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Biomedical subjects

F Jamali

Publications and source records attributed to F Jamali.

At least 55 records · Page 3Linked to original sources
PubMed1995

Diurnal variation in the pharmacokinetics of nizatidine in healthy volunteers and in patients with peptic ulcer disease.

Six healthy volunteers and six patients with asymptomatic duodenal ulcer disease received placebo or 300 mg nizatidine once at night or twice daily (morning and evening) for a week in a random, cross-over fashion. Steady-state serum nizatidine concentrations and gastric pH were measured over a 24-hour period. No significant differences in the pharmacokinetic indices were observed between the healthy volunteers and patients with duodenal ulcer disease. In patients with duodenal ulcers, significantly lower peak serum concentrations, longer half-life (t1/2) and larger volume of distribution (Vd) were observed after the night doses compared with the daytime doses. The diurnal variation in drug kinetics between the nighttime and daytime doses in the twice daily regimen may be caused by a slower absorption rate, paralleled with a higher extent of distribution. Despite lower serum nizatidine concentrations, gastric pH was higher in the evening than in the daytime; it is speculated that this was due to a time-dependent enhanced distribution of the H2-receptor blocker into the site of action.

Adult↗
PubMed1995

Inclusion complexation of heptakis(2,6-di-O-ethyl)-beta-cyclodextrin with tiaprofenic acid: pharmacokinetic consequences of a pH-dependent release and stereoselective dissolution.

beta-Cyclodextrin was ethylated at the 2- and 6-hydroxyl positions. Diethyl sulfate was employed as an alkylating reagent. NMR spectra data indicate that heptakis(2,6-di-O-ethyl)-beta-cyclodextrin (DCD) is the principal component of the product obtained. In addition, the FAB mass spectra obtained in nitrobenzyl alcohol and glycerin matrices gave pseudo-molecular ions with m/z ratios of 1630.75 and 1711.90 corresponding to C70H126O35[2Na.NaCl] and C70H126O35[2C3H8O3], respectively. The dissolution of tiaprofenic acid (TA) enantiomers, from TA powder (10 mg) and inclusion complex and/or coprecipitate (IC) (TA:DCD 1:1 molar ratio, equivalent to 10 mg of free TA), were examined using the dispersion method at pH values of 1.5, 3.0, and 7.4. Complex formation with the hydrophobic DCD resulted in a significant reduction in the release rate of both R- and S-TA, as compared to that observed with the powder. At pH 1.5, tiaprofenic acid enantiomers were not released from IC, compared to 20.52 +/- 1.47% of R-TA and 20.47 +/- 1.64% of S-TA dissolved from the powder. The greatest stereoselectivity in release profiles was found at pH 3.0 from IC [S:R 24 h cumulative percent release (sigma R24) ratio of 0.88 +/- 0.04]. Elevation of the pH to 7.4, which resulted in a faster dissolution and greater sigma R24 of enantiomers from both powder and IC, was accompanied by a parallel reduction in the stereoselectivity. Following single 20 mg/kg oral doses of racemic TA as both powder or IC to Sprague-Dawley rats, significant stereoselectivity was observed in the plasma concentration profiles of the enantiomers (S:R AUC(0-infinity) = 1.5). Despite significant reduction in the rate and extent of absorption, there was not a significant difference in the observed in vivo stereoselectivity between the two formulations. Therefore the in vivo importance of the observed stereoselectivity in release at pH 3.0 is ruled out. Nevertheless, consideration must be given to the possibility of stereoselective release when chiral excipients are used in the formulation of racemic drugs.

Animals↗
PubMed1995

Sucrose urinary excretion in the rat measured using a simple assay: a model of gastroduodenal permeability.

