Biomedical subjects

Amal Kaddoumi

Publications and source records attributed to Amal Kaddoumi.

10 recordsLinked to original sources

PubMed2006

Factors influencing regional differences in intestinal absorption of UK-343,664 in rat: possible role in dose-dependent pharmacokinetics.

The objective of this study was to evaluate potential contributions of intestinal export and metabolism to the oral dose-dependent pharmacokinetics of the human cGMP-specific phosphodiesterase type 5 inhibitor, UK-343,664. Differences between jejunal and ileal handling of this CYP3A and P-gp substrate were investigated. CYP3A and P-gp display differing activities in the upper and lower mammalian small intestine and their impact on variable drug absorption can be mechanistically assessed for individual compounds with in situ perfusion of rat's small intestine. Isolated segments of rat jejunum and ileum were perfused with UK-343,664 solution and measurements were made as a function of drug concentration for dose dependence and in the presence of CYP3A and P-gp inhibitors. Intestinal permeability and metabolism were measured by total drug disappearance and major metabolite, UK-347,334 (N-desethyl metabolite), appearance in the intestinal lumen. Intestinal tissue and mesenteric blood measurements of drug and metabolite were also determined. The effective permeability (P(eff)) of UK-343,664 and metabolite formation (F(met)) increased as a function of concentration. Regional differences in P(eff) and F(met) were observed with low-intestinal metabolism of UK-343,664 in both regions (<10%). P-gp inhibition caused significant increase in P(eff) and F(met) in jejunum and ileum while ketoconazole, a P-gp and CYP3A inhibitor, has only limited effect on metabolism. In conclusion, UK-343,664 absorption is mainly regulated by P-gp in jejunum and ileum while CYP3A intestinal metabolism has minimal effect. This role of P-gp could explain the dose-dependent pharmacokinetics of UK-343,664 and its unusual behavior of t(max) as a function of dose.

Animals↗

PubMed2004

Hair analysis for fenfluramine and norfenfluramine as biomarkers for N-nitrosofenfluramine ingestion.

In this paper, a high performance liquid chromatographic method with fluorescence detection (HPLC-FL) for the determination of fenfluramine (Fen) and norfenfluramine (Norf) in human hair as biomarker metabolites of N-nitrosofenfluramine (N-Fen) is described. Washed and cut hair segments were extracted by ultrasonication for 1h at room temperature in methanol. The extract was evaporated and applied for derivatization with the fluorescent reagent 4-(4,5-diphenyl-1H-imidazol-2-yl)benzoyl chloride (DIB-Cl). An HPLC-FL analysis was performed using an ODS column with mobile phase composition of acetonitrile and water (65:35, v/v) and monitored at 430 nm (excitation 325 nm). The method was sensitive with detection limits of 36 and 16 pg/mg hair for Fen and Norf, respectively. The linearity was assessed in the range 0.036-144 ng/mg for Fen and 0.016-127 ng/mg for Norf with correlation coefficients larger than 0.999. The method was successfully used for the segmental determination of Fen and Norf in hair samples obtained from hospitalized patients diagnosed with hepatotoxicity and suspected to ingest N-Fen. Both Fen and Norf could be detected in these patients' hair samples in the ranges 43-1389 pg/mg for Fen and 18-680 pg/mg for Norf and the results showed that the patients might ingest N-Fen for a period of not less than 5 months. As well, the method was applied for the determination of Fen and Norf in rats that possess pigmented and non-pigmented hair after an intraperitoneal administration of Fen. Both compounds were determined in black as well as in white hair.

Animals↗

PubMed2004

High performance liquid chromatography with fluorescence detection for the determination of phenylpropanolamine in human plasma and rat's blood and brain microdialysates using DIB-Cl as a label.

A high performance liquid chromatographic method for the determination of phenylpropanolamine (PPA) in human plasma and rat's brain and blood microdialysates using fluorescence (FL) detection after precolumn derivatization with 4-(4,5-diphenyl-1H-imidazole-2-yl)benzoyl chloride (DIB-Cl) is described. PPA was extracted from plasma samples by a liquid-liquid extraction method with ethyl acetate followed by derivatization with DIB-Cl, while the blood and brain microdialysates were directly subjected for derivatization. The DIB-derivatives of PPA and the internal standard, ephedrine (EP), were then separated using an isocratic HPLC-FL set at excitation and emission wavelengths of 325 and 430 nm, respectively, on an ODS column. Calibration curves of PPA in spiked human plasma were linear over the concentration range of 5-5000 nM (0.755-755 ng/ml) and those in spiked blood and brain microdialysates were linear over the range of 25-5000 nM (3.775-755 ng/ml) with limits of detection of 17, 48 and 40 fmol on column in plasma and blood and brain microdialysates, respectively. As well, the intra- and the inter-assay precisions were lower than 12% for human plasma and the microdialysates. The method was successfully applied for the monitoring of PPA levels in rat's brain and blood microdialysates administered with a single oral dose of PPA (2.5 mg/kg).

