The pharmacokinetics and metabolism of DuP 532, a non-peptide angiotensin II receptor antagonist,in rats and dogs

DuP 532, 2-propyl-4-pentafluoroethyl-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl] methyl} imidazole-5-carboxylic acid, is an orally active, non-peptide angiotensin II (AII) receptor antagonist. DuP 532 is more potent and longer acting than losartan, another AII receptor antagonist currently undergoing phase III clinical trials. The pharmacokinetics and the effect of the salt form on the bioavailability of DuP 532 were determined in rats and dogs. In rats, the absolute oral bioavailability and half-life averaged 8·0% and 3·5 h, respectively, after the sodium bicarbonate solution and 7·6% and 3·6 h, respectively, after the methyl cellulose suspension. In dogs, the absolute oral bioavailability averaged 13.4% after the sodium bicarbonate solution and 11·9% after hard gelatin capsules containing the neat powder. The data demonstrated that there were no differences in bioavailability between the free acid and the sodium salt of DuP 532 after oral administration to rats and dogs. The in vitro metabolism of ¹⁴C-DuP 532 was evaluated with rat, dog, and human liver microsomes. HPLC analyses with UV and radiochemical flow detection showed that recovery of DuP 532 was greater than 99%, suggesting that there was little if any metabolism by liver microsomal enzymes. Therefore, the low oral bioavailability in rats was probably due to poor absorption of DuP 532 from the GI tract rather than extensive metabolism.     

Absorption of iothalamate after oral administration and absorption enhancement by amino acids in dogs and rats

The oral absorption of iothalamate and the effect of amino acids on its absorption were studied in 6 dogs and 6 rats using a simple HPLC assay. The results showed that iothalamate was absorbed in dogs, averaging 9.9, 8.5, and 10.0 per cent following the administration of 40 and 100 mg kg-1 of iothalamic acid capsules and 50 mg kg-1 of sodium iothalamate solution, respectively. The absorption from the capsule was slower and more sustained than that from the solution. In rats, the absorption appeared to be dose-independent (averaging about 4.2 per cent) in the dose range of 20-800 mg kg-1. The low bioavailability obtained was mainly due to the high polarity of iothalamate molecules as suggested by the GI recovery and in vitro partition studies. Among several amino acids tested as possible ion-pair formers, only homoarginine hydrochloride increased the partition of iothalamate into chloroform layer. However, both homoarginine hydrochloride and arginine hydrochloride at the amino acid/iothalamate molar ratio of 25 were found to significantly enhance (about 70 per cent) the iothalamate absorption in dogs. The in situ rat small intestinal loop study indicated that the absorption-enhancing effect of arginine was sodium dependent. At the sodium chloride concentration of 0.09 M, no significant increase in the absorption was observed, while at the concentration of 0.3 M or higher, a marked increase (about twofold) was obtained in both upper and lower intestine. Thus, the mechanism of the amino acids in facilitating the iothalamate absorption may be more closely related to the active amino acid transport system rather than the possible increase in lipophilicity of the ion-pair formed. The potential use of such naturally occurring, relatively non-toxic amino acids for increasing the GI absorption of water-soluble weak acids or bases through ion-pair formation remains to be fully investigated.     

Effect of encapsulation of mefenamic acid with cationic Eudragit E on its bioavailability and gastric ulcerogenic activity in rabbits

Encapsulation of mefenamic acid (MFA), a potent non-steroidal anti-inflammatory drug with cationic acrylic resin, Eudragit E, was carried out using a fluidized-bed granulator (Glatt AG). Three drug:polymer ratios were prepared using 50 ml of 1, 2.5 and 5 per cent w/v aqueous suspension of Eudragit to coat 100 mg powdered drug. The bioavailability of the coated and uncoated drug was studied using four groups of animals, each consisting of six male rabbits (2-2.5 kg). Investigations were performed using the rabbits to examine the effects of prolonged administration of the coated and the uncoated MFA with Eudragit E(1 and 5 per cent) in a dose of 100 mg filled in hard gelatin capsules. One capsule was given daily for 30 days. Plasma levels of MFA with Eudragit E were significantly higher than those of drug only. Meanwhile, 5 per cent w/v polymer coating afforded higher drug availability than 2.5 per cent w/v which induced a higher level than 1 per cent w/v. Chronic gastric ulcers with different severities were found in the internal mucosa of all animals. In addition, there were multiple erosions in the glandular mucosa of stomachs of rabbits receiving MFA within the treatment period. IN the control group the gastric photograph was normal in every instance. Despite the extensive morphological damage at the end of treatment, the observed changes in the stomach of rabbits given coated drug is less deleterious than that treated with uncoated drug. The results of this study indicate that the coating of MFA with cationic Eudragit E increases its bioavailability and decreases the probability of ulceration.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Preparation and Evaluation of a Tablet Dosage Form of Cyclosporine in Dogs

