Biomedical subjects

S D Hall

Publications and source records attributed to S D Hall.

At least 73 records · Page 4Linked to original sources

PubMed1992

Stereoselective disposition of flurbiprofen in uraemic patients.

1. Both single and multiple oral doses of 50 mg racemic flurbiprofen were given to eight patients with mild to moderate renal impairment. The plasma and urine concentrations of the R- and S-enantiomers of flurbiprofen and its major metabolites were measured by a stereoselective h.p.l.c. assay. 2. For R-flurbiprofen the oral clearance (mean +/- s.d.: 38.3 +/- 12.8 vs 30.8 +/- 11.5 ml min-1) and volume of distribution (Vz; 17.6 +/- 3.9 vs 14.6 +/- 2.5 l) were significantly greater (P less than 0.05) than for the S-enantiomer. A significantly greater (P less than 0.05) percent of the dose was excreted in the urine R-configuration (16.4 +/- 6.0 vs 10.9 +/- 4.2%). 3. Plasma protein binding of the enantiomers of flurbiprofen was determined by ultrafiltration. The unbound clearance and unbound Vz were not different between enantiomers consistent with the (not significantly) greater percent unbound of R-flurbiprofen (0.079 +/- 0.014%) vs S-flurbiprofen (0.064 +/- 0.015%). 4. Relative to normal volunteers, the uraemic subjects exhibited a significantly greater (P less than 0.05) oral clearance, Vz and percent unbound for both enantiomers; unbound clearance and unbound Vz did not differ from healthy controls. 5. The disposition of flurbiprofen enantiomers was not changed upon multiple dosing and no evidence of futile cycling was found. Adjustment of flurbiprofen dosing rate in uraemic subjects is not indicated on the basis of pharmacokinetics.

Aged↗

PubMed1992

Effects of flurbiprofen on renal function in patients with moderate renal insufficiency.

1. Renal function was assessed in eight patients with chronic renal insufficiency following the administration of flurbiprofen 50 mg as a single dose and after chronic administration of 50 mg four times daily for 8 and 27 days. Diet and fluid intake were controlled. 2. Inulin and creatinine clearances and urinary excretion of sodium were measured at baseline and every 20 min for at least 3 h after dosing. The time of the mean peak concentration of (S)-flurbiprofen was used to guide the analysis of the clearances. Creatinine clearance, urinary excretion of sodium, and serum sodium and potassium were also assessed for 24 h after the dose and on a daily basis. Body weight and blood pressure were measured on a daily basis. 3. Decrements in inulin and creatinine clearances were small and reversible within 3 h of an oral dose of flurbiprofen. Comparison of baseline clearances for the three study periods (first dose and at 8 and 27 days of chronic dosing) revealed a lack of chronic effect on glomerular filtration rate. 4. In contrast, flurbiprofen caused a substantial (73 to 86%) and progressive decrease in the urinary excretion of sodium that reached a nadir within 4-5 h after drug administration. However, comparison of baseline values did not differ, indicating that balance conditions had been re-established. 5. Results of 24 h assessments were in agreement with the clearance study results. Reduced urinary excretion of sodium appeared to be limited to the first few days of flurbiprofen administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1992

Effect of 3'-azido-3'-deoxythymidine (AZT) on organic ion transport in rat renal brush border membrane vesicles.

3'-Azido-3'-deoxythymidine (AZT), a nucleoside analog which has potent activity against the acquired immunodeficiency virus, is actively secreted by the mammalian kidney. In order to study the mechanism of renal drug transport, the effect of AZT on the organic cation and organic anion transport systems in rat renal brush border membrane vesicles was examined by using a rapid filtration assay. The following prototypic substrates were used: [3H]N1-methylnicotinamide and [3H]tetraethylammonium for organic cations and p-[3H]aminohippurate for an organic anion. AZT inhibited pH-driven [3H]N'-methylnicotinamide transport (pHi = 6.0, pH0 = 7.5), but not as effectively as mepiperphenidol (MEPI), a known organic cation transport blocker; the corresponding IC50 values for AZT and MEPI were 2500 and 25 microM, respectively. Counterflow studies, which examined the capability of the drug to cross the plasma membrane, indicated that [3H] tetraethylammonium and MEPI trans-stimulated [3H]tetraethyl-ammonium uptake, but AZT did not. To clarify further the actions of AZT on the organic cation transporter, kinetic studies were undertaken. A Hanes-Woolf transformation of the data revealed that both AZT and MEPI inhibited [3H]N'-methylnicotinamide transport in a competitive manner. The specificity of competition was studied by looking at the effect of AZT on the organic anion transporter. Probenecid, a classical inhibitor of organic anion transport, blocked p-[3H]aminohippurate transport, but AZT did not. We conclude that AZT is a weak inhibitor of the renal brush border organic cation transport system.

