Biomedical subjects

F Jamali

Publications and source records attributed to F Jamali.

At least 73 records · Page 4Linked to original sources

PubMed1993

Selective effect of adjuvant arthritis on the disposition of propranolol enantiomers in rats detected using a stereospecific HPLC assay.

Nonstereospecific studies have indicated that the pharmacokinetics of propranolol (PR) are altered in inflammatory conditions such as arthritis. However, as the kinetics and dynamics of PR are stereoselective, we examined the effect of adjuvant arthritis (AA) on the disposition of the individual enantiomers. A novel normal-phase stereospecific HPLC assay for PR was developed involving chiral derivatization with S-(naphthyl)ethyl isocyanate and fluorescence detection. Oral and iv doses of racemic PR were administered to control and AA rats (n = 6). AA had no significant effect on either clearance or S:R ratio after iv doses. On the other hand, after oral doses, clearance was significantly decreased in AA. Although significant for both enantiomers, this effect was more pronounced on the less active R-enantiomer. The AUC R:S ratio was, therefore, significantly altered (AA, 14 +/- 3.0; control, 4.3 +/- 1.2). Increased total (S+R) plasma concentrations of PR in AA, possibly due to a reduced intrinsic clearance, therefore, reflect mainly increased concentrations of the less active R-enantiomer.

Administration, Oral↗

PubMed1993

Stereoselective dissolution of propranolol hydrochloride from hydroxypropyl methylcellulose matrices.

Since many chiral pharmaceutical excipients, such as cellulose polymers and cyclodextrins, are used as stationary phases for the separation of enantiomers by high performance liquid chromatography (HPLC), it is hypothesized that one enantiomer of a chiral drug will be released faster than the other from a pharmaceutical formulation containing a racemic drug and a chiral excipient. The mechanism of such an event may arise from preferential intermolecular interaction between the chiral excipient and one of the enantiomers. To test this hypothesis, the release of the enantiomers of propranolol hydrochloride into water from formulations containing the chiral excipients, hydroxypropyl methylcellulose (HPMC) or beta-cyclodextrin, was investigated by stereospecific HPLC analysis of the dissolved concentrations of each of the enantiomers from the formulations. The release of the enantiomers of propranolol hydrochloride from the formulations containing HPMC, although variable, was found to be stereoselective. However, the release of propranolol hydrochloride enantiomers from the beta-cyclodextrin complex was found to be non-stereoselective.

Cyclodextrins↗

PubMed1992

Improved high-performance liquid chromatographic assay method for the enantiomers of ibuprofen.

A rapid, inexpensive and sensitive high-performance liquid chromatographic method for the quantitation of ibuprofen enantiomers from a variety of biological fluids is reported. This method uses a commercially available internal standard and has significantly less interference from endogenous co-extracted solutes than do previously reported methods. The method involves the acid extraction of drug and internal standard [(+/-)-fenoprofen] from the biological fluid with isooctane-isopropanol (95:5) followed by evaporation and derivatization with ethylchloroformate and R-(+)-alpha-phenylethylamine. Excellent linearity was observed between the peak-area ratio and enantiomer concentration (r > 0.99) over a concentration range of 0.25-50 micrograms/ml. This method is suitable for the quantitation of ibuprofen from single-dose pharmacokinetic studies involving either rats or humans.

Animals↗

PubMed1992

High-performance liquid chromatographic analysis of methocarbamol enantiomers in biological fluids.