Cyclosporine (CsA) is commercially available for oral administration as a solution in olive oil with alcohol and an emulsifier. To improve its variable absorption and low patient acceptability, several oral formulations were prepared and tested in vitro and in vivo in dogs. A tablet formulation prepared by direct compression was then selected for comparison with the commercial oil solution placed into soft gelatin capsules. The study involved a randomized crossover design in six dogs. In order to determine absolute bioavailability and to compensate for any time-dependent changes in clearance, an intravenous tracer dose of ³H-CsA was administered along with each oral test product on each of two occasions. Absolute bioavailability (mean ± SD) was 46.0 ± 11.1 and 45.4 ± 9.9% for the capsules and tablets, respectively. C _max, t _max, and mean absorption time were not significantly different between the two products. No differences were observed in the pharmacokinetics of the intravenously administered CsA in the two experiments, which were separated by 8–13 days. We conclude that the proposed tablet formulation for CsA is equivalent in dogs to the commercial dosage form placed into soft gelatin capsules.     

Sustained release properties of the once daily theophylline capsule BY912 as compared with Theo-24 capsules

In a multiple dose cross-over experiment in 12 healthy male adults the bioavailability and sustained release characteristics of new once daily BY912 400 mg theophylline capsules (= B, Byk Gulden Research Laboratories, FRG) were studied using Theo-24 capsules (= T, Searle & Co., USA) as reference. Both products were given once daily for a period of 7 days as an 800 mg theophylline dose at 8 am, half an hour after a standardized breakfast. Theophylline concentrations in plasma were measured on days 1, 6, and 7 using high-performance liquid chromatography. Significantly better sustained release characteristics, resulting in longer plateau time (t75%, 11.6 vs 9.2 h on day 6 and 13.1 vs 8.8 h on day 7) and smaller per cent peak-trough fluctuation in the steady state (per cent PTF, 80 vs 103 per cent on day 6 and 66 vs 100 per cent on day 7), were found for B in comparison with T. The extent of absorption on both days, however, was smaller for B compared with T (relative bioavailability 84 per cent and 81 per cent, respectively). In conclusion, the absorption of theophylline from B resulted in a more extended shape of the plateau phase, indicating better sustained release characteristics. The extent of absorption, however, over the dosing intervals was more complete with T.     

Bioavailability of medroxalol in man

Ten healthy male volunteers received single oral doses of 100 mg of medroxalol administered as a solution, a preliminary tablet formulation and a single dose of 100 mg administered intravenously in a randomized three-way crossover study. Mean terminal half-lives of 12·4, 134, and 11·3 h were observed for the intravenous, solution and tablet formulation, respectively. Mean urinary recovery of parent drug at 48 h was 8·9 per cent, 3·9 per cent, and 3·2 per cent. Absolute bioavailability estimated from plasma AUC was 54 per cent for the solution and 38 per cent for the tablet, and the relative bioavailability from the tablet was 71 per cent.     

Relative bioavailability of danazol in dogs from liquid-filled hard gelatin capsules

Danazol was dissolved in non-aqueous mixtures containing either polyethylene glycol 400 or polysorbate 80, and filled into hard gelatin capsules at 50 mg concentrations. The bioavailability of these formulations was compared with commercial danazol capsules in a two-way crossover study using young female beagle dogs. Both formulations showed greater oral bioavailability when compared with either the 100 or 200 mg commercial brand of danazol. The bioavailability of the polyethylene glycol 400 and polysorbate 80 formulations was enhanced 3.7 and 15.8 times, respectively, when compared at the 100 mg dose level.Copyright     

Effects of particle size,food, and capsule shell composition on the oral bioavailability of dabrafenib,a BRAF inhibitor,in patients with BRAF mutation-positive tumors