PURPOSE: To develop a non-invasive animal model suitable for studies of altered gastroduodenal (GD) permeability, which is suggested to indicate GD damage; to validate a low cost and convenient assay for sucrose in urine, a permeability marker of GD. METHODS: Control (n = 87) and treated male Sprague-Dawley rats were dosed orally with 1 g of sucrose. Urinary excretion of the sucrose (0-8 h) was measured indirectly by cleavage to glucose and subsequent measurement of glucose in urine using a calorimetric assay. Treated rats were administered single oral doses of 10 and 20 mg/kg indomethacin, or 42 mg/kg aspirin alone or with 0.5 mL 50% ethanol (n = 7 in each group). RESULTS: The assay was linear within the examined range of 10-100 ug/mL sucrose. The inter and intraday variations were 7.63% and 6.89%, respectively. The urinary excretion of sucrose was complete in 8 h. In control rats the urinary excretion of sucrose exhibited a left skewed frequency distribution curve with a mean of 0.6 +/- 0.14% of the dose excreted. All treatment, with the exception of 10 mg/kg indomethacin significantly increased the GD permeability. The GD effect was found to be dose dependent and parallels those reported for humans. CONCLUSIONS: The rat is a suitable model for studies of GD permeability. Combined use of sucrose and 51Cr-EDTA, a marker of intestinal permeability, allows for non-invasive examination of abnormalities of the entire gut. The sucrose assay is convenient and cost effective. The rat model may be useful in the preclinical screening of NSAID formulations and also in the detection of other GI abnormalities.

Animals↗
PubMed1995

The problem of racemization in the stereospecific assay and pharmacokinetic evaluation of ketorolac in human and rats.

PURPOSE: A comparison of a previously reported indirect (precolumn derivatization) assay for ketorolac (KT) and a new direct method described here was made to establish the conditions under which KT may undergo racemization and to explain the observed discrepancies in the pharmacokinetics of KT reported in the literature. METHODS: A previously reported pre-column derivatization method and a new direct method were employed to determine the effect of pH and ionic strength on racemization. Using the conditions where no racemization occurred, the pharmacokinetics in humans and rats, and protein binding of KT enantiomers were determined. RESULTS: Under the chromatographic conditions employed for the direct assay, no racemization was observed. Under high pH and ionic strength, however, both methods resulted in KT racemization. The indirect method resulted in rapid and complete racemization due to the strong basic conditions required for derivatization. In both humans and rats, the pharmacokinetics of racemic KT were stereoselective with the R enantiomer being predominant (AUC S/R: humans, 0.26; Rats: 0.45). This is likely due to more extensive plasma protein binding of S than its antipode (unbound S/R: 1.35). CONCLUSIONS: The discrepancies in the literature may be explained by rapid racemization of KT that occurs during sample preparation for the pre-column derivatization method. Considerations should be given to the possibility of racemization during the assay development and validation.

Animals↗
PubMed1995

Influence of severity of inflammation on the disposition kinetics of propranolol enantiomers in ketoprofen-treated and untreated adjuvant arthritis.

Clearance of the beta-blocker, propranolol (PR), is decreased in inflammatory conditions such as arthritis, in both humans and rats. However, inflammation in arthritic patients is often controlled by drugs such as the nonsteroidal antiinflammatory drugs (NSAIDs). Therefore, it is possible that arthritic-induced changes in drug disposition are minimized or suppressed in subjects receiving NSAIDs. To examine this hypothesis, we induced mild and severe adjuvant arthritis (AA) in rats and daily doses of the NSAID, ketoprofen (KT), were given to half of these rats. The pharmacokinetics of PR were thus examined in nontreated (MILDcontrol and SEVEREcontrol) and KT-treated (MILDKT and SEVEREKT) arthritic rats. Treatment with KT significantly reduced the arthritic index (AI) in the severe model of AA. In AA, the AUC0-8 of R- and S-PR were not significantly different in MILDKT rats (R, 15.8 +/- 9.5; S, 1.72 +/- 9.1 mg.hr/liter) as compared with MILDcontrol rats (R, 16.2 +/- 12; S, 1.76 +/- 1.2 mg.hr/liter). On the other hand, the AUC0-8 of both enantiomers were significantly lower in SEVEREKT (R, 39.2 +/- 13.2; S, 2.92 +/- 1.2 mg.hr/liter) as compared with SEVEREcontrol (R, 79.9 +/- 17; S, 6.88 +/- 2.1 mg.hr/liter). A high correlation between disease severity (AI) and the AUC0-8 of R- (r = 0.82) and S-PR (r = 0.81) was observed in all groups. Furthermore, the relationship between the AI and protein binding of R- and S-PR was significant in severe AA. Therefore, increased plasma concentrations of PR in arthritis are related to the degree of inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Evidence of absorption rate dependency of ibuprofen inversion in the rat.

