In silico vs. in vivo human intestinal permeability.

The aim of this research is to calculate human intestinal permeability in silico and correlate results with those measured in vivo. Optimized human intestinal permeability values were calculated for 16 drugs by de-convolution of human plasma profiles using Parameter Estimation module of SimCYP program V13. Results showed high in silico-in vivo correlation coefficient of 0.89 for drugs with high/low permeability values. In silico permeability, if properly optimized, can be used as surrogate for in vivo permeability for BCS class I drugs and hence is suggested that such methodology could be employed as a support for waiver of in vivo studies.

Pharmacokinetics and bioavailability of sulfadiazine and trimethoprim following intravenous, intramuscular and oral administration in ostriches (Struthio camelus).

A pharmacokinetic and bioavailability study of sulfadiazine combined with trimethoprim (sulfadiazine/trimethoprim) was carried out in fifteen healthy young ostriches after intravenous (i.v.), intramuscular (i.m.) and oral administration at a total dose of 30 mg/kg body weight (bw) (25 and 5 mg/kg bw of sulfadiazine and trimethoprim, respectively). The study followed a single dose, three periods, cross-over randomized design. The sulfadiazine/trimethoprim combination was administered to ostriches after an overnight fasting on three treatment days, each separated by a 2-week washout period. Blood samples were collected at 0 (pretreatment), 0.08, 0.25, 0.50, 1, 2, 4, 6, 8, 12, 24 and 48 h after drug administration. Following i.v. administration, the elimination half-life (t(1/2beta)), the mean residence time (MRT), volume of distribution at steady-state (V(d(ss))), volume of distribution based on terminal phase (V(d(z))), and the total body clearance (Cl(B)) were (13.23 +/- 2.24 and 1.95 +/- 0.19 h), (10.06 +/- 0.33 and 2.17 +/- 0.20 h), (0.60 +/- 0.08, and 2.35 +/- 0.14 L/kg), (0.79 +/- 0.12 and 2.49 +/- 0.14 L/kg) and (0.69 +/- 0.03 and 16.12 +/- 1.38 mL/min/kg), for sulfadiazine and trimethoprim, respectively. No significant difference in C(max) (35.47 +/- 2.52 and 37.50 +/- 3.39 microg/mL), t(max) (2.47 +/- 0.31 and 2.47 +/- 0.36 h), t((1/2)beta) (11.79 +/- 0.79 and 10.96 +/- 0.56 h), V(d(z))/F (0.77 +/- 0.06 and 0.89 +/- 0.07 L/kg), Cl(B)/F (0.76 +/- 0.04 and 0.89 +/- 0.07) and MRT (12.39 +/- 0.40 and 12.08 +/- 0.36 h) were found in sulfadiazine after i.m. and oral dosing, respectively. There were also no differences in C(max) (0.71 +/- 0.06 and 0.78 +/- 0.10 microg/mL), t(max) (2.07 +/- 0.28 and 3.27 +/- 0.28 h), t((1/2)beta) (3.30 +/- 0.25 and 3.83 +/- 0.33 h), V(d(z))/F (6.2 +/- 0.56 and 6.27 +/- 0.77 L/kg), Cl(B)/F (21.9 +/- 1.46 and 18.83 +/- 1.72) and MRT (3.68 +/- 0.19 and 4.34 +/- 0.14 h) for trimethoprim after i.m. and oral dosing, respectively. The absolute bioavailability (F) was 95.41% and 86.20% for sulfadiazine and 70.02% and 79.58% for trimethoprim after i.m. and oral administration, respectively.

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 microg/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 (t (1/2beta)), the mean residence time (MRT), the volume of distribution at steady state (V (ss)), the volume of distribution (V (d,area)) and the total body clearance (Cl(B)) 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 (C (max)) were 11.37 +/- 0.73 and 16.65 +/- 1.36 microg/ml, achieved at a post-injection times (t (max)) of 0.55 +/- 0.05 and 0.75 +/- 0.08 h, respectively. The t (1/2beta) was 2.87 +/- 0.44 and 3.48 +/- 0.37 h, respectively after i.m. and s.c. administration. The V (d,area) and Cl(B) 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%.

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 (AUC(0-72)), maximum plasma concentration (C(max)), time to peak concentration (t(max)), elimination half-life (t(1/2beta)), elimination rate (k(el)), clearance (Cl(B)), mean residence time (MRT) and volume of distribution (V(d,area)) were determined for both formulations. The average means of AUC(0-72) for Provitil and Pulmotil AC were very close (24.24 +/- 3.86, 21.82 +/- 3.14 (microg x 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 C(max) (2.09 +/- 0.37, 2.12 +/- 0.40 microg/ml), tmax (3.99 +/- 0.84, 5.82 +/- 1.04 h), t(1/2beta) (47.4 +/- 9.32, 45.0 +/- 5.73 h), k(el) (0.021 +/- 0.0037, 0.022 +/- 0.0038 h(-1)), Cl(B) (19.73 +/- 3.73, 21.37 +/- 4.54ml/(min/kg)), MRT (71.20 +/- 12.87, 67.15 +/- 9.01 h) and V(d,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.

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

PURPOSE: 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) x 10(-4) cm/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) x 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.

A novel approach to increase oral drug absorption.

A comprehensive analytical solution that accounts for many factors and assumptions affecting drug concentration profile in the gastrointestinal tract was presented. A sensitivity analysis approach was utilized in order to investigate the importance of different parameters in the model. The partition coefficient is found to be the key parameter. Hence, for drugs stable in the intestinal wall, increasing partition coefficient only can lead to higher drug absorption. However, for drugs unstable in the intestinal wall, increasing partition coefficient and diffusivity is needed to counteract drug instability. On the other hand, the model is essentially insensitive to degradation in the intestinal lumen for degradation half lives greater than 0.7 min at a given intestinal length. However, a high model sensitivity to the rate of luminal degradation is obtained at higher intestinal length values. The proposed model can be used as a guide for oral drug delivery.

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.

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 2(3) 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 (> or = 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.

Human intestinal permeability of piroxicam, propranolol, phenylalanine, and PEG 400 determined by jejunal perfusion.

PURPOSE: 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 P(eff) (+/-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 x 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 CV's 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.