Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: verapamil hydrochloride, propranolol hydrochloride, and atenolol.

Literature data related to the Biopharmaceutics Classification System (BCS) are presented on verapamil hydrochloride, propranolol hydrochloride, and atenolol in the form of BCS-monographs. Data on the qualitative composition of immediate release (IR) tablets containing these active substances with a Marketing Authorization (MA) in the Netherlands (NL) are also provided; in view of these MA's the assumption was made that these tablets were bioequivalent to the innovator product. The development of a database with BCS-related data is announced by the International Pharmaceutical Federation (FIP).

In vitro/in vivo correlations of dissolution data of carbamazepine immediate release tablets with pharmacokinetic data obtained in healthy volunteers.

The aim of the study was to select a dissolution test method for carbamazepine (CBZ) immediate release tablets, giving the best in vitro/in vivo correlations (IVIVC) and to determine the potential of this method as an estimate for bioequivalence testing. Four 200 mg CBZ products which are sold on the Dutch market, covering the innovator and three generic products, were selected. They had been tested in a randomised, fourway cross-over bioavailability study in healthy volunteers. Their dissolution rate behaviour in vitro was investigated in two dissolution media: (1) 1% sodium lauryl sulphate in water (SLS), in accordance with the United States Pharmacopeia (USP); (2) 0.1 mol/l Hydrochloric acid in water (HC). In the bioavailability study these products had shown no large differences in the extent of absorption (AUC(0-infinity);) but large differences in absorption rate. The products now also showed large differences in dissolution rate in vitro in both dissolution media, the rank order being the same as for the absorption rate. It was concluded that the absorption rate in vivo depends on the dissolution rate in vivo. 'Level C' IVIVC according to the USP were optimised by plotting percentages dissolved on selected time points (D values) or their reciprocals (1/D values), against several pharmacokinetic parameters primarily related to the absorption phase and against AUC(0-infinity). In this way for each IVIVC the optimum D or 1/D value, was calculated. For both media no meaningful IVIVC were obtained with AUC(0-infinity), but favourable IVIVC were obtained with the parameters primarily related to the absorption phase. In the bioavailability study indicated above it was found that, among the pharmacokinetic characteristics primarily related to the absorption phase, C(max) is the most promising in expressing rate of absorption in bioequivalence testing in single dose studies with CBZ immediate release tablets. Consequently, C(max) was selected for expressing rate of absorption. The most favourable IVIVC were obtained with D(20) in SLS versus C(max). From this IVIVC and the requirements for bioequivalence (AUC(0-infinity): 0.8-1.25 and C(max) : 0.75-1.35; 90% confidence interval), a specification for dissolution testing in SLS was calculated as follows: 'after 20 minutes, 34-99% dissolved'. Owing to the fact that the rate of absorption in vivo depends on i.a. the dissolution rate in vivo, it can be concluded that with this specification bioequivalence with respect to both rate of absorption and extent of absorption is ensured. As this specification is comparable with the USP specification: 'not less than 75% dissolved after 1 h', it is concluded that the USP specification is suitable to ensure bioequivalence of CBZ immediate release tablets.

Bioavailability of carbamazepine from four different products and the occurrence of side effects.

The relative bioavailability of four different carbamazepine products, showing large differences in in vitro dissolution profiles, was studied in healthy volunteers to correlate the occurrence of side effects with a measure of the rate of absorption in vivo for bioequivalence testing. Two of the three generic products investigated showed bioequivalence with respect to the extent of absorption with Tegretol. In vivo, the differences found in absorption rate were reflected in the occurrence of side effects, especially dizziness. As a measure for the rate of absorption, the partial AUC did not seem to be a good characteristic to test bioequivalence, as the variability is very high and dependent on the AUC taken. The Cmax/AUCpart seems more promising, especially the partial AUC directly after completion of the absorption process. The variability is low in the case of carbamazepine after a single dose. However, as long as no consensus on the use of other metrics and the objective (clinical or quality control aspects) of bioequivalence testing is reached, and no other pharmacokinetic characteristic is validated, Cmax should be the characteristic of choice for the rate of absorption in single-dose studies with carbamazepine products.