Ibuprofen (IB) is a chiral 2-arylpropionic acid derivative used as a nonsteroidal antiinflammatory drug (NSAID). It undergoes substantial R to S chiral inversion in humans and rats. In addition to systemic inversion, presystemic chiral inversion has been suggested for IB in humans but only after administration of formulations with slow absorption rates. In search for a suitable animal model, the absorption rate dependency of the extent of inversion was examined in male Sprague-Dawley rats given 20 mg/kg of racemic IB in aqueous solution (Tmax, 0.6 h), suspension (Tmax, 1 h) or as sustained release granules (Tmax, 2.3 h). In addition, (R)-IB (5 mg/liter) was incubated in the presence of everted rat gut segments in an organ bath at 37 degrees. After sustained release granules, the S:R AUC ratios (7.3 +/- 1.5) were significantly higher than suspension (3.6 +/- 1.1) and solution (3.5 +/- 0.2). Accordingly, AUCS and AUCR, as percent of the total AUC (S+R), significantly increased and decreased, respectively, after administration of the sustained released granules as compared with the solution and suspension. A significant positive linear correlation was found between the S:R AUC ratios and the corresponding Tmax for (R)-IB (r = 0.82). In vitro, (R)-IB was inverted by everted jejunum (12.2 +/- 1.6%), ileum (14.2 +/- 2.0%), and colon (4.4 +/- 0.6%) segments. IB was also glucuronidated in the presence of the intestinal segments. Therefore, similar to earlier observations made in humans, in the rat, the S:R AUC ratio was positively and significantly correlated with the absorption rate from the dosage form.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Hematologic disposition of hydroxychloroquine enantiomers.

Hydroxychloroquine (HCQ) is a racemic antiarthritic agent that has a long half-life (t1/2) in plasma and accumulates in blood cells. To study the relationships between HCQ concentrations in plasma, serum, and whole blood and to determine the optimal blood fraction to use for therapeutic drug monitoring of the drug, we studied the relative distribution of the HCQ enantiomers in various fractions of human blood under in vivo and in vitro conditions. Substantially greater concentrations of both enantiomers were found in serum as compared with plasma because of release via platelet activation. After in vitro incubations of the separated blood cells with HCQ, high concentrations of both enantiomers were found in leukocytes, and low concentrations in erythrocytes and platelets; the R:S ratio in vitro was near unity in all of the cells examined. Unlike the in vitro cellular uptake, the concentrations of HCQ in vivo were significantly lower and stereoselective (R:S ratio = 2). There was almost no drug in the polymorphonuclear cells (PMN) in vivo, despite a substantial uptake in vitro after incubation of separated cells. The enantiomeric (R:S) ratio in the urinary excretion of the enantiomers was significantly correlated with that in plasma. The plasma-protein binding of the enantiomers was stereoselective and complimented the cellular uptake findings; the unbound fraction was dependent on the plasma concentrations of alpha 1-acid glycoprotein, but not albumin. Although concentrations in whole blood correlated well with those in lymphocytes and monocytes (the proposed site of HCQ action), stronger correlations were found between concentrations in serum and in the mononuclear cells.

Adult↗
PubMed1994

Human pharmacokinetics of tiaprofenic acid after regular and sustained release formulations: lack of chiral inversion and stereoselective release.