Dabrafenib is a small-molecule inhibitor of BRAF kinase activity that is currently being developed for the treatment of BRAF V600 mutation-positive melanoma. This clinical, open-label, two-cohort (n = 14 per cohort), randomized study was designed to evaluate the effect of drug substance particle size, and food on the plasma pharmacokinetics of a single oral dose of dabrafenib in patients with BRAF V600 mutation-positive solid tumors. In addition, an exploratory cross-cohort comparison of the relative bioavailability of single-dose dabrafenib administered in gelatin and hydroxypropyl methylcellulose (HPMC) capsules was performed. Higher bioavailability was noted with nonmicronized drug substance (larger particle size), under fasting conditions, and with HPMC capsules. Initial dissolution results at pH 1.2 showed higher dissolution of gelatin relative to HPMC capsules inconsistent with clinical data. Subsequent in vitro dissolution studies were conducted in fasted-state simulated gastric fluid over a 24-h period and showed that HPMC capsules reached a higher percentage of dabrafenib dissolved than gelatin capsules. The presence of HPMC is believed to inhibit precipitation of dabrafenib as the freebase, thereby maintaining a supersaturated solution over an extended period of time. Dabrafenib has been administered in pivotal clinical studies on an empty stomach using micronized drug substance in HPMC capsules. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3100–3109, 2013     

Relative bioavailability of olsalazine from tablets and capsules: a drug targeted for local effect in the colon

The aim of this investigation was to compare two formulations of the prodrug olsalazine (OLZ) with regard to local bioavailability of 5-aminosalicylic acid (5-ASA) in the colon. Since 5-ASA can not be measured directly in the colon, the bioavailability was evaluated by studying the plasma concentration and cumulative urinary excretion (Ae) of its main metabolite N-acetyl-5-aminosalicylic acid (ac-5-ASA). The absorption of OLZ was also studied. A single dose of 1g OLZ tablets and capsules was given to nine healthy fasting volunteers in two repeated two-period cross-over studies. Blood and urine samples were collected for 72 and 96 h, respectively. AUC, Cmax and Ae data from both studies were combined for statistical analysis. Ninety per cent confidence limits for differences in mean AUC for ac-5-ASA (tablet-capsule) compared to that of capsules were -0.31 per cent and 30.8 per cent. This indicates bioequivalence if a more relaxed criterion than the conventional +/- 20 per cent is applied, which is justified in this situation. The 90 per cent confidence limits for Cmax were -10.5 per cent and 36.9 per cent while for Ae the values were -20.5 per cent and 23.7 per cent. Within and between subject variability estimates for AUC of ac-5-ASA were 24 per cent and 46 per cent, respectively.     

First-pass elimination of lidocaine in the rabbit after peroral and rectal route of administration

Lidocaine shows pronounced first-pass metabolism upon peroral administration in man (about 30 per cent peroral bioavailability). Since the rectal bioavailability is about 65 per cent in man it is assumed that some drug is directly absorbed into systemic circulation by-passing the liver. In rats peroral bioavailability is about 8 per cent whereas rectal bioavailability is about 100 per cent. This indicates that the rat is not a suitable model to study rectal lidocaine dosage forms. The purpose of this study was to investigate lidocaine disposition and bioavailability in rabbits after peroral and rectal administration. The peroral bioavailability in rabbits was found to be about 6 per cent and the rectal bioavailability is about 33 per cent. The results indicate that the rabbit is a suitable model for the study of systemic absorption of rectal lidocaine dosage forms.     

Study on the peroral absorption of the endekapeptide cyclosporine A

The beagle dog was found to be a suitable model for pharmacokinetic and bioavailability studies of cyclosporine A (CsA). All pharmacokinetic parameters studied were in the same order of magnitude as those found in man. Three CsA peroral formulations in the form of capsules were compared with a commercially available P.O. solution (to be diluted for administration) and a solution for intravenous administration. Of the three experimental capsule formulations, one based on a microemulsion resulted in an extent of absolute and relative bioavailability not different from that of the available P.O. solution. The advantage, however, is that it is a capsule preparation, ready to swallow, and does not need any manipulation by the patient to dilute the solution. The other two capsule preparations, based on a Gelucire gel with sorption promoters and a microemulsion containing Azone, resulted in a lesser bioavailability than the solution.     

Bioavailability of flufenamic acid in hard and soft gelatin capsules.

The biological availability of flufenamic acid after oral administration of the drug in both hard and soft gelatin capsules was studied in dogs and humans. The soft gelatin capsules produced consistently higher plasma concentration-time curves.     

