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Biomedical subjects

F Jamali

Publications and source records attributed to F Jamali.

At least 91 records · Page 5Linked to original sources
PubMed1991

Urinary metabolites of doxapram in premature neonates.

1. Urine samples from 20 premature neonates who received doxapram by i.v. infusion were analysed for drug metabolites by g.l.c-mass spectrometry. 2. In addition to doxapram, all urines contained at least one metabolite, but the known metabolite, 3-ketodoxapram, was detected in only 50% of the samples, and in some instances only in trace amounts. 3. Significant inter-individual differences in the metabolic pathways of doxapram were observed. 4. A total of six metabolites of doxapram were isolated three of which have not been observed previously in human or in dog. 5. Appropriate structures for the new metabolites have been deduced from their mass spectral fragmentation pathways, and are 1-ethyl-4-[2-(N-formyl-N-(2-hydroxy-ethyl)amino)ethyl]-3,3-diphenyl-2- pyrrolidinone (VII), 1-ethyl-4-[2-(4-morpholin-2-onyl)ethyl]-3,3-diphenyl-2-pyrro lidinone (IX) and 4-ethenyl-1-ethyl-3,3-diphenyl-2-pyrrolidinone (X).

Doxapram↗
PubMed1991

Presystemic and systemic chiral inversion of R-(-)-fenoprofen in the rat.

Fenoprofen (FN), a member of the 2-arylpropionic acid (2-APA) class of nonsteroidal anti-inflammatory drugs is administered clinically as a racemate. In humans, FN has been shown to rapidly undergo substantial in vivo unidirectional chiral inversion with the inactive R-isomer converted to its active antipode. As with any p.o. administered drug, before reaching the systemic circulation. FN may undergo first-pass metabolism, the major organs involved being the gastrointestinal tract and/or the liver. The site(s) of inversion for the 2-APAs have been a subject of debate, with presystemic intestinal metabolism in humans and hepatic systemic metabolism in rats receiving the most attention. The inversion of R-FN was studied in the male Sprague-Dawley rat 1) in vivo after p.o. and i.v. administration of racemic-FN and R-FN, 2) after perfusion of R-FN into isolated liver (single-pass and recirculation) and 3) after a 2-hr incubation with everted intestinal tissue (duodenum, jejunum, ileum and colon) and noneverted stomach pouch. The enantiomers and their acyl-glucuronides were quantitated using a previously developed stereospecific assay. With the isolated liver, R-FN was shown to invert in both the single-pass and recirculation systems, with a first-pass extraction ratio of 0.3. A significant but variable inversion in all intestinal segments was observed. Substantial inversion by the duodenum was observed (serosal S:R ratio, 1.2) with maximal inversion by the jejunum (serosal S:R ratio, 2.2), whereas inversion of R-FN was absent in the stomach. Considerable glucuronidation was observed in all tissues studied including first-pass glucuronidation of both enantiomers after single-pass perfusion through the isolated liver and stereoselective glucuronidation in intestinal tissue segments. The results indicate that, in the male Sprague-Dawley rat, R-FN undergoes presystemic inversion by both the gastrointestinal tract and liver. These results, however, must be viewed with caution as they may not necessarily be extrapolated to other 2-APAs or species.

Animals↗
PubMed1991

Lack of a pharmacokinetic interaction between doxapram and theophylline in apnea of prematurity.

To examine the possibility of a pharmacokinetic interaction between doxapram and theophylline, both drugs (1.5 mg/kg/h doxapram, and 0.5 mg/kg/h theophylline) were administered in that order and in reverse order to patients with apnea of prematurity. During the therapeutic steady state phase of doxapram considerable serum theophylline concentrations were found despite discontinuation of the latter drug for at least 48 h. Serum doxapram concentrations during theophylline steady state were negligible. Pretreatments of theophylline failed to alter the pharmacokinetic indices of doxapram. Thus, a lack of pharmacokinetic interaction between the two drugs was demonstrated.

Apnea↗
PubMed1990

Stereospecific high-performance liquid chromatographic assay of acebutolol in human plasma and urine.

A sensitive high-performance liquid chromatographic technique is described for the separation of R- and S-acebutolol in human plasma and urine. The procedure involves derivatization with the chiral reagent S-(+)-1-(1-naphthyl)ethyl isocyanate. The resulting diastereoisomers are quantified using normal-phase high-performance liquid chromatography with fluorescence detection (220/389 nm). Virtual baseline separation, free from interference, with achieved (resolution factor = 1.45). Excellent linearity (r greater than 0.998) was observed throughout the range 10-500 ng/l and 2-100 mg/l in plasma and urine, respectively. Inter-assay variability was less than 5% for each enantiomer at concentrations of 10 ng/ml. This method is applicable for the determination of the pharmacokinetics, in man, of acebutolol enantiomers in plasma and urine.