The pharmacokinetics of tiaprofenic acid (TA) enantiomers was studied following oral administration of 300 mg of racemic TA in regular or sustained release (SR) capsules to four healthy male subjects, in cross-over fashion. The possibility of stereoselective release from either formulations was examined using the USP basket dissolution apparatus. In vitro dissolution rate from regular tablets was very rapid and comparable for S- and R-TA. While, the release from the SR capsules at pH 7.4 was slow and incomplete, with R-TA having 10.1 +/- 9.4% greater 24 h cumulative release than S-TA, the apparent stereoselectivity in dissolution disappeared at pH 8.0. After the regular formulation, TA was absorbed rapidly (Tmax, 1.5 h) and eliminated with a t1/2 of 2 h and superimposable plasma concentration-time curves. The SR formulation had a slower rate of absorption (Tmax, 4 h) and bioavailability comparable to that of the regular formulation. Similar to the examined regular release tablet, no significant stereoselectivity was observed in the plasma concentration and urinary excretion of the enantiomers after the SR formulation, suggesting that the dissolution test at pH 8.0 better reflects the in vivo conditions. Therefore, R-TA does not undergo significant chiral inversion in humans.

Adult↗
PubMed1994

Dose-dependency of flurbiprofen enantiomer pharmacokinetics in the rat.

Flurbiprofen is a chiral 2-arylpropionate used clinically as a racemate. Previously a significant pharmacokinetic interaction between the enantiomers of flurbiprofen has been reported in both rats and humans. The possible mechanism for this interaction was believed to involve competitive protein binding between the enantiomers. In addition, the saturable binding of flurbiprofen enantiomers in vitro in human plasma has been demonstrated. In this study different doses of racemic flurbiprofen were administered to rats to create differing extents of competition for protein binding sites between the enantiomers. There was a statistically significant dose-dependent increase in total body clearance and volume of distribution of both the R and S enantiomers. However, there was no change in either the S/R AUC ratio or the elimination rate constants for (R)- or (S)-flurbiprofen with increasing dose. These results are consistent with the hypothesis that the increasing amount of (R)- and (S)-flurbiprofen in the body causes displacement of flurbiprofen enantiomers from their protein binding sites, resulting in their increased total body clearance and volume of distribution. Further, the data suggest that previously reported extents of R to S enantiomeric inversion for other 2-arylpropionates may not be accurate if the enantiomers exhibit nonlinear kinetics or there is a significant kinetic interaction between the enantiomers.

Animals↗
PubMed1994

Antiinflammatory drug-induced small intestinal permeability: the rat is a suitable model.

Excretion of orally administrated 51Cr-EDTA as a marker of small intestinal permeability (a proposed prerequisite for human enteropathy) is increased by corticosteroids and non-steroidal antiinflammatory drugs (NSAIDs). We have investigated the suitability of the rat as an animal model of small intestinal permeability using orally administered 51Cr-EDTA. We dosed Sprague-Dawley rats with NSAIDs and corticosterone followed by 51Cr-EDTA under conditions reported for humans and measured urinary excretion of the marker. In control rats, the urinary excretion of 51Cr-EDTA exhibited a skewed-to-the-left frequency distribution curve with a median of 2.13% of the dose. No sex-related differences were noticed in the baseline permeability. In male rats, single therapeutically equivalent doses of indomethacin, flurbiprofen, ibuprofen, naproxen, diclofenac, sulindac, nambumetone, and corticosterone, increased the intestinal permeability by different extents with indomethacin eliciting the maximum effect, and the last four drugs showing minimal potencies. Therapeutically relevant doses of aspirin did not have any significant effect. The increase in permeability was dependent upon the NSAIDs dose. Administration of glucose/citrate, misoprostol and sulfasalazine significantly reduced the effect of indomethacin. Misoprostol antagonized the effect of naproxen but H2-antagonists and sucralfate did not. All the above observations made in the rat were similar to those previously reported for humans. Thus the rat is a suitable model for studies of small intestinal permeability.

Animals↗
PubMed1994

Etodolac clinical pharmacokinetics.