Preliminary observations on dissolution and bioavailability of triamterene–hydrochlorothiazide combination products

The dissolution profiles of two brands of triamterene–hydrocholorthiazide (TRM–HCT) combination tablets and two brands of TRM–HCT combination capsules were studied using the USP paddle method at 100 rev min^?1 in acid medium (0·1 N). The tablets represent two products marketed in Germany, whereas the capsules represent the approved innovator's product and an unapproved generic product. The tablets dissolved almost 100 per cent in 15 min whereas the capsules dissolved less than 25 per cent in 60 min. A pilot bioavailability study was carried out in four normal healthy male volunteers. Urine samples were collected over a 48 h period and analysed for TRM, its major metabolite TRM-sulfate, and HCT using HPLC methods. The dissolution characteristics of TRM can be associated with the total drug excretion (absorption) of the product. On the other hand, the excretion (absorption) of HCT was independent of dissolution characteristics of the products. However, in TRM–HCT combination product, there appears to be a 50 per cent reduction in HCT excretion (absorption) when compared to the reported excretion (absorption) from a marketed single-entity product.     

Pharmacokinetics and bioavailability of papaverine HCl following intravenous, peroral, rectal, vaginal, topical and buccal administration in beagle dogs

This in vivo study was designed to obtain bioavailability data and a definite pharmacokinetic profile of papaverine HCl in Beagle dogs following intravenous (IV), peroral (PO), rectal, vaginal, topical, and buccal administration of different papaverine HCl formulations. Blood samples were analyzed by high-performance liquid chromatography. The pharmacokinetic parameters were determined using either a curve fitting program (RESID) or a compartment model independent program (AUC-RPP). The plasma concentration-time profiles show that papaverine HCl pharmacokinetics is best described by an open two-compartment model. The absolute bioavailability of papaverine HCl was determined to be 57.2 per cent, 25.2 per cent, 53.2 per cent, 3.2 per cent and 7.5 per cent, respectively, following P.O., rectal, vaginal, topical and buccal administration.     

THE BIOAVAILABILITY OF ORAL DOSAGE FORMS OF A NEW HIV-1 PROTEASE INHIBITOR,KNI-272, IN BEAGLE DOGS

The bioavailability (BA) of a tripeptide protease inhibitor, KNI-272, which has a strong pharmacological potential for treating human immunodeficiency virus type 1 (HIV-1), has been studied in beagle dogs by administering several oral dosage forms. The tested dosage forms were form 1, plain gelatin capsules; forms 2 and 3, gelatin capsules of which the inner and outer surfaces were coated with 7G ethylcellulose (EC, 30 μm thickness) and an enteric coating material, hydroxypropyl methylcellulose phthalate (HP-55), respectively; and form 4, gelatin capsules of which the inner surface is coated with 10G EC (60 μm thickness). The difference between forms 2 and 3 was the amount of citric acid contained in the capsule, namely 100 mg in form 2 and 200 mg in form 3. One hundred milligrams of KNI-272 was placed in each capsule after being dissolved with propylene glycol (PG). These capsules were used to deliver KNI-272 to the stomach for form 1, to the upper part of the small intestine for forms 2 and 3, and to the middle part of the small intestine for form 4. As a reference, 50.0 mg of KNI-272 was administered to the same dogs by intravenous (IV) infusion for 15 min. By measuring the plasma drug levels with the HPLC method, BAs were estimated for each test dosage form. Form 1 showed the highest BA of 26·2±7·0% (mean±SE), though the other capsules showed BAs of approximately 10%, namely 6·6±0·4% for form 2, 10·3±1·1% for form 3 and 14·2±1·0% for form 4. Therefore, as the site where KNI-272 is released from the capsule becomes higher, the BA increases. In addition, as the amount of citric acid contained in a capsule increases, the BA value tends to increase. These results suggest that KNI-272 is stable and not extensively hydrolysed in the gut after oral administration, that the dissolution process into GI fluids is important for the BA of KNI-272, and that the most appropriate absorption site of KNI-272 in dogs is the duodenum. The potential of this new tripeptide compound as an orally active anti—AIDS drug has been confirmed.     