Acebutolol↗
PubMed1990

High-performance liquid chromatographic determination of the enantiomers of flecainide in human plasma and urine.

A stereospecific high-performance liquid chromatographic method for the determination of (R,S)-flecainide acetate [(R,S)-N-(2-piperidylmethyl)-2,5-bis-(2,2,2-trifluoroethoxy)benzam ide acetate] in human plasma and urine is described. After addition of the internal standard [IS; (R,S)-N-(2-piperidylmethyl)-2,3-bis(2,2,2-trifluoroethoxy)- benzamide hydrochloride], a single-step extraction of alkalinized samples was performed with distilled diethyl ether. The organic layer was evaporated and the drug and IS were derivatized with 1-[(4-nitrophenyl)sulfonyl]-L-propyl chloride at 80 degrees C for 2 h. The diastereomeric derivatives of flecainide and IS were chromatographed on a C18 reversed-phase column with a mobile phase consisting of acetonitrile: water:triethylamine (45:55:0.2) at a flow rate of 1 mL/min. Flecainide diastereomers were separated with a resolution factor of 1.25 and detected by UV spectroscopy at a wavelength of 280 nm. An excellent linearity was observed between the peak area ratios (flecainide derivatives:IS) and plasma concentrations, and the intra- and interday coefficients of variation were always less than 9.8%. The lowest quantifiable concentration was set at 50 ng/mL for each enantiomer (CV of 4.9 and 4.4%), while the lowest limit of detection (signal:noise, 3:1) was on the order of a few nanograms. The assay was used to study the pharmacokinetics of flecainide enantiomers in a patient receiving (R,S)-flecainide therapy. The steady-state plasma time courses for the enantiomers were found to be parallel, but the difference between (R)- and (S)-flecainide concentrations was significant. The urinary excretion data were consistent with the plasma results. The method is suitable for therapeutic monitoring of flecainide enantiomers and for stereoselective pharmacokinetic studies in humans.

Adult↗
PubMed1990

Clinical pharmacokinetics of ketoprofen and its enantiomers.

Ketoprofen, a potent nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid class, has been used clinically for over 15 years in Europe, and has recently been introduced in the United States. Although it possesses a chiral centre, with only the S-enantiomer possessing beneficial pharmacological activity, all ketoprofen preparations to date are marketed as the racemate. Ketoprofen exhibits little stereoselectivity in its pharmacokinetics. The enantiomers have similar plasma time-courses and do not seem to interact with one another. Hence, the data generated using nonstereospecific assays may be used to explain the pharmacokinetics of individual enantiomers. The absorption of ketoprofen is rapid and almost complete when given orally. Sustained release dosage forms are available, which may be beneficial due to the short terminal phase half-life of ketoprofen (1 to 3h). They may also decrease local gastrointestinal side effects. Although with these preparations the peak plasma drug concentration is reduced and time to peak is prolonged, the bioavailability is the same as that with regular release counterparts. Ketoprofen binds extensively to plasma albumin, apparently in a stereoselective manner. Substantial concentrations of the drug are attained in synovial fluid, the proposed site of action of NSAIDs. It is eliminated following extensive biotransformation to inactive glucuroconjugated metabolite. There is about 10% R to S inversion upon oral administration. Conjugates are excreted in urine, and virtually no drug is eliminated unchanged. The excretion of conjugates is closely tied to renal function; accumulation of conjugates occurs in the elderly, but not in young subjects or patients. Significant drug interactions have been demonstrated for probenecid, aspirin and methotrexate. There appears to be circadian variation, particularly in the absorption of ketoprofen. The relationship between concentration and anti-inflammatory effect has yet to be elucidated for this drug.

Drug Interactions↗
PubMed1990

Lack of significant interaction between low dose methotrexate and ibuprofen or flurbiprofen in patients with arthritis.

Low dose methotrexate (MTX) is widely used in the treatment of rheumatoid arthritis. Current product recommendations accompanying MTX preparations advise against concurrent usage of nonsteroidal antiinflammatory drugs (NSAID), and adverse pharmacokinetic interactions have been reported with this combination. Six patients who were receiving MTX were studied with both oral and parenteral MTX, 10-25 mg/dose, without NSAID and with ibuprofen (2400 mg/day) and flurbiprofen (300 mg/day) for 6 weekly doses. Serum MTX levels were obtained at frequent intervals. Serum was separated and MTX analyzed using a radioimmunoassay (RIA). There was no observable interaction between MTX and either ibuprofen or flurbiprofen, with respect to the area under the curve per unit dose, Cmax, Cmax/dose, Tmax, and serum half-life. The pharmacokinetic indices were not significantly influenced by the route of administration.

Administration, Oral↗
PubMed1989

Enantiomeric interaction of flurbiprofen in the rat.

