Nasir M. Idkaidek

Human jejunal permeability of two polar drugs: cimetidine and ranitidine.

AbstractPurpose. To determine the human jejunal permeability of cimetidine and ranitidine using a regional jejunal perfusion approach, and to integrate such determinations with previous efforts to establish a baseline correlation between permeability and fraction dose absorbed in humans for soluble drugs. Methods. A sterile multi-channel perfusion tube, Loc-I-Gut®, was inserted orally and positioned in the proximal region of the jejunum. A solution containing cimetidine or ranitidine and phenylalanine, propranolol, PEG 400, and PEG 4000 was perfused through a 10 cm jejunal segment in 6 and 8 subjects, respectively. Results. The mean Peff (± se) of cimetidine and ranitidine averaged over both phases were 0.30 (0.045) and 0.27 (0.062) × 10−4cm/s, respectively, and the differences between the two were found to be statistically insignificant. The mean permeabilities for propranolol, phenylalanine, and PEG 400 averaged over both phases and studies were 3.88 (0.72), 3.36 (0.50), and 0.56 (0.08) × 10−4 cm/s, respectively. The differences in permeability for a given marker were not significant between phases or between the two studies. Conclusions. The 10-fold lower permeabilities found for cimetidine and ranitidine in this study, compared to propranolol and phenylalanine, appear to be consistent with their less than complete absorption in humans.

Human Intestinal Permeability of Piroxicam, Propranolol, Phenylalanine, and PEG 400 Determined by Jejunal Perfusion

AbstractPurpose. To determine the human jejunal permeabilities of compounds utilizing different transport mechanisms using a regional perfusion approach and to establish a standard procedure for determining drug permeability class to be used for the establishment of drug product bioequivalence standards. Methods. Six healthy male volunteers participated in this study. A multi-lumen perfusion tube was inserted orally and positioned in the proximal region of the jejunum. A solution containing piroxicam, phenylalanine, propranolol, PEG 400 and PEG 4000 was perfused through the intestinal segment at a rate of 3.0 ml/min. Perfusate samples were quantitatively collected every 10 minutes for two 100 minute periods with an intermediate wash out period to determine intra and intersubject variation. Results. The mean Peff (±SD) of piroxicam, phenylalanine, propranolol, and PEG 400 were 10.40 ± 5.93, 6.67 ± 3.42, 3.59 ± 1.60, 0.80 ± 0.46 × 10−4 cm/sec, respectively. The coefficient of variation for the intersubject variability, first and second perfusion periods were: piroxicam, 60.5% and 57.1%; phenylalanine, 52.8% and 57.8%: propranolol, 62.1 % and 44.6%; and PEG 400, 81.7% and 42.3%, indicating a slightly lower CV for the second perfusion period in the same subject. The intrasubject CVs between the two perfusion periods were: 19.4%, 21.3%, 23.6% and 41.0% respectively, indicating a smaller intraindividual variation for all compounds studied. Conclusions. Piroxicam, a nonpolar drug exhibited the highest permeability of the compounds studied. The intrasubject CV was lower than the intersubject CV, indicating consistent permeability estimation within subjects. The methodology is useful for permeability estimation regardless of absorption mechanism and can be used to establish a consistent data base of human permeabilities for estimation of human drug absorption and for establishing the biopharmaceutic permeability class of drugs.

Formulation and Release Behavior of Diclofenac Sodium in Compritol 888 Matrix Beads Encapsulated in Alginate

Sustained-release polymer beads containing diclofenac sodium (DNa) dispersed in Compritol 888 and encapsulated in calcium alginate shell were prepared utilizing 23 factorial design. The effect of sodium alginate concentration, drug:Compritol 888 weight ratio and CaCl2 concentration on drug content (%), time for 50% and 80% of the drug to be released, and mean dissolution time (MDT) were evaluated with analysis of variance (ANOVA). An increase in the level of all these factors caused retardation in the release, and t50%, t80%, and MDT were increased. The drug release was dependent on the pH of the release media. A formula that gives a release comparable to commercial products was prepared.