Etodolac is a chiral nonsteroidal anti-inflammatory drug (NSAID) that is marked as the racemate. Currently, the drug is available in several countries for the treatment of arthritis and the alleviation of pain. Etodolac possesses several unique disposition features mainly due to its stereoselective pharmacokinetics. In plasma, the concentrations of the 'inactive' R-enantiomer are about 10-fold higher than those of the active S-enantiomer, an observation that is novel among the chiral NSAIDs. In common with other NSAIDs, the drug is highly plasma protein bound, and undergoes virtually complete biotransformation to oxidised metabolites and acyl-glucuronides. Etodolac is well absorbed, with maximal plasma concentrations attained within 1 to 2 hours in healthy volunteers. The area under the plasma concentration-time curve of racemic etodolac increases linearly with doses used clinically. The elimination half-life of etodolac is between 6 and 8 hours in plasma, and is similar for both enantiomers. The volume of distribution (Vd) of racemic etodolac is higher than that of most other NSAIDs mainly because of the extensive distribution of the S-enantiomer. The very large Vd of the S-enantiomer, compared with its antipode is, at least in part, due to its less extensive plasma protein binding. In addition to the unchanged drug, substantial concentrations of the acyl-glucuronides of etodolac are found in both plasma and the synovial fluid of patients with arthritis. A limited amount of conjugated etodolac is found in the bile of patients following cholecystectomy. Hepatic cirrhosis has no effect on the pharmacokinetics of racemic etodolac, although the effect of hepatic dysfunction on the pharmacokinetics of the individual enantiomers has yet to be determined. In elderly non-arthritic individuals with excellent kidney function, aging does not affect the pharmacokinetics of etodolac. The pharmacokinetics of the drug in patients with renal failure have not been published, and may be important because the acyl-glucuronides are renally cleared.

Aging↗
PubMed1993

Limited extent of stereochemical conversion of chiral non-steroidal anti-inflammatory drugs induced by derivatization methods employing ethyl chloroformate.

A potential problem with chiral derivatization is the possibility of stereochemical conversion during the derivatization reaction. This possibility has been examined using the non-steroidal anti-inflammatory drugs ibuprofen, ketoprofen, etodolac and flurbiprofen. To avoid possible interference from stereochemical impurities, male Sprague-Dawley rats were dosed intraperitoneally with the S enantiomer (100 mg/kg) of each drug and the R enantiomer of etodolac. Blood samples were taken 4 h afterwards. The plasma samples were analyzed using published stereospecific methods involving chiral derivatization with ethyl chloroformate followed by either R-(+)-alpha-phenylethylamine or L-leucinamide. For all the drugs examined, the percentage of formation of the antipode was between 1.0 and 5.8%. In vitro studies of the R and S enantiomers demonstrate that the apparent extent of conversion is inversely related to the concentration of ethyl chloroformate present during the derivatization reaction for ibuprofen, ketoprofen and flurbiprofen but not for etodolac. However, both the R and S enantiomers appear to be inverted to the same extent in the presence of ethyl chloroformate. These results suggest that the degree of stereochemical conversion induced by these assay procedures is small and would not contribute significantly to analytical error in the absence of a large difference in concentrations of the enantiomers.

Animals↗
PubMed1993

Influence of the route of administration on the pharmacokinetics of pirprofen enantiomers in the rat.

The pharmacokinetics of the enantiomers of the non-steroidal anti-inflammatory drug pirprofen were studied in male Sprague-Dawley rats after oral and intravenous (iv) doses of the racemate. No significant differences were detected between the enantiomers after oral or iv dosing in t1/2, Vd, or sigma Xu. However, the R:S area under the plasma concentration (AUC) ratio after oral doses (0.92 +/- 0.13) was slightly but significantly lower than after matching iv doses (1.05 +/- 0.036). The absolute bioavailability of the active S-enantiomer (78.5%) after oral doses was higher than the inactive R-enantiomer (69.3%). The plasma protein binding of both enantiomers was saturable over a fivefold range of plasma concentrations. At higher plasma concentrations, the S-enantiomer was less bound than the R-enantiomer. In an in vitro experiment using everted rat jejunum, no chiral inversion was discernible. The dependency of the AUC ratio of the enantiomers on the route of administration may be due to stereoselective first-pass metabolism.