Flurbiprofen [FL, (+/-)-2-(2-fluoro-4-biphenylyl)propionic acid] is a 2-arylpropionic acid nonsteroidal anti-inflammatory drug which is commercially available as a racemate. The anti-inflammatory activity of FL, however, appears to be mainly due to the S enantiomer. Recently, it has been postulated that, in both humans and rats, the two enantiomers of FL may interact when racemic doses are given. This study examines the above postulate in the rat by administration of single iv doses of racemic FL (10 mg/kg), and R- and S-FL (5 mg/kg of each). Plasma concentrations (0-12 h) of the enantiomers were measured using a stereospecific HPLC assay. A significant interaction was noticed between the enantiomers: mean AUC +/- SD of R-FL was reduced from 115.3 +/- 21.3 to 49.0 +/- 10.4 mg/L.h as a result of S-FL coadministration. A trend towards reduced S-FL plasma concentration was also evident when the enantiomer was given as the racemate [mean AUC +/- SD; 176.8 +/- 37.7 racemate versus 241.4 +/- 86.2 mg/L.h alone]. The reduction in S-FL, however, was not significant due perhaps to the observed interanimal variation. While the enantiomeric interaction caused a significant enlargement of the volume of distribution of R-FL, it failed to alter the terminal half-life of the enantiomer. It is suggested that the interaction is a result of displacement from plasma protein binding sites of one enantiomer by the other.

Animals↗
PubMed1989

Pharmacokinetics of ketoprofen enantiomers in cholecystectomy patients: influence of probenecid.

Ketoprofen (KT), a 2-arylpropionic acid nonsteroidal antiinflammatory drug, is administered as a racemate. Previous reports suggest stereoselective biliary excretion of KT enantiomers. This hypothesis was tested by administering 50 mg racemic KT to five patients who required bile drainage following cholecystectomy surgery. Subsequently, to study the influence of probenecid (PB), an inhibitor of KT renal elimination, on the biliary excretion, 1000 mg PB was administered 1.5 h before KT to the same patients. The unchanged and conjugated (as glucuronides) KT enantiomers were measured in plasma, urine and bile. In general, KT enantiomers had different plasma concentration-time curves. As compared to normal subjects, these patients had comparable AUCs and shorter t1/2s. Biliary concentrations of conjugated S-KT were greater than R-KT. Nevertheless, the total cumulative biliary excretion of conjugated KT did not exceed 2% of the dose ruling out this pathway as a significant route of KT elimination. There was a positive and significant correlation between the cumulative urinary excretion of conjugated KT enantiomers and creatinine clearance. Although PB did not influence the pattern of stereoselectivity of KT, it increased AUC and prolonged t1/2 of the enantiomers. While reducing cumulative urinary excretion, PB increased total biliary elimination of conjugated KT enantiomers. This, however, did not totally compensate for the reduced urinary excretion. It is suggested that the impaired conjugation of KT caused by PB administration may result in the augmentation of other, otherwise minor, metabolic pathways.

Adult↗
PubMed1988

Rapid and sensitive high-performance liquid chromatographic assay of tiaprofenic acid enantiomers in human plasma and urine.

A sensitive stereospecific high-performance liquid chromatographic assay of tiaprofenic acid (TA) enantiomers in human plasma and urine was developed. The biological specimens are acidified, and the drug and internal standard, (+/-)-2-(4-benzoylphenyl)butyric acid, extracted with an isooctane-isopropanol (95:5) mixture (plasma) or chloroform (urine), followed by sequential reaction of the enantiomers with trichloroethyl chloroformate and L-leucinamide. The reactions were complete at ambient temperature in less than 3 min. The diastereoisomers of TA and internal standard were then extracted into chloroform. The organic layer was evaporated, and the reconstituted residue chromatographed at ambient temperature on a C18 reversed-phase column with a mobile phase consisting of 0.06 M monopotassium phosphate-acetonitrile-triethylamine (65:35:0.02) at a flow-rate of 1 ml/min. The TA diastereoisomers were detected at 310 nm, free of interfering peaks, with a resolution factor of 2.1. Within the examined plasma and urine enantiomeric concentration ranges of 0.2-20 and 10-100 mg/l, respectively, an excellent linear relationship was obtained between the peak-area ratios and the corresponding concentrations. The assay was reproducible and sufficiently accurate to be applied to the stereoselective pharmacokinetic analysis of TA enantiomers in plasma and urine following administration of therapeutic doses of the drug.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1988

Pharmacokinetics of ketoprofen enantiomers in healthy subjects following single and multiple doses.