Methocarbamol enantiomers in rat and human plasma were quantified using a stereospecific high-performance liquid chromatographic method. Racemic methocarbamol and internal standard, (R)-(-)-flecainide, were isolated from plasma by a single-step extraction with ethyl acetate. After derivatization with the enantiomerically pure reagent (S)-(+)-1-(1-naphthyl)ethyl isocyanate, methocarbamol diastereomers and the (R)-flecainide derivative were separated on a normal-phase silica column with a mobile phase consisting of hexane-isopropanol (95:5, v/v) at a flow-rate of 1.6 ml/min. Ultraviolet detection was carried out at a wavelength of 280 nm. The resolution factor between the diastereomers was 2.1 (alpha = 1.24). An excellent linearity was observed between the methocarbamol diastereomers/internal standard derivative peak-area ratios and plasma concentrations, and the intra- and inter-day coefficients of variation were always < 9.8%. The lowest quantifiable concentration was 0.5 microgram/ml for each enantiomer (coefficients of variation of 9.8 and 8.8% for (S)- and (R)-methocarbamol, respectively), while the limit of detection (signal-to-noise ratio 3:1) was approximately 10 ng/ml. The assay was used to study the pharmacokinetics of methocarbamol enantiomers in a rat following intravenous administration of a 120 mg/kg dose of racemic methocarbamol and to evaluate plasma and urine concentrations in a human volunteer after oral administration of a 1000-mg dose of the racemate. The method is suitable for stereoselective pharmacokinetic studies in humans as well as in animal models.

Animals↗

PubMed1992

Analytical and semi-preparative high-performance liquid chromatographic separation and assay of hydroxychloroquine enantiomers.

(+/-)-Hydroxychloroquine (HCQ) is an antimalarial and anti-arthritic drug which is administered as the racemate. An accurate, precise and sensitive high-performance liquid chromatographic assay was developed for the determination of HCQ enantiomers in samples from human plasma, serum, whole blood, and urine. After addition of (+/-)-chloroquine (internal standard), samples of blood component (0.5 ml) or urine (0.1 ml) were alkalinized and extracted with 5 ml of diethyl ether. After solvent evaporation the residues were derivatized with (+)-di-O-acetyl-L-tartaric anhydride at 45 degrees C for 30 min. The resulting diastereomers were then resolved using a C8 analytical column with a mobile phase consisting of 0.05 M KH2PO4 (pH 3)-methanol-ethanol-triethylamine (78:22:1:0.08). The ultraviolet detection wavelength was set at 343 nm. The derivatized HCQ enantiomers eluted in less than 40 min, free of interfering peaks. Excellent linear relationships (r2 > 0.997) were obtained between the area ratios and the corresponding plasma concentrations over a range of 12.5-500 ng/ml. The diastereomers could be hydrolysed using microwave energy and neutral pH, which enabled us to resolve the enantiomers on a semi-preparative (C18 column) scale. The method was suitable for the analysis and semi-preparative separation of HCQ enantiomers.

Adult↗

PubMed1992

Stereospecific high-performance liquid chromatographic assay of pirprofen enantiomers in rat plasma and urine.

A stereospecific high-performance liquid chromatographic method was developed for the assay of pirprofen enantiomers in rat plasma and urine. Following addition of internal standard (ketoprofen) and acidifier (L-ascorbic acid) to biological fluids, pirprofen was extracted into an isopropanol-isooctane (5:95) mixture. Diastereomers of pirprofen enantiomers, which were formed using L-leucinamide, were separated on a reversed-phase column with ultraviolet detection at 275 nm using 0.06 M KH2PO4-acetonitrile-triethylamine (64:36:0.1) as mobile phase. The limit of quantitation was 0.1 microgram/ml for each enantiomer, based on 100 microliters of rat plasma. No spontaneous oxidation of pirprofen to its pyrrole metabolite occurred during sample preparation and analysis. In three female rats which were dosed with 10 mg/kg racemic pirprofen orally, plasma concentrations of the enantiomers could be followed for 24 h. Pirprofen enantiomers in plasma were virtually unconjugated, and negligible concentrations of pyrrole metabolites were observed. Less than 10% of the total dose was recovered in urine as intact drug and its glucuroconjugates. The assay was found suitable for the study of the pharmacokinetics of pirprofen enantiomers in the rat.

Animals↗

PubMed1992

The stereoselective pharmacokinetics of etodolac in young and elderly subjects, and after cholecystectomy.