Determination of the Population Pharmacokinetic Parameters of Sustained-Release and Enteric-Coated Oral Formulations, and the Suppository Formulation of Diclofenac Sodium by Simultaneous Data Fitting Using NONMEM

Data from sustained‐release and enteric‐coated oral formulations, and the suppository formulation of diclofenac sodium are fitted simultaneously using NONMEM® and the general linear model, ADVAN 5. Absorption and disposition parameters, serum levels, and absorption profiles were determined. The in vivo absorption profiles were determined using the program TOPFIT®. The in vivo absorption for the sustained‐release formulation is slow first order and follows a flip‐flop model since disposition rate constants are greater than absorption rate constants. Absorption from the enteric‐coated form is essentially complete (≥95%) at about 7.5 h, while it is 95% complete at 24 h from the sustained‐release formulation. This suggests likely absorption from the colon in the case of the sustained‐release formulation since absorption is only 75% complete during the first 10 h. The sustained‐release relative bioavailability is 90–99%. Absorption from the suppository is essentially complete at about 4.5 h. However, the relative bioavailability of the suppository formulation is low (55%), since defecation may remove the drug from the absorption site before complete absorption.

Pharmacokinetics of Tilmicosin (Provitil Powder and Pulmotil Liquid AC) Oral Formulations in Chickens

A bioavailability and pharmacokinetics study of powder and liquid tilmicosin formulations was carried out in 18 healthy chickens according to a single-dose, two-period, two-sequence, crossover randomized design. The two formulations were Provitil and Pulmotil AC. Both drugs were administered to each chicken after an overnight fast on two treatment days separated by a 2-week washout period. A modified rapid and sensitive HPLC method was used for determination of tilmicosin concentrations in chicken plasma. Various pharmacokinetic parameters including area under plasma concentration–time curve (AUC0−72), maximum plasma concentration (Cmax), time to peak concentration (tmax), elimination half-life (t1/2β), elimination rate (kel), clearance (ClB), mean residence time (MRT) and volume of distribution (Vd,area) were determined for both formulations. The average means of AUC0−72 for Provitil and Pulmotil AC were very close (24.24 ± 3.86, 21.82 ± 3.14 (μg.h)/ml, respectively), with no significant differences based on ANOVA. The relative bioavailability of Provitil as compared to Pulmotil AC was 111%. In addition, there were no significant differences in the Cmax  (2.09 ± 0.37, 2.12 ± 0.40 μg/ml), tmax  (3.99 ± 0.84, 5.82 ± 1.04 h), t1/2β (47.4 ± 9.32, 45.0 ± 5.73 h), kel (0.021 ± 0.0037, 0.022 ± 0.0038 h−1), ClB (19.73 ± 3.73, 21.37 ± 4.54 ml/(min/kg)), MRT (71.20 ± 12.87, 67.15 ± 9.01 h) and Vd,area (1024.8 ± 87.5, 1009.8 ± 79.5 ml/kg) between Pulmotil AC and Provitil, respectively. In conclusion, tilmicosin was rapidly absorbed and slowly eliminated after oral administration of single dose of tilmicosin aqueous and powder formulations. Provitil and Pulmotil AC can be used as interchangeable therapeutic agents.

Enhancement of oral absorption of metronidazole suspension in humans.