Animals↗

PubMed1992

Correlation of serum concentrations of ibuprofen stereoisomers with clinical response in the treatment of hip and knee osteoarthritis.

Stereoselective pharmacokinetic measurements of the active enantiomer, S-ibuprofen, were correlated with clinical response in 45 participants in a randomized double blinded 4 week comparison of ibuprofen, 1200 or 2400 mg/day, for treatment of hip or knee osteoarthritis. Ibuprofen dose correlated with S-ibuprofen area under the serum concentration curve (AUC), trough and average concentration, but not with clinical outcome. AUC of S-ibuprofen correlated with improvement in disability, rest pain and in the physician's global assessment (p = 0.02, 0.08, and 0.10, respectively), and negatively with the subject's weight and creatinine clearance (p = 0.09 and 0.07, respectively). Some individual variation in responsiveness to ibuprofen (and other nonsteroidal antiinflammatory drugs) may be attributed to pharmacokinetic differences.

Adult↗

PubMed1991

Determination of the epimeric composition of ibuprofenyl-CoA.

Ibuprofen [racemic2-(4-isobutylphenyl)propionic acid] is a 2-arylpropionic acid nonsteroidal anti-inflammatory drug which undergoes unidirectional, R to S chiral inversion in vivo. It has been proposed that this chiral inversion phenomenon occurs via a coenzyme A (CoA) thioester intermediate. To characterize the formation and metabolism of this metabolic intermediate, ibuprofenyl-CoA, reference standards were needed and thus the CoA derivatives of (R)-, (S)-, and racemic ibuprofen were chemically synthesized. An HPLC assay employing a C18 reverse-phase column was developed to quantitate "total" ibuprofenyl CoA. Samples collected from this assay were then analyzed for ibuprofenyl-CoA epimeric composition by chiral chromatography employing a Chiral-AGP alpha 1-acid glycoprotein column. The applicability of these methods was demonstrated by assessing (R)- and (S)-ibuprofenyl-CoA hydrolysis and epimerization following incubation with rat liver homogenates. Rat liver homogenate catalyzed the complete and rapid epimerization of ibuprofenyl-CoA and the rate constants for (R)- and (S)-ibuprofenyl-CoA hydrolysis were equal. ATP and CoA were found to inhibit rat liver-catalyzed ibuprofenyl-CoA hydrolysis by 70-80% with no effect on epimerization. Additionally, it was demonstrated that traditional indirect ibuprofenyl-CoA assays which employ basic hydrolysis result in erroneous epimeric ratio determinations due to chemical epimerization.

Acyl Coenzyme A↗

PubMed1991

Furosemide absorption in patients with cirrhosis.

Twelve patients with cirrhosis (seven mild and five severe) were administered intravenous and oral furosemide in random order to assess its absorption and disposition. Total serum clearance (113 +/- 49 ml/min), volume of distribution (11.9 +/- 4.5 L), and elimination half-life (166 +/- 149 minutes) were similar to those reported previously in both healthy control subjects and patients with cirrhosis. Bioavailability of 58% +/- 17% (range, 37% to 82%) was comparable to that of previous studies, and there was no difference between patients with mild and those with severe cirrhosis. In 9 of 12 patients the mean absorption time was longer than the mean residence time determined after intravenous administration (mean for all patients, 203 +/- 86 versus 134 +/- 101 minutes; p less than 0.05), indicating that furosemide followed a "flip-flop" model in these patients. In all patients the mean absorption time was prolonged relative to normal subjects irrespective of the presence of edema. As such, the slower absorption of furosemide in edematous states, such as congestive heart failure and cirrhosis, does not appear to be a consequence of edema per se. Moreover, because similar changes occur in patients with congestive heart failure, it seems that diseases with diverse pathophysiology can slow furosemide absorption.