The pharmacokinetics of the enantiomers of etodolac were studied in six young subjects (ages 28 +/- 3.3 years), 6 nonarthritic elderly subjects (ages 73 +/- 6.0 years), and in three cholecystectomy patients after single oral doses of the racemate (200 mg). In all subjects, the plasma concentrations of R-etodolac, which is pharmacologically inactive, greatly exceeded those of the pharmacologically active S-enantiomer. Stereoselectivity was reflected in the pharmacokinetics, with R > S for maximum peak plasma concentration and area under the concentration versus time curve, and S > R for apparent oral clearance and apparent volume of distribution. On average, less than 25% of the dose of each enantiomer was excreted in the urine within 24 hours as alkali-labile conjugates; little or no unchanged drug was recovered. Bile constituted a minor route of elimination of etodolac as conjugated enantiomers. There were no significant differences in the pharmacokinetics of etodolac enantiomers between the young and elderly subjects. The results reflect the importance of considering stereoselectivity in evaluating the pharmacokinetics of etodolac.

Administration, Oral↗

PubMed1992

Effect of aging on the pharmacokinetics of acebutolol enantiomers.

Acebutolol (AC) is a chiral beta-blocker that is metabolized to an equipotent chiral metabolite, diacetolol (DC). A stereoselective disposition of AC and DC enantiomers has recently been reported in young healthy subjects. As many physiologic properties affecting drug disposition are progressively altered with increasing age, the effect of aging on the pharmacokinetics of AC and DC enantiomers were investigated in nine subjects ranging from 60 to 75 years after administration of an oral 200-mg dose of racemic AC. Increasing age resulted in a significant prolongation of the elimination t1/2s of R- (r = 0.913) and S-DC (r = 0.811). Also, the S:R ratios of AC urinary excretion (sigma Xu) of enantiomers was significantly correlated with age (r = 0.677). Contribution of declining renal function to age-associated pharmacokinetics changes was subsequently examined. Renal clearance and cumulative urinary excretion of both AC and DC enantiomers were positively correlated with creatinine clearance. In addition, declining creatinine clearance was associated with a subsequent decline in the enantiomer S:R ratio of AC in plasma (AUC S:R, r = 0.807) and urine (sigma Xu S:R r = 0.807). Similarly, a progressive decline in the S:R ratio of DC collected in urine was evident (r = 0.689). Age-related changes in the enantiomers ratios may suggest that an active stereoselective pathway such as renal tubular secretion or nonrenal excretion may be affected in the elderly.

Acebutolol↗

PubMed1992

Stereochemistry and bioequivalence.

Despite the fact that many important drugs are chiral, for a variety of reasons they are marketed as racemates (i.e., an equal proportion of two enantiomers). Although enantiomers of racemic drugs often differ from one another in their pharmacodynamic and pharmacokinetic properties, bioequivalence assessments are made using nonstereospecific assays. Such an approach may provide a poor assessment of therapeutic equality. This can be true particularly for drugs with complicated pharmacokinetics and those that exhibit extensive stereoselectivity in their disposition kinetics. Accordingly, examples of bioequivalence studies based on stereospecific assays have started to appear in the literature. Fortunately, facile stereospecific assays have become available in the last several years for many drugs. Consequently, regulatory agencies have started to take the issue of stereochemistry into consideration in the assessment of bioequivalence, particularly from the standpoint of generic substitution.

Chemistry, Organic↗

PubMed1992

Human pharmacokinetics of ibuprofen enantiomers following different doses and formulations: intestinal chiral inversion.