The purpose of this study was to investigate oral absorption of two metronidazole suspension products, Flagyl((R)) and a test product. Twenty-four healthy volunteers participated in the study. The crossover study was done in a two-phase, two-sequence manner with a 2-week washout period. Individual disposition kinetics were determined by non-compartmental analysis. AUC(0-infinity) and C(max) values were 1.26 and 1.86 times more in the case of test formulation. Mean plasma drug concentrations were analyzed to estimate the rate and extent of oral absorption. The optimized duodenal, jejunal1, jejunal2, illial1, ileal2, ilial3, ilial4, colonic permeability values (x10(-4)) for the test and Flagyl products were 3.96, 3.96, 3. 96, 0.68, 0.37, 0.01, 0.12, 0.38 and 2.34, 0, 0, 1.2, 1.1, 0.9, 0.3, 0.04cm/s, respectively. The total fraction of oral dose absorbed for the test and Flagyl products were 95.5% and 65.6% respectively, consistent with the pharmacokinetic ratios. The test product exhibited significantly higher absorption rate and extent than Flagyl, but both show similar half-lives. Sensitivity analysis showed that drug absorption is sensitive to effective permeability but not sensitive to particle radius and small intestinal transit time. The two products were found bio-inequivalent which is suggested to be due to differences in formulation additives that decreased the effective permeability of Flagyl.

Pharmacokinetics and bioavailability of doxycycline in ostriches (Struthio camelus) at two different dose rates.

A bioavailability and pharmacokinetics study of doxycycline was carried out on 30 healthy ostriches after a single intravenous (IV), intramuscular (IM) and oral dose of 15 mg/kg body weight. The plasma doxycycline concentration was determined by HPLC/UV at 0 (pretreatment), 0.08, 0.25, 0.5 1, 2, 4, 6, 8, 12, 24 and 48 h after administration. The plasma concentration-time curves were examined using non-compartmental methods based on the statistical moment theory for only the higher dose. After IV administration, the elimination half-life (t1/2β), mean residence time (MRT), volume of distribution at the steady-state (Vss), volume of distribution (Vdarea) and total body clearance (ClB) were 7.67 ± 0.62 h, 6.68 ± 0.86 h, 0.86 ± 0.16 l/kg, 1.67 ± 0.52 l/kg and 2.51 ± 0.63 ml/min/kg, respectively. After IM and oral dosing, the mean peak plasma concentrations (Cmax) were 1.34 ± 0.33 and 0.30 ± 0.04 µg/ml, respectively, which were achieved at a post-administration time (tmax) of 0.75 ± 0.18, 3.03 ± 0.48 h, respectively. The t1/2β, Vdarea and ClB after IM administration were 25.02 ± 3.98 h, 23.99 ± 3.4 l/kg and 12.14 ± 1.71 ml/min/kg, respectively and 19.25 ± 2.53 h, 61.49 ± 7 l/kg and 40.19 ± 3.79 ml/min/kg after oral administration, respectively. The absolute bioavailability (F) of doxycycline was 5.03 and 17.52% after oral and IM administration, respectively. These results show that the dose data from other animals particularly mammals cannot be extrapolated to ostriches. Therefore, based on these results along with those reported in the literature, further studies on the pharmacokinetic/pharmacodynamic, in vitro minimum inhibitory concentration values and clinical applications of doxycycline in ostriches are required.

Comparative Pharmacokinetics of Gentamicin after Intravenous, Intramuscular, Subcutaneous and Oral Administration in Broiler Chickens

The pharmacokinetics and bioavailability of gentamicin sulphate (5 mg/kg body weight) were studied in 50 female broiler chickens after single intravenous (i.v.), intramuscular (i.m.), subcutaneous (s.c.) and oral administration. Blood samples were collected at time 0 (pretreatment), and at 5, 15 and 30 min and 1, 2, 4, 6, 8, 12, 24 and 48 h after drug administration. Gentamicin concentrations were determined using a microbiological assay and Bacillus subtillis ATCC 6633 as a test organism. The limit of quantification was 0.2 μg/ml. The plasma concentration–time curves were analysed using non-compartmental methods based on statistical moment theory. Following i.v. administration, the elimination half-life (t1/2β), the mean residence time (MRT), the volume of distribution at steady state (Vss), the volume of distribution (Vd,area) and the total body clearance (ClB) were 2.93 ± 0.15 h, 2.08 ± 0.12 h, 0.77 ± 0.05 L/kg, 1.68 ± 0.39 L/kg and 5.06 ± 0.21 ml/min per kg, respectively. After i.m. and s.c. dosing, the mean peak plasma concentrations (Cmax) were 11.37 ± 0.73 and 16.65 ± 1.36 μg/ml, achieved at a post-injection times (tmax) of 0.55 ± 0.05 and 0.75 ± 0.08 h, respectively. The t1/2β was 2.87 ± 0.44 and 3.48 ± 0.37 h, respectively after i.m. and s.c. administration. The Vd,area and ClB were 1.49 ± 0.21 L/kg and 6.18 ± 0.31 ml/min per kg, respectively, after i.m. administration and were 1.43 ± 0.19 L/kg and 4.7 ± 0.33 ml/min per kg, respectively, after s.c. administration. The absolute bioavailability (F) of gentamicin after i.m. administration was lower (79%) than that after s.c. administration (100%). Substantial differences in the resultant kinetics data were obtained between i.m. and s.c. administration. The in vitro protein binding of gentamicin in chicken plasma was 6.46%.