Absorption↗

PubMed1991

Stereoselective metabolism of ibuprofen in humans: administration of R-, S- and racemic ibuprofen.

Using stable isotope methodology, we studied the effect of the enantiomeric composition of dosage form on ibuprofen metabolism. Eight healthy human subjects received racemic ibuprofen (800 mg) plus S-[aromatic-2H4]ibuprofen (10 mg), R-ibuprofen (600 mg) plus S-[aromatic-2H4]ibuprofen (10 mg) and S-ibuprofen (600 mg) orally on separate occasions in random order. Stereoselective gas chromatography-mass spectrometry was used to quantify deuterated and nondeuterated ibuprofen in serum up to 24 h postdose. Urinary excretion of the stereoisomeric forms of carboxyibuprofen, hydroxyibuprofen and ibuprofen glucuronide were determined up to 24 h postdose by stereoselective high performance liquid chromatography. The metabolism of ibuprofen enantiomers was not influenced by the enantiomeric composition of the dose. For racemic ibuprofen, the mean clearances (+/- S.D.) of S-ibuprofen, R-ibuprofen inversion and R-ibuprofen noninversion were 87.4 +/- 25.9, 57.3 +/- 31.0 and 56.3 +/- 29.0 ml/min, respectively. The fractional inversion of ibuprofen was significantly greater (P less than .05) using the stereochemical composition of the urinary metabolites (0.63 +/- 0.05) vs. the method using the clearance of deuterated S-ibuprofen (0.51 +/- 0.08) after the dose of racemate. Unreliable estimates of fractional inversion were obtained when the S-ibuprofen and racemic ibuprofen doses were combined. Metabolite formation clearances suggested that S-ibuprofen is preferred over R-ibuprofen in the formation of hydroxyibuprofen, carboxyibuprofen and ibuprofen glucuronide. Product stereoselectivity in the formation of the four diastereomers of carboxyibuprofen was modest in favor of SS- and RR-carboxyibuprofen for S- and R-ibuprofen, respectively.

Adult↗

PubMed1991

Interaction of 3'-azido-3'-deoxythymidine with organic ion transport in rat renal basolateral membrane vesicles.

3'-Azido-3'-deoxythymidine (AZT), a nucleoside analog effective against the acquired immunodeficiency syndrome virus, is actively secreted by rat, rabbit and human kidney. The mechanism of AZT transport across the basolateral membrane was characterized by examining the effect of AZT on organic cation and organic anion transport systems in rat renal basolateral membrane vesicles (BLMV) by using a rapid filtration assay. The following prototypic substrates were used: N1-[3H]methylnicotinamide and [3H]tetraethylammonium (TEA) for organic cations and p-[3H]aminohippurate (PAH) for an organic anion. AZT was an effective inhibitor of PAH transport. The dose-response curves for AZT and probenecid, an organic anion inhibitor, revealed IC50 values of 225 and 15 microM, respectively. To clarify further the actions of AZT at the organic anion transporter, counterflow studies were performed. Preloading BLMV with AZT trans-stimulated the uptake of PAH. The specificity of transport was assessed by examining the effect of AZT on organic cation transport. AZT did not inhibit uptake of NMN or TEA (pHin = pHout = 7.5). However, AZT slightly inhibited uptake of TEA under optimized transport conditions (1 mM TEA load). We conclude that AZT transport in rat BLMV is mediated predominantly by the renal organic anion transport system which is consistent with the capability of an organic anion to reduce the renal clearance of AZT in vivo.

Animals↗

PubMed1990

High-performance liquid chromatographic determination of the stereoisomeric metabolites of ibuprofen.