Administration, Oral↗
PubMed1993

Ketoprofen pharmacokinetics in the elderly: influence of rheumatic disease, renal function, and dose.

An age-related accumulation of ketoprofen due to a reduced clearance has been reported in the elderly. Other studies have not observed these changes in the kinetics of unchanged ketoprofen, but have reported increased plasma levels and reduced urinary excretion of conjugated ketoprofen. The authors examined the effects of dose, renal function, and the presence of arthritis on the stereoselective kinetics of ketoprofen in five nonarthritic and six arthritic elderly subjects. There was a significant difference in renal function (CLCr, mL/min; arthritic, 71.8 +/- 12.3, nonarthritic, 91.4 +/- 11.1), but not in age or weight between the two groups. Subjects received 50 mg and then 150 mg enteric-coated racemic ketoprofen, and plasma and urine samples were collected for 24 hours. No significant differences in CL/F, area under the curve (AUC), half-life (t1/2), time to reach peak concentration (tmax), or maximum peak plasma concentration (Cmax) were found between groups or between doses, and values were similar to those previously reported in young adults. Urinary ketoprofen conjugate (S:R) ratio was 1.6 +/- .25 and 1.65 +/- .27 for arthritic and nonarthritic subjects. Greater amounts of conjugated ketoprofen enantiomers were present in the plasma of the arthritic compared with nonarthritic subjects. Renal clearance of ketoprofen conjugates exhibited stereoselectivity (R > S), and was decreased in the arthritic group. Significant changes in the kinetics of unchanged ketoprofen was not found to occur in elderly subjects in the presence or absence of rheumatic disease or moderate renal impairment.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1993

Ketoprofen-probenecid interaction in the rat: a probenecid concentration-dependent stereoselective process.

Probenecid (PB) is believed to interact with the chiral nonsteroidal anti-inflammatory drug ketoprofen (KT) through competition for glucuronide conjugation and subsequent renal and/or biliary excretion of formed KT conjugates. It is unknown whether the interaction is dependent on PB concentration and whether both KT enantiomers are affected to the same extent. We measured intact and conjugated R-KT, S-KT, and PB in the plasma and urine of female Sprague-Dawley rats after intravenous doses of 10 mg of racemic KT per kg and 0, 25, 50, 100, 150, 175, and 200 mg of PB per kg. Elevated levels of both enantiomers were observed, with S-KT being affected to a much greater extent. Significant positive correlations were found between the concentrations in plasma of KT enantiomers and PB at various sampling times, with the strongest correlations being found at 2 h for R-KT (r = 0.708) and 1.5 h for S-KT (r = 0.913). The areas under the concentration-time curve (AUC) from 0-24 h for R-KT (r = 0.697) and S-KT (r = 0.848) also showed strong correlation with AUC of PB. Our data show that as the dose of PB was increased (0-200 mg/kg), the mean S-KT/R-KT ratios for both the AUC and the fraction of the dose excreted as enantiomer conjugates in urine over 24 h increased progressively from 12.1 +/- 2.3 to 27.6 +/- 5.0 and from 6.8 +/- 0.7 to 36.4 +/- 12.2, respectively. These findings clearly demonstrate that the KT-PB interaction in the rat is a PB concentration-dependent process.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Methods for the analysis of enantiomers of racemic drugs application to pharmacological and pharmacokinetic studies.

Although the existence and differences in biological behavior of optical isomers have long been appreciated, there has been an apparent reluctance to address these differences in pharmacology and the pharmaceutical sciences. At least part of this reluctance arises from the belief that the separation of enantiomers requires highly specialized analytical equipment and expertise. The purpose of this review is to present general principles that allow the separation of stereoisomers and demonstrate that these procedures can be accomplished using available and convenient chromatography techniques.

Chromatography, High Pressure Liquid↗