active S-ibuprofen was estimated by a urinary metabolite method. For the 15 patients in both the chronic and single dose studies, there were no significant differences in the clearance of R-ibuprofen or F(inv). The elimination half-lives of R- and S-ibuprofen were comparable for the single and chronic dosing studies. The area under the curve (AUC) values, 6-h trough concentrations, and average steady state concentrations of the R- and S-enantiomers were statistically different after chronic dosing. Despite considerable variability in the clearances in these patients, e.g., clearance (CL) of R-ibuprofen showed 28-49% CV, much less variability was seen in F(inv) (range 9-19% CV), implying that patients would receive similar effective doses of active S-ibuprofen in spite of large differences in kinetics.

Adult↗

PubMed1992

Stereoselective disposition of flurbiprofen in normal volunteers.

1. The concentrations of the R- and S-enantiomers of flurbiprofen and its metabolites were measured in plasma and urine following the oral administration of 50 mg racemic flurbiprofen to six normal volunteers. 2. The AUC and half-life of the R-enantiomer were significantly lower than the corresponding S-enantiomer values reflecting the greater clearance of R-flurbiprofen (20.42 +/- 4.71 vs 16.12 +/- 3.60 ml min-1). 3. Ex vivo protein binding studies indicated that the percent unbound of R-flurbiprofen was (not significantly) greater than that of the S-enantiomer (0.055 +/- 0.008 vs 0.049 +/- 0.009) and the corresponding unbound clearances did not show enantioselectivity. 4. Both enantiomers were cleared primarily by metabolism to an acylglucuronide and 4'-hydroxyflurbiprofen. There was significant enantioselectivity (R greater than S) in the formation clearances of these metabolites which remained when unbound metabolite formation clearances were considered. 5. In conclusion, the disposition of the enantiomers of flurbiprofen exhibits enantioselectivity at the level of protein binding and metabolite formation.

Adult↗