Pharmacokinetics and cognitive effects of carbamazepine formulations with different dissolution rates.

OBJECTIVE: In this study our aim was to assess pharmacokinetic effects and adverse cognitive effects of switches between generic and branded formulations of carbamazepine (CBZ). METHOD: Twelve patients were included in a randomized open-label, observer-blind, cross-over design with a double-baseline period, comparing three different formulations of carbamazepine in monotherapy--the innovatory branded form Tegretol and two generic forms, CBZ Pharmachemie and CBZ Pharbita. Cognitive assessment was carried out at baseline and 3 days after a cross-over. RESULTS: Area under the curve and a number of pharmacokinetic properties (serum concentration day curves, change in serum concentration (delta scores), peak/trough concentrations and peak time) did not differ among the three CBZ formulations. Therefore, the basic assumption for this study, i.e. to test pharmacokinetic-related differences in cognitive profile, was not met. In line with these findings, none of the cognitive variables showed statistically significant differences with respect to the cognitive profile during the day. CONCLUSION: Switches between the investigated generic CBZ formulations and the branded product did not result in any difference in cognitive profiles. These results are not necessarily valid, though, for other generic forms of CBZ, for other types of antiepileptic drugs or for CBZ treatment in higher doses or in polytherapy.

Embryotoxicity of carbamazepine in rat postimplantation embryo culture after in vitro exposure via three different routes.

Postimplantation rat embryo culture is used widely for studies of embryotoxic effects on the isolated embryo after in vitro exposure to xenobiotic compounds. In this study, the relevance of three routes of exposure of the embryo in vitro was evaluated using the embryotoxic anticonvulsant carbamazepine. Embryotoxic effects were assessed, and analyses in conceptus tissues were done to reveal uptake and metabolism of the compound. Exposure via the culture medium resulted in neural tube defects and general retardation of growth and development. After injections into the amniotic or exocoelomic space, local membrane adhesions were found. Intra-amniotic exposure caused adhesions of the amniotic membrane with the embryonic neural plate, resulting in trapping of the membrane in the closing neural tube, as well as in open neural tube defects occurring in various areas of the neural tube. Only after exposure via the culture medium were amounts of carbamazepine detectable in the embryonic tissue, correlating with the systemic effects found. It is concluded that uptake from the culture medium via the yolk sac circulation is the relevant exposure route to be used for embryotoxicity effect assessment.

Residue study of mebendazole and its metabolites hydroxy-mebendazole and amino-mebendazole in eel (Anguilla anguilla) after bath treatment.

Mebendazole (MBZ) is extensively used in eel culture for treatment of Pseudodactylogyrus spp. infections. This use may lead to residues of MBZ in eel tissues. Consequently, the residue profile of MBZ in eel after treatment with the drug is of special concern. Therefore, a residue study was performed in European eels (Anguilla anguilla), bath-treated with MBZ at a dose of 1 mg/liter for 24 hr and kept at a water temperature of 25 degrees C. Liver, kidney, fat, skin, and muscle tissues samples were collected at intervals during and after treatment and analyzed for MBZ and its metabolites, hydroxy-MBZ (MBZ-OH) and amino-MBZ (MBZ-NH2), by HPLC. Results showed that MBZ is extensively metabolized to MBZ-OH and MBZ-NH2. Liver and kidney were found to contain the highest levels of MBZ metabolites, and fat contained the highest levels of the parent compound. Skin contained higher residue levels for all three compounds, compared with muscle tissue. MBZ and its hydroxy metabolite were eliminated within 5 days from the edible parts (muscle and skin) of the eels, whereas MBZ-NH2 could be detected by the 14th day after the end of the treatment period. Consequently, although MBZ and MBZ-OH constitute the residues of toxicological concern, MBZ-NH2 should be taken as the compound of interest for estimating the withdrawal time for consumption of eel treated with MBZ.

Teratogenicity of a single oral dose of retinyl palmitate in the rat, and the role of dietary vitamin A status.