An improvement in digoxin bioavailability. Studies with soft gelatin capsules containing a solution of digoxin

A study of relative bioavailability of two digoxin formulations was carried out on 28 healthy volunteer human subjects of both sexes. A commercial digoxin in tablet form was compared with a new commercial formulation which contains a solution of digoxin in soft gelatin capsules. The parameters investigated were: plasma levels, area under the plasma level-time curve, daily urinary excretion of digoxin and a series of polycardiographic measurements, all the parameters being evaluated in a steady-state condition (14 days of treatment). All the parameters investigated demonstrated better bioavailability in the capsules than in the tablets, the average improvement being 26.1%. The better bioavailability of digoxin capsules also resulted in more rapid and wider variations in the polycardiographic parameters.     

Improving the Oral Bioavailability of Sulpiride by Sodium Oleate in Rabbits

To improve the limited oral bioavailability of sulpiride, a dosage form containing sodium oleate as an absorption enhancer was developed and evaluated using gastric-emptying-controlled rabbits in a cross-over manner. In addition to the known properties of sodium oleate with respect to modifying the permeability of biomembranes, it was found to be capable of improving the physicochemical properties of sulpiride toward a higher lipophilicity (by ion-pair association) and a higher solubility (by micellar solubilization). Nonetheless, the incorporation of sodium oleate with sulpiride as a mixture filled in hard gelatin capsules failed to increase intestinal absorption, whereas the use of enteric capsules, instead of the hard gelatin capsules resulted in a significant increase (P < 0·05) in the oral bioavailability.     

Experimental evaluation of bioavailability of tetramezine from tablets

The absolute bioavailability f of the new antipsychotic drug tetramezine from tablets with intestine-soluble shell upon peroral administration in dogs amounted to 65.4% and was significantly higher than upon administration in the form of an aqueous solution of the parent substance (f = 48.1%). Comparative data on the peroral administration of the aqueous solution of tetramezine in dogs and rats showed that the bioavailability of tetramezine in dogs (48.1%) was much higher than that in rats (10%). The higher bioavailability of tetramezine from tablets is due to the intestine-soluble shell, which prevents the premature biotransformation of the drug in the acid medium of the stomach. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 9, pp. 3–4, September, 2006.     

Formulation parameters affecting the performance of coated gelatin capsules with pulsatile release profiles

The objective of this study was to develop and evaluate a rupturable pulsatile drug delivery system based on soft gelatin capsules with or without a swelling layer and an external water-insoluble but -permeable polymer coating, which released the drug after a lag time (rupturing of the external polymer coating). The swelling of the gelatin capsule itself was insufficient to rupture the external polymer coating, an additional swelling layer was applied between the capsule and the polymer coating. Croscarmellose sodium (Ac-Di-Sol) was more effective as a swelling agent than low and high molecular weight hydroxypropylmethyl cellulose (HPMC; E5 or K100M). Brittle polymers, such as ethyl cellulose (EC) and cellulose acetate propionate (CAPr), led to a better rupturing and therefore more complete drug release than the flexible polymer coating, Eudragit RS. The lag time of the release system increased with higher polymer coating levels and decreased with the addition of a hydrophilic pore-former, HPMC E5 and also with an increasing amount of the intermediate swelling layer. The water uptake of the capsules was linear until rupture and was higher with CAPr than with EC. Soft gelatin capsule-based systems showed shorter lag times compared to hard gelatin capsules because of the higher hardness/filling state of the soft gelatin capsules. The swelling pressure was therefore more directed to the external polymer coating with the soft gelatin capsules. Typical pulsatile drug release profiles were obtained at lower polymer coating levels, while the release was slower and incomplete at the higher coating levels. CAPr-coated capsules resulted in a more complete release than EC-coated capsules.     

Bioavailability and related heart function index of digoxin capsules and tablets in cardiac patients.

A loading dose of digoxin (750 microgram) in two commercial formulations was administered to 14 patients with heart disease according to a crossover design. One formulation consisted of soft gelatin capsules containing a solution of digoxin; the other formulation was compressed tablets. All parameters investigated, i.e., serum peak height, time of the peak, area under the serum level--time curve (AUC), and area above the Q--S2I (electromechanical systole) decrease (obtained from polycardiographic evaluation), showed better bioavailability of digoxin capsules than tablets, averaging 36.3%. The better bioavailability of digoxin capsules than tablets seems to be more evident in heart disease patients than that encountered previously in healthy subjects. The AUC and the area above the Q-S2I decrease were linearly correlated only with digoxin capsules.