The influences of absorption rate and dosage size on the pharmacokinetics of ibuprofen (IB) enantiomers were studied in six healthy subjects. Rapidly absorbed solutions (50, 100, 200, 400, 600, and 1200 mg) and regular 600-mg tablets of racemic IB were given orally, and plasma concentration-time courses of the enantiomers were followed. Solutions were absorbed faster (tmax less than 0.25 h) than the tablet (tmax = 2.17 +/- 1.17 h). While the S:R AUC ratios were unaffected by increasing the dose, they were significantly greater after the tablet (1.35 +/- 0.14) as compared with the solutions (1.15 +/- 0.16 to 1.24 +/- 0.26). This indicates a greater extent of chiral inversion for the tablet, perhaps due to a longer residence time in the gut, thereby allowing more presystemic inversion. To test this hypothesis, R-IB was incubated at 37 degrees C in the presence of excised segments of human ileum and colon obtained from three patients. Chiral inversion was evident in all segments. After 3 h, the extent of inversion ranged from 20.0 to 33.0%. In addition, incubation resulted in the formation of up to 23.3 and 13.0% of acylglucuronides of S- and R-IB, respectively. In all subjects, the AUC-dose relationships were nonlinear, indicating a gradual increase in the clearance of both enantiomers due, perhaps, to a parallel saturation of plasma protein binding sites. In humans, the chiral inversion of IB is not influenced by the dosage size but is enhanced by prolongation of the residence time in the intestine.

Administration, Oral↗

PubMed1992

Effect of adjuvant arthritis on the disposition of acebutolol enantiomers in rats.

Disease states such as arthritis may interact with the kinetics of beta-blockers. Acebutolol (AC) is a chiral beta-blocker which is available as a racemate. The beneficial properties of AC, however, is attributed mainly to the S-(+)-enantiomer. The disposition of AC enantiomers and their active, chiral metabolites, diacetolol (DC) were examined after oral administration to healthy and adjuvant-induced arthritic (AA) female Sprague-Dawley rats. Arthritis was induced by tail base injection of Mycobacterium butyricum. Swelling of hind and forepaws were apparent in 10-16 days in AA but not controls. Control and AA rats were sacrificed at 0.5, 1, 2, 4, 6 and 8 h after a 25 mg/kg oral AC dose and blood was collected (n = 6). Significant three to tenfold increases in the initial plasma concentrations (0.5-2 h) of AC were observed in AA. Enantiomers were equally affected, thus AC S:R ratio was not changed. Higher plasma concentrations of the metabolite were only significant at 2 h. The ratio of DC:AC, however, was unaffected by AA. The DC S:R ratio was significantly decreased at 0.5 and 1 h in AA. The limited protein binding of AC (10%) was neither stereoselective nor affected by AA. Reduced intrinsic clearance in AA may be responsible for these observations.

Acebutolol↗

PubMed1992

Clinical pharmacokinetics of ketorolac tromethamine.

Ketorolac is a new chiral nonsteroidal anti-inflammatory drug (NSAID) which is marketed for analgesia as the racemate. The drug is administered as the water soluble tromethamine salt and is available in tablets or as an intramuscular injection. The absorption of ketorolac is rapid, Cmax being attained between 20 to 60 min. Its oral bioavailability is estimated to range from 80 to 100%. The drug is extensively bound (> 99%) to plasma proteins and has a volume of distribution (0.1 to 0.3 L/kg) comparable with those of other NSAIDs. Only small concentrations of ketorolac are detectable in umbilical vein blood after administration to women in labour. The elimination half-life is between 4 and 6h and is moderate in comparison with other NSAIDs. The area under the plasma concentration-time curve of ketorolac is proportional to the dose after intramuscular administration of therapeutic doses to young healthy volunteers. Ketorolac is extensively metabolised through glucuronidation and oxidation; little if any drug is eliminated unchanged. Most of the dose of ketorolac is recovered in the urine as conjugated drug. Although ketorolac is excreted into the breast milk, the amount of drug transferred comprises only a small fraction of the maternal exposure. Little stereoselectivity was present in the pharmacokinetics of ketorolac in a healthy volunteer receiving single intravenous or oral doses. The elderly exhibit reduced clearance of the drug. Renal insufficiency appears to cause an accumulation of ketorolac in plasma, although hepatic disease may not affect the pharmacokinetics.

Absorption↗

PubMed1991

Simultaneous determination of ketoprofen enantiomers and probenecid in plasma and urine by high-performance liquid chromatography.