A stereospecific reversed-phase high-performance liquid chromatographic (HPLC) method has been developed to simultaneously quantitate the stereoisomers of the two major metabolites of ibuprofen: hydroxyibuprofen and carboxyibuprofen. The metabolites were derivatized with S-(alpha)-methylbenzylamine to form diastereomeric amides which were separated and quantified on a C8 column. The validity of the stereoselective assay was confirmed by comparison with a non-stereoselective HPLC method. The stereoselective assay was applied to the quantification of all the stereoisomeric ibuprofen metabolites in urine from human volunteers dosed with racemic ibuprofen or the individual enantiomers of ibuprofen. Significant substrate and product stereo-selectivities were observed in the formation of carboxyibuprofen.

Amides↗

PubMed1990

Stereoselective arylpropionyl-CoA thioester formation in vitro.

The inversion from R- to S-enantiomer that occurs for some arylpropionic acids may have both toxicological and therapeutic implications. To characterize some properties of this inversion, arylpropionyl-CoA thioester formation was studied in rat tissue homogenates and subcellular fractions for the enantiomers of fenoprofen, ibuprofen, and flurbiprofen. Thioesters were formed from (R)-fenoprofen (64%) and (R)-ibuprofen (33%) but not from the corresponding S-enantiomers or the enantiomers of flurbiprofen. This correlates with the extensive inversion of fenoprofen and ibuprofen and lack of inversion of flurbiprofen in vivo. Subcellular fractions from rat liver showed thioester formation to occur in mitochondria and microsomes but not cytosol. Once formed, the thioesters were readily racemized by whole rat liver homogenate, mitochondria, and cytosol, but only partially inverted (S:R = 0.3) in microsomes. Thioester formation from fenoprofen and ibuprofen was studied in tissue homogenate obtained from liver, diaphragm, kidney, lung, skeletal muscle, smooth muscle, fat, caecum, and intestines. The liver was at least 50-fold more efficient than the other tissues studied and would be expected to be a major organ of enantiomeric inversion. Our data support the hypothesis that R- to S-enantiomeric inversion of arylpropionic acids proceeds via the stereoselective formation of CoA thioesters followed by enzymatic racemization and hydrolysis of the thioesters to regenerate free acid.

Acyl Coenzyme A↗

PubMed1989

High-performance liquid chromatographic analysis of the enantiomers of flurbiprofen and its metabolites in plasma and urine.

Reversed-phase high-performance liquid chromatographic methods have been developed to quantitate the R- and S-enantiomers of flurbiprofen and its major metabolites, 4'-hydroxyflurbiprofen, 3'-hydroxy-4'-methoxyflurbiprofen, and 3',4'-dihydroxyflurbiprofen. The compounds are extracted from plasma or urine and derivatized with S-(alpha)-methylbenzylamine to form diastereomeric amides which are readily separated on a C18 column. Fluorescence detection resulted in detection limits that readily allowed us to characterize the disposition of R- and S-flurbiprofen and its major metabolites in man following therapeutic doses.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1989

Impaired hepatic elimination of paranitrophenol and its metabolites in the rat following chronic ethanol pretreatment.

Chronic ethanol feeding has been shown to enhance hepatic microsomal drug oxidation in humans and in laboratory animals. However, the effects of chronic ethanol administration on drug conjugation are less conclusive. We have studied the effects of chronic ethanol feeding on (a) the conjugation and elimination of p-nitrophenol (PNP) by the isolated perfused rat liver, (b) the formation of PNP glucuronide by hepatic microsomal PNP-glucuronyltransferase in vitro and (c) the hepatic content of UDP-glucuronic acid (UDPGA). PNP elimination from the isolated perfused rat liver was best described as a combination of parallel saturable and first-order processes. Ethanol pretreatment did not influence the former but resulted in a 48% reduction in the rate of elimination by the latter. This was associated with a significant reduction in recovery of PNP-glucuronide from bile, but no change in concentrations of PNP glucuronide or sulfate in perfusate. Michaelis constants and Vmax for PNP-glucuronyltransferase in native and solubilized microsomes and UDPGA concentrations in liver were not influenced by ethanol pretreatment. These results suggest that chronic ethanol treatment reduces PNP elimination in the intact liver primarily via a reduction in the biliary excretion of PNP glucuronide without altering glucuronidation per se.