Animals↗

PubMed2004

High-performance liquid chromatography with fluorescence detection for the simultaneous determination of 3,4-methylenedioxymethamphetamine, methamphetamine and their metabolites in human hair using DIB-Cl as a label.

This paper describes a highly sensitive HPLC method for the simultaneous determination of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), amphetamine (AP) and methamphetamine (MP) in human hair samples. The amphetamines investigated were derivatized with the fluorescent reagent, DIB-Cl to yield highly fluorescent DIB-derivatives, which were then analyzed by HPLC with fluorescence detection at excitation and emission wavelengths of 325 nm and 430 nm, respectively. The separation was achieved on an ODS column with an isocratic mobile phase composed of acetonitrile-methanol-water (30:40:30, v/v/v). The limits of detection for the four compounds obtained by the proposed method ranged from 11 to 200 pg/mg. The method was successfully applied to the determination of MDMA and MDA in hair samples obtained from MDMA abuser.

3,4-Methylenedioxyamphetamine↗

PubMed2004

Pharmacokinetic interactions between phenylpropanolamine, caffeine and chlorpheniramine in rats.

As the mechanism involved in the serious adverse effects associated with phenylpropanolamine (PPA) has not yet been clarified, and as PPA in usual cases is not being ingested without other drugs combination, the aim of this study was to characterize the possibility of pharmacokinetic interactions between PPA and most often combined drugs existing in the same dosage. The pharmacokinetics of PPA in rat brain and blood were evaluated when administered alone (group I), combined with caffeine (group II), combined with chlorpheniramine (group III), combined with both caffeine and chlorpheniramine (group IV) and finally when existed in one of the available OTC products (group V). This product contains multiple ingredients of PPA, caffeine and chlorpheniramine. In brain the pharmacokinetic parameters of PPA were significantly affected with the combined administration of caffeine and/or chlorpheniramine. The single intraperitoneal administration of caffeine (5 mg/kg) with PPA (2.5 mg/kg) to rats caused 1.6-fold increase in the AUC of PPA in brain compared to the single administration of PPA, and was comparable to the 1.5-fold increase caused by chlorpheniramine (0.4 mg/kg). The multiple combinations caused an increase in the AUC by 1.9-fold, which is comparable to the increase in the AUC of PPA obtained from the OTC product (2.2-fold). On the other hand, there was no significant difference in the pharmacokinetics of PPA in blood between the groups except for the C(max) of PPA in groups I and IV. The observed adverse effects associated with PPA use could be related to the significant increase in its levels in the brain.

Animals↗

PubMed2003

Liquid chromatography studies on the pharmacokinetics of phentermine and fenfluramine in brain and blood microdialysates after intraperitoneal administration to rats.

A highly sensitive and simple HPLC method with fluorescence detection for the determination of phentermine (Phen), fenfluramine (Fen) and norfenfluramine (Norf, the active metabolite of Fen) in rat brain and blood microdialysates has been developed. The brain and blood microdialysates were directly subjected to derivatization with 4-(4,5-diphenyl-1H-imidazol-2-yl) benzoyl chloride (DIB-Cl) in the presence of carbonate buffer (0.1 M, pH 9.0) at room temperature. The chromatographic conditions consisted of an ODS column and mobile phase composition of acetonitrile and water (65:35, v/v) with flow rate set at 1.0 ml/min. The detection was performed at excitation and emission wavelengths of 325 and 430 nm, respectively. Under these conditions, the DIB-derivatives of Phen, Fen and Norf were well separated and showed good linearities in the studied ranges (5-2000 nM for Phen and 10-2000 nM for Norf and Fen) with correlation coefficients greater than 0.999. The obtained detection limits were less than 23 fmol on column (for the three compounds) in both brain and blood microdialysates at a signal-to-noise ratio of 3 (S/N=3). The intra- and the inter-assay precisions were lower than 10%. The method coupled with microdialysis was applied for a pharmacokinetic drug-drug interaction study of Phen and Fen following individual and combined intraperitoneal administration to rats. In addition, since the role of protein binding in drug interactions can be quite involved, the method was applied for the determination of total and free Phen and Fen in rat plasma and ultrafiltrate, respectively. The results showed that Fen and/or Norf significantly altered the pharmacokinetic parameters of Phen in both blood and brain but did not alter its protein binding. On the other hand, there was no significant difference in the pharmacokinetics of Fen when administered with Phen.

Animals↗

PubMed2003

Semi-micro column HPLC of triazolam in rat plasma and brain microdialysate and its application to drug interaction study with itraconazole.