A rapid, sensitive, stereospecific reversed-phase high-performance liquid chromatographic method was developed for simultaneous quantitation of ketoprofen enantiomers, probenecid and their conjugates in biological fluids. Following addition of the internal standard, indoprofen, the constituents were extracted into isooctane-isopropanol (95:5), water-washed, extracted with chloroform, then evaporated and the residue sequentially derivatized with ethyl chloroformate and L-leucinamide hydrochloride. The formed diastereomers were chromatographed on a reversed-phase column with a mobile phase of 0.06 M KH2PO4-acetonitrile-triethylamine (65:35:0.1) at a flow-rate of 1 ml/min and a detection wavelength of 275 nm. The minimum quantifiable concentration was 0.5 micrograms/ml in 100 microliters of rat plasma and urine samples. The intra- and inter-day coefficients of variation for this method are less than 10%. The assay is successfully applied to a pharmacokinetic study. The simultaneous analysis of probenecid with several other non-steroidal anti-inflammatory drugs was also successful.

Animals↗

PubMed1991

Stereoselective disposition of etodolac enantiomers in synovial fluid.

The synovial fluid (SF) uptake of the chiral nonsteroidal anti-inflammatory drug, etodolac, was studied in six arthritic patients, 2 hours (n = 1) or 12 hours (n = 5) after a single 200 mg dose of racemate. Marked stereoselectivity was seen in both SF and plasma; concentrations of pharmacologically inactive R-etodolac were up to 10-fold greater than active S-etodolac. Concentrations of S-etodolac were greater in SF than in plasma (SF:plasma ratio = 1.98 +/- 0.8): No such difference was seen for R-etodolac (SF:plasma = 0.91 +/- 0.3). Considerable concentrations of conjugated enantiomers were present in SF. In vitro equilibrium dialysis studies in drug-spiked samples showed that the unbound fraction of both enantiomers in SF was greater than in plasma; both fluids bound R more extensively than S etodolac. Therapeutically active S-etodolac has greater concentrations in synovial fluid than plasma during the post-distributive phase, which may be of possible clinical relevance.

Aged↗

PubMed1991

Pharmacokinetics of acebutolol enantiomers in humans.

The chiral beta-blocker acebutolol (AC) is marketed as a racemic mixture. Both AC and its major metabolite, diacetotol (DC), are chiral, the S-enantiomer possessing beta-blocking activity. The pharmacokinetics of AC and DC enantiomers was determined in 12 healthy subjects following oral administration of 200 mg of AC. Plasma and urine were collected over a 24-hr period and both AC and DC enantiomers were measured utilizing a stereospecific HPLC assay. Concentrations of S-AC were predominant in both plasma and urine [AUC S:R, 1.20 +/- 0.1; cumulative urinary excretion (sigma Xu) S:R, 1.17 +/- 0.05), which corresponded to a significantly greater oral clearance of R-AC (106 +/- 30 L/h) than S-AC (87 +/- 22 L/h). The Cmax of R-DC was significantly greater than for S-DC (S/R 0.7 +/- 0.1). The half-life (t1/2) of R-DC (6.4 +/- 1.6 h) was significantly shorter than that of S-DC (8.8 +/- 2.4 h). The observed AUC values for R- and S-DC were not significantly different. Renal clearance of R-DC (70 +/- 34 mL/min) was significantly greater than that of S-DC (53 +/- 29 mL/min). The data suggest that the first-pass metabolism of R-AC to R-DC is stereoselective. This metabolism, coupled with the stereoselective renal excretion of R-DC is likely a major contributor to the observed stereoselective disposition of AC and its major metabolite in humans.

Acebutolol↗

PubMed1991

Enantioselective pharmacokinetics of etodolac in the rat: tissue distribution, tissue binding, and in vitro metabolism.