Comparison of two cyclosporine formulations in healthy Middle Eastern volunteers: bioequivalence of the new Sigmasporin Microoral and Sandimmun Neoral

A study was conducted to establish bioequivalence between two oral cyclosporine 100 mg capsules, Sigmasporin Microoral (Gulf Pharmaceutical Industries - Julphar, United Arab Emirates, under technical co-operation with Sigma Pharma, Brazil) and Sandimmun Neoral (Novartis, Switzerland), in a Middle Eastern population, even though both formulations were found to be bioequivalent earlier in a Brazilian population (data on file). It was designed as a randomized, open label, two-way crossover study in which 30 fasting, healthy male volunteers received a single 100 mg cyclosporine dose with 240 ml of water on two treatment days separated by a 1 week washout period. After dosing, serial blood samples were collected for a period of 24 h. Plasma was analyzed for cyclosporine A by a sensitive, reproducible and accurate HPLC method with MS detection capable of detecting cyclosporine A in the range of 5-400 ng/ml with a limit of quantitation of 5 ng/ml. Various pharmacokinetic parameters including AUC(0-t), AUC(0- proportional, variant ), C(max), T(max), T(1/2), and lambda(Z) were determined from plasma concentrations of both formulations. AUC(0-t), AUC(0- proportional, variant ), and C(max) were tested for bioequivalence after log-transformation of data. No significant difference was found based on ANOVA; 90% confidence intervals (82.98-110.57% for AUC(0-t), 81.57-124.71% for AUC(0- proportional, variant ), 80.15-98.91% for C(max)) for these parameters were found to be within the bioequivalence acceptance range of 80-125%. Based on these statistical inferences, it was concluded that Sigmasporin Microoral is bioequivalent to Sandimmun Neoral.

Synthesis, In Vitro and In Vivo Evaluation of the N-ethoxycarbonylmorpholine Ester of Diclofenac as a Prodrug

The N-ethoxycarbonylmorpholine moiety was evaluated as a novel prodrug moiety for carboxylic acid containing drugs represented by diclofenac (1). Compound 2, the N-ethoxycarbonylmorpholine ester of diclofenac was synthesized and evaluated as a potential prodrug. The stability of the synthesized prodrug was evaluated in solutions of pH 1 and 7.4, and in plasma. The ester’s half lives were found to be 8 h, 47 h and 21 min in pH 1, pH 7.4 and plasma, respectively. Equimolar doses of diclofenac sodium and its synthesized prodrug were administered orally to a group of rabbits in a crossover study to evaluate their pharmacokinetic parameters. The prodrug 2 shows a similar rate and extent of absorption as the parent drug (1). The ulcerogenicity of the prepared prodrug was evaluated and compared with the parent drug. The prodrug showed less ulcerogenicity as detected by fewer number and smaller size of ulcers. In conclusion, the newly synthesized N-ethoxycarbonylmorpholine ester of diclofenac prodrug showed appropriate stability properties at different pHs, similar pharmacokinetic profile, and much less ulcerogenecity at the GIT compared to the parent drug diclofenac.