Semi-micro column high-performance liquid chromatographic method with ultraviolet detection for the determination of triazolam (TZ) in rat plasma and brain microdialysate is described. The separation was achieved on a 250 x 1.5 mm, i.d. C(18) column and the column effluent was monitored at 222 nm. The detection limits at a signal-to-noise ratio of 3 obtained using spiked plasma and artificial cerebrospinal fluid were 2.1 and 0.7 ng/ml, respectively. The method was applied to drug-drug interaction study of TZ with itraconazole (ITZ). The peak concentration (C(max)) and the area under the curve (AUC) of TZ in brain microdialysate after simultaneous administration of TZ (2.5 mg/kg, intravenously (i.v.)) and ITZ (25 mg/kg, p.o.) to rats increased 3.4-folds (P<0.001) and 2.9-folds (P<0.001), respectively, compared to those of TZ alone. Also, the AUC of TZ in plasma increased 2.6-folds and remarkable delay in its elimination half-life (t(1/2)) was observed. The concentrations of TZ in brain microdialysate and plasma were also measured after single administration of TZ (2.5 mg/kg, i.v.) to rats pretreated with daily administration of ITZ (25 mg/kg, p.o.) once a day for a week. There was no significant difference in TZ's C(max) in both ITZ treatments (P>0.2) however its t(1/2) after the daily pretreatment with ITZ was significantly increased (P<0.05). In plasma, the AUC of TZ after daily pretreatment of ITZ was lower than the single combined treatment, but significantly different from TZ's AUC in the absence of ITZ (P<0.05). As a result, single simultaneous administration of TZ with ITZ and single administration of TZ after daily pretreatment with ITZ to rats, ITZ seriously interfered with the pharmacokinetic parameters of TZ in plasma and brain micodialysate.

Animals↗

PubMed2003

Determination of methamphetamine and amphetamine in abusers' plasma and hair samples with HPLC-FL.

This paper describes highly sensitive HPLC methods for the determination of amphetamine (AP) and methamphetamine (MP) in abusers' plasma and hair samples. AP and MP were derivatized with the fluorescent reagent, DIB-Cl, to yield a highly fluorescent DIB-derivatives of AP and MP, which were then analyzed by HPLC with fluorescence detection at excitation and emission wavelengths of 325 and 430 nm, respectively. The separation was achieved on an ODS column with isocratic mobile phases composed of acetoniltrile and citrate buffer (55:45, v/v) for plasma samples and of acetonitrile-methanol-citrate buffer (45:20:37.5, v/v/v) for hair samples. The limits of detection were less than 0.87 ng/mL and 0.12 ng/mg in plasma and hair samples, respectively, for both AP and MP. The methods were then applied to the determination of MP and its metabolite AP in plasma obtained from two cases of illegally ingested MP and in one of the cases' hair received later. Case I was treated with dialysis; samples before and after dialysis were analyzed by the described method. After dialysis for 5 h, the total plasma levels of AP and MP decreased from 720 to 190 ng/mL. For case II, MP and AP levels were monitored for 3 days after digestion. Total plasma levels decreased from 57 ng/mL in the day of digestion to 11 ng/mL after 3 days. In hair samples, AP and MP could also be detected in very low concentrations.

Adult↗

PubMed2002

HPLC determination of phenylpropanolamine in pharmaceutical OTC preparations.

A convenient HPLC method to determine phenylpropanolamine (PPA) in addition to phenylephrine (PE) and chlorpheniramine (CPA) in commercially available over-the-counter (OTC) preparations has been developed. Sample solutions were prepared by dilution with water or methanol followed by filtration and direct injection into the HPLC system. The mobile phase was a mixture of methanol-acetonitrile-acetic acid (0.1 M)-triethylamine (20:20:60:0.6, v/v/v/v) containing sodium heptanesulfonate (0.5 mM) as an ion pair. The separation was achieved on a reversed-phase ODS column with detection wavelength set at 254 nm. The compounds showed good linearity in the range 2.5-1000 micro M with detection limits ranged from 0.13 to 0.48 micro M. PE, caffeine and CPA were well separated when present together with PPA. The method was applied to the determination of PPA in pharmaceutical preparations including hard and soft capsules.

Chromatography, High Pressure Liquid↗

PubMedDate not supplied

Pentazocine monitoring in rat hair and plasma by HPLC-fluorescence detection with DIB-Cl as a labelling reagent.

Pentazocine (PZ) in rat hair and plasma was determined by HPLC-fluorescence detection with 4-(4,5-diphenyl-1H-imidazol-2-yl)benzoyl chloride (DIB-Cl) as a labelling reagent and cyclazocine (CZ) as an internal standard (IS). PZ and IS extracted from hair or plasma sample were derivatized with DIB-Cl and the resulted solution was cleaned up with solid phase extraction. The isocratic separation of DIB-PZ and -CZ within 20 min could be achieved by a Wakopak Handy-ODS column (250 x 4.6 mm i.d.) using a mobile phase composed of 0.1 mol/L acetate buffer (pH 6.2):acetonitrile (25:75, v/v). The detection limits of PZ at a signal-to-noise ratio of 3 for rat hair and plasma were 0.18 ng/mg and 0.57 ng/mL, respectively. Reproducible and precise results could be obtained by an IS method with RSD values less than 6.6% for within- and between-day measurements. The method was successfully applied for the monitoring of PZ levels in Zucker rat hair and plasma samples after a single administration of 25 mg/kg PZ. Moreover, incorporation rates of PZ into black and white hair of Zucker rat were evaluated.

Animals↗