The nonsteroidal anti-inflammatory agent etodolac (ET) exhibits stereoselectivity in its pharmacokinetics following administration to humans and rats. To underline the factors responsible for this stereoselectivity, the tissue distribution, in vitro tissue binding, and microsomal metabolism of ET enantiomers were studied in the rat. Following iv administration of racemic ET, the S:R AUC ratios in tissues were stereoselective, and different from that in plasma. Binding of enantiomers to tissues was stereoselective, although it did not relate well with in vivo tissue distribution. Rather, the tissue distribution of enantiomers appeared to be better explained by the unbound fractions of enantiomers in plasma. With respect to in vitro glucuronidation by liver microsomes, the Vmax of S-ET was 3.4-fold greater than that of R-ET; the enantiomers possessed similar Km. There appeared to be stereoselectivity in the oxidative metabolism of ET enantiomers by liver and kidney microsomes, in favor of the R-enantiomer. The lower AUC in rat plasma of pharmacologically active S-ET as compared with its antipode is due to its relatively greater distribution to tissues, owing to a lesser degree of binding to plasma proteins, and to its higher rate of glucuronidation.

Animals↗

PubMed1991

Stereoselective disposition of ibuprofen enantiomers in the isolated perfused rat kidney.

The renal clearance of ibuprofen enantiomer was studied separately in the isolated perfused rat kidney at initial perfusate concentrations of 10 micrograms/ml (n = 4) and 100 micrograms/ml (n = 4). Perfusate and urine samples were measured for R(-) and S(+)-ibuprofen using a stereospecific HPLC assay; urine samples were also analyzed after alkaline hydrolysis. Functional viability of the kidney was assured by determining the fractional excretion of glucose and glomerular filtration rate (GFR) at similar perfusion pressures. The clearance of ibuprofen was equivalent to the apparent formation clearance of conjugated enantiomer since unchanged ibuprofen could not be detected in the urine. At 10 and 100 micrograms/ml, the clearance (+/- SD) of R(-)-ibuprofen was 2.50 +/- 1.28 and 2.19 +/- 1.42 microliters/min, respectively. At 100 micrograms/ml, the clearance of S(+)-ibuprofen was 0.805 +/- 0.290 microliters/min. The protein binding of ibuprofen was found to be concentration dependent and favored the R(-)-enantiomer. The excretion ratio (clearance corrected for free fraction and GFR) of R(-)-ibuprofen was 0.398 +/- 0.209 and 0.295 +/- 0.209 for perfusate concentrations of 10 and 100 micrograms/ml, respectively. The excretion ratio of S(+)-ibuprofen was 0.0886 +/- 0.0335 for perfusate concentrations of 100 micrograms/ml. These results demonstrate that the sum of renal mechanisms involved for the clearance of R(-)- and S(+)-ibuprofen was net reabsorption. Ibuprofen was recovered in the urine solely as conjugated material and no evidence of R(-) to S(+) conversion was observed. In addition, the data suggest that R(-)-ibuprofen is cleared through the kidney faster than its S(+)-enantiomer.

Animals↗

PubMed1991

Clinical pharmacokinetics of drugs used in juvenile arthritis.

Juvenile arthritis is defined as the occurrence of objective evidence of arthritis for a minimum of 6 weeks, in a child 16 years of age or younger. With a reported incidence of 9 to 19.6 per 100,000 children, juvenile arthritis is considered to be a rare disease. There is no known cure; however, up to 75% of patients will undergo remission by late adolescence. Drugs used in the treatment of juvenile arthritis are divided into 2 major classes: (a) the nonsteroidal anti-inflammatory drugs (NSAIDs) including salicylates, naproxen, ibuprofen, fenoprofen, ketoprofen, flurbiprofen, indomethacin, sulindac, tolmetin and diclofenac, and (b) disease modifying agents which encompass drugs such as antimalarial agents, gold, methotrexate, penicillamine and sulfasalazine. In almost all the reports dealing with the pharmacokinetics of NSAIDs, the level of disease activity has not been noted. The level of activity is important since, during a flare, the plasma albumin may fall to the point that it causes a substantial and clinically significant increase in the unbound serum concentration of highly bound drugs. The relationship between the concentration of these drugs in the systemic circulation and their efficacy is not clear. However, for many of them, therapeutic drug monitoring is recommended as a means of reducing the possibility of toxic reactions. Further pharmacokinetic and -dynamic evaluations are needed for many of these drugs in juvenile arthritis.

Adolescent↗