Animals↗

PubMed1989

Plasma protein binding of flurbiprofen: enantioselectivity and influence of pathophysiological status.

Ultrafiltration was used to study the enantioselective binding of R-, S- and racemic flurbiprofen, an arylpropionic acid nonsteroidal anti-inflammatory drug, to human plasma protein in eight normal volunteers. The percent free of the R was greater than that of the S for most subjects, but the ratio of percent unbound R to S ranged from 0.52 to 1.33. In extensive studies with a single representative plasma, the percent unbound of the individual enantiomers was independent of concentration up to 26 micrograms/ml, although the binding of the S enantiomer (0.048 +/- 0.007%) was greater than that of the R (0.082 +/- 0.017%), whereas that of the racemate (0.065 +/- 0.028%) was intermediate. At supratherapeutic concentrations of the enantiomers, the percent free of both R- and S-flurbiprofen increased to 0.252 at 100 micrograms/ml. A one-site binding model with nonspecific binding described the data well for R-, S- and racemic flurbiprofen; resulting Ka values were 3.39 X 10(6), 7.31 X 10(6) and 4.35 X 10(6) M-1, respectively. The binding of each enantiomer in the presence of varying amounts of its antipode was described best by a simple competitive inhibition model where mutual displacement occurred as concentrations increased beyond 26 micrograms/ml. The binding of racemic flurbiprofen in elderly and obese volunteers and patients with liver disease was not significantly different from normal subjects, but binding was less in hypoalbuminemic patients and patients with renal impairment. Uremia decreased the binding of R-flurbiprofen preferentially.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1988

Relationship between lipophilicity and tubular reabsorption for a series of 5-alkyl-5-ethylbarbituric acids in the isolated perfused rat kidney preparation.

The renal clearances of a homologous series of six 5-substituted barbituric acids, of varying lipophilicity, were examined using a recirculating isolated perfused rat kidney preparation. Renal clearance was found to decrease with increasing lipophilicity. The renal clearance of the individual compounds was shown to be dependent on urine flow, with the dependence increasing with increasing lipophilicity. A simple physiologically based model of tubular reabsorption, evoking nonequilibrium permeability considerations, is used to explain this influence of urine flow on renal clearance. The relationship between clearance and tubular permeability was examined with the purpose of integrating lipophilicity into the model.

Animals↗

PubMed1988

The assessment of bioavailability in the presence of nonlinear elimination.

The simultaneous administration of an oral dose and intravenous tracer dose, as a method to determine bioavailability, was examined by means of computer simulation for drugs exhibiting Michaelis-Menten type elimination. A physiological pharmacokinetic model parameterized for man and including first-order absorption and elimination solely from the liver was employed. This tracer method provided good estimates of the true availability, with an error of 6% or less, over a wide range of dosing and dispositional conditions. Poorer estimates were noted when large doses of drugs with very short half-lives were considered. This poor performance was improved by administering the intravenous tracer at some time after the oral dose but an a priori basis for establishing this time was not apparent. The tracer method, therefore, appears to be a robust means of assessing, in man, oral bioavailability in the presence of Michaelis-Menten type elimination for drugs characterized by the general properties of the physiological model employed and with half-lives in excess of approximately 40 min. These findings together with the statistical power and simplicity of performance of the tracer method indicate that it is a valid technique for the assessment of bioavailability under a wide range of kinetic conditions.

Biological Availability↗

PubMed1988

Brain uptake of benzodiazepines: effects of lipophilicity and plasma protein binding.