Ketoprofen (KT; m-benzoylhydratropic acid), a 2-arylpropionic acid (2-APA) nonsteroidal anti-inflammatory drug (NSAID), is marketed and used as a racemic mixture. Although generally the activity of 2-APAs is suggested to be mainly due to the S-enantiomer, information on KT pharmacokinetics is based on measurement of total concentrations of S- and R-enantiomers. In this work, using a crossover fashion, the pharmacokinetics of KT enantiomers following single (50 mg, po) and then multiple (50 mg, q6h for 3 d) doses were delineated in eight healthy subjects. A sensitive stereospecific HPLC assay was used to measure KT enantiomers in plasma and urine, and conjugated KT enantiomers in urine. There were no significant differences between the pharmacokinetic indices calculated after single and multiple administration of KT. In plasma, small but significant differences were found between concentrations of the enantiomers (mean S:R ratios of 0.81 +/- 0.19 after single and 0.87 +/- 0.11 after repeated doses). Negligible amounts of unchanged KT enantiomers were found in urine. More than 80% of the given doses was found in urine as conjugated S- and R-KT, the predominant enantiomer being S-KT (mean S:R ratios of 1.19 +/- 0.05 after single and 1.17 +/- 0.05 after repeated doses). No significant difference between the elimination t1/2 of the enantiomers was observed. It is suggested that stereoselective conjugation followed by preferential biliary excretion of the conjugated R-KT enantiomer is responsible for the observed stereoselectivity in the pharmacokinetics of the drug.

Adolescent↗
PubMed1988

Pharmacokinetics of ketoprofen enantiomers in young and elderly arthritic patients following single and multiple doses.

Ketoprofen (KT), a chiral nonsteroidal anti-inflammatory drug (NSAID), is marketed and used as a racemic mixture. In healthy volunteers, negligible differences have been reported between the plasma time courses of KT enantiomers. Using a stereospecific high-performance liquid chromatographic (HPLC) assay measuring (R)- and (S)-KT in plasma and urine, pharmacokinetics of the enantiomers following single (50 mg) and then multiple (50 mg every 6 h for 3 d) doses were delineated in nine young and nine elderly arthritic patients. There were no significant differences between pharmacokinetic indices calculated after single and multiple doses, or between the two groups. In plasma, there were no significant differences between intact enantiomers in either patient group. However, significantly more conjugated (S)-KT was found in elderly patient plasma. Similar to findings in healthy volunteers, elimination of conjugated KT in both patient groups was more extensive for the (S)-, as compared with the (R)-isomer. It is suggested that age-dependent impaired elimination of conjugated (S)-KT, along with preferential biliary excretion of conjugated (R)-KT, is responsible for these observations.

Adult↗
PubMed1988

Stereoselective pharmacokinetics of flurbiprofen in humans and rats.

Flurbiprofen, a 2-arylpropionic acid (2-APA) nonsteroidal anti-inflammatory drug (NSAID), exists as racemate and is used as such. Although the activity of 2-APAs is due mainly to their S-enantiomers, information on the pharmacokinetics of flurbiprofen is usually based on the measurement of total concentrations of S- and R-flurbiprofen. In this work, the pharmacokinetics of flurbiprofen enantiomers following single doses were studied in humans and rats. Upon iv administration of 10 mg/kg of racemic flurbiprofen to male Sprague-Dawley rats, the plasma concentrations were consistently higher for S-flurbiprofen than for R-flurbiprofen (AUC = 134 +/- 39 versus 41 +/- 9 mg.L-1 h). In bile duct-cannulated rats, the biliary excretion contained only 3.6-5.2% of the dose as conjugated flurbiprofen (S:R = 1.2-2.1). After administration of R-flurbiprofen to the rat, both enantiomers were found in plasma [AUC(R):AUC(S) = 0.10-0.16], indicating a limited extent of enantiomeric bioinversion. This is consistent with the previously reported limited extent of flurbiprofen uptake into fat. In healthy volunteers also, significant stereoselectivity was observed in the plasma concentration of the drug after 100-mg oral racemic doses [AUC-(S):AUC(R) = 45.4 +/- 12.7:40.1 +/- 14.3 mg.L-1.h]. As compared with the R-enantiomer, S-flurbiprofen has a smaller volume of distribution (7.23 +/- 1.9 versus 8.41 +/- 3.0 L) and total clearance (1.23 +/- 0.34 versus 1.47 +/- 0.50 L/h), but an equal half-life (4.21 +/- 1.2 versus 4.18 +/- 1.3 h). In urine, on the other hand, the R-configuration was predominant, as greater amounts of the R-enantiomer were found both as conjugated flurbiprofen and as an unidentified metabolite. Negligible amounts of intact flurbiprofen enantiomers were detected in urine. The observed stereoselectivity in humans cannot be attributed to enantiomeric bioinversion, as S-flurbiprofen was not detected in plasma and urine after oral administration of R-flurbiprofen.

Administration, Oral↗