The rapid intracarotid injection technique was used to determine the unidirectional brain uptake of a number of benzodiazepines in the rat. The drugs varied considerably in their lipophilicity and, within the series oxazepam, lorazepam, chlordiazepoxide, desmethyldiazepam and diazepam, brain extraction of unbound moiety was enhanced as the octanol-water (pH = 7.4) partition coefficient increased. However, with flunitrazepam and midazolam, two fluorine-containing benzodiazepines, extraction was more and less extensive, respectively, than predicted from their lipophilicities. Importantly, the uptake findings were consistent with the characteristic onsets of central effects of the drugs established clinically in humans. The effects of reversible protein binding on uptake also were investigated by the addition of albumin (0-8 g.dl-1) to the injectate. This affected markedly the unbound fraction, determined in vitro by equilibrium dialysis, and also the brain uptake of all drugs. As the unbound fraction was reduced, the unidirectional brain extraction ratio decreased in a curvilinear fashion toward zero. However, attempts to describe the data were unsuccessful using a conventional model based on transcapillary uptake of only unbound drug whose binding kinetics with albumin were assumed to be the same as those indicated by equilibrium dialysis. The observed brain extraction was greater than predicted, and the discrepancy became more apparent as binding and albumin concentration increased. The data for all of the benzodiazepines could be fitted, however, if the equilibrium association constant was assumed to be smaller in vivo than in vitro, so that the effective unbound fraction in the brain capillaries was substantially higher (5- to 25-fold, dependent on the particular drug) than that estimated in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Characterization and inhibition of mephenytoin 4-hydroxylase activity in human liver microsomes.

The in vivo metabolism in humans of the anticonvulsant mephenytoin exhibits stereoselectivity as well as genetic polymorphism of the 4-hydroxylation pathway. The characteristics of the involved cytochrome P-450 isozyme are, however, not known completely. Accordingly, the ability of human liver microsomes to metabolize mephenytoin and its enantiomers was investigated in vitro, and the ability of related anticonvulsants and other compounds to inhibit 4-hydroxylation was studied. Marked stereoselectivity was observed in the conversion of S-mephenytoin to its 4-hydroxy metabolite, but N-demethylation was essentially similar for both enantiomers. The intrinsic clearance (Vmax/Km) for 4-hydroxymephenytoin formation showed an almost 10-fold range in five livers and was 150- to 1000-fold greater than that for N-demethylation. Competitive inhibition of 4-hydroxylation was observed with ethotoin, mephobarbital, methsuximide and phensuximide, but not other commonly used anticonvulsants such as ethosuximide, phenobarbital, phenytoin and primidone. However, synthetic N-alkyl analogs of the latter compounds were found to be inhibitory. An aryl residue alpha to the carbonyl carbon of an N-alkyl lactam in a 5- or 6-membered ring, therefore, appears to be a minimal requirement for strong interaction with the 4-hydroxylase. Warfarin, but not diazepam, ketoconazole or iodochlorohydroxyquin, were also competitive inhibitors, but at much higher concentrations than the anticonvulsants. Competitive inhibition at concentrations similar to the Km of 4-hydroxymephenytoin formation (30-350 microM) may indicate that the isozyme is involved in the metabolism of the substrates under consideration and, therefore, their in vivo metabolism may be regulated to some extent by the same genetic factor(s) that determine mephenytoin's biotransformation.

Anticonvulsants↗

PubMed1987

Hepatic metabolism of tolbutamide: characterization of the form of cytochrome P-450 involved in methyl hydroxylation and relationship to in vivo disposition.

In vitro investigations suggest the same human liver cytochrome P-450 that catalyzes S-mephenytoin 4-hydroxylation, P-450MP, is responsible for methyl hydroxylation of the oral hypoglycemic agent tolbutamide. Tolbutamide hydroxylase activity copurified with P-450MP; electrophoretically homogenous P-450MP catalyzed both tolbutamide and S-mephenytoin hydroxylation. Each substrate competitively inhibited hydroxylation of the other, and anti-P-450MP inhibited tolbutamide hydroxylation in human liver microsomes. Significant correlation between tolbutamide and S-mephenytoin hydroxylase activities was seen in a set of human liver samples. These findings suggested that subjects with a genetically determined impairment in ability to hydroxylate mephenytoin might also have deficient tolbutamide metabolism. However, plasma tolbutamide concentration-time profiles and urinary excretion of metabolites formed via the hydroxylation pathway were similar in four phenotypically poor and six extensive metabolizers of mephenytoin. We suggest that alteration of a substrate binding site of P-450MP may reduce its ability to hydroxylate S-mephenytoin but not tolbutamide.

Adult↗