Vitamin A, known for its teratogenic properties, may be present in high concentrations in consumption liver. It is as yet unclear whether congenital malformations can result from a single liver meal. In our first experiment, the teratogenicity of a single dose of retinyl palmitate was tested in the rat. Pregnant rats were treated at day 10 of gestation by gavage with 100, 300 or 1000 mg/kg body weight retinyl palmitate on a dietary background level of 5 mg/kg feed. At gestation day 11 the number of embryos with an open cranial neural tube had increased with the dose. At gestation day 21, the high dose group showed an increase in late resorptions, whereas both the high and the medium dose groups had a high incidence of foetuses with malformations typical of retinoid embryopathy. The data suggest that delayed neural tube closure had occurred in a large proportion of the embryos. In a second experiment, the high oral dose was applied on gestation day 10 in pregnant rats receiving retinyl palmitate at 1.5, 5, 15, or 50 mg/kg feed for 6 weeks. Delayed neural tube closure, post-implantation loss and the nature and incidence of malformations were similar between diet groups, as well as being reminiscent of the high dose group in the first experiment. Thus the dietary status of the animals did not seem to influence the teratogenic potential of a single high dose of retinyl palmitate.

Congener-specific bioavailability of PCDD/Fs and coplanar PCBs in cows: laboratory and field measurements.

To estimate congener-specific bioavailabilities for 17 PCDD/Fs in cows grazing near a MSW incinerator both a controlled lab study and a field study were performed. In the lab study the estimates were derived from the elevated concentrations in milk from two cows after administration of a single dose of contaminated fly ash. In the field study, located near a large MSW incinerator, daily samples of grass and milk collected over a period of 60 days were pooled to two monthly bulk samples. The concentrations in these bulk samples of grass and milk were used to estimate the bioavailabilities of the 17 PCDD/Fs as well as of three coplanar PCBs. With the concentrations of PCDD/Fs expressed in I-TEQs the bioavailability in cows was estimated at +/- 7.5% in the field study. The congener-specific bioavailabilities correlated well between the two studies, as well as with previously reported values in the literature. However, the absolute levels differed considerably between studies, indicating a strong matrix effect.

Rabbit model for estimating relative bioavailability, residues and tissue tolerance of intramuscular products: comparison of two ampicillin products.

A rabbit model for simultaneous investigation of the bioavailability, tissue residues and tissue tolerance of intramuscularly administered veterinary medicines is described. The bioavailability of ampicillin from two intramuscular products, which had been found to be different in calves, were compared in a two-way crossover design. The ampicillin levels in plasma, ampicillin residues in tissues, the plasma creatine kinase activity and the tissue damage at the injection sites were studied. The absolute bioavailabilities for the products were 100% and 40%. Differences in pharmacokinetics of ampicillin between sexes were observed after intravenous and intramuscular administration. Only slight tissue damage could be detected at the injection sites after intramuscular administration of these products. The results were compared with those obtained previously in calves and were found to be similar. Further investigations with other intramuscular drug products to validate this model are under way.

The bioavailability of diclofenac from enteric coated products in healthy volunteers with normal and artificially decreased gastric acidity.

The relative bioavailability of four monolithic enteric coated (MEC) diclofenac products was compared in 16 healthy volunteers. Only one generic product was fully bioequivalent with the reference product Voltaren with regard to AUC, Cmax, and tlag. Two products showed significant differences in tlag. In a second experiment with eight volunteers the influence of increased gastric pH (ranitidine treatment) on the two mutually most differing products was studied. They showed equivalence in AUC, but not in Cmax. Analysis of tlag suggests that the product with the low tlag disintegrates within the non-acid stomach, whereas the product with the long tlag passes the non-acid stomach intact. Several in vitro dissolution tests were conducted. The European Pharmacopeia test did not detect any differences between the products. At pH 5, both with and without mechanical stress, only the product with the shortest tlag released diclofenac. The in vivo results were best predicted by the in vitro dissolution tests performed at several fixed pH values with mechanical stress.

Comparative antidotal efficacy of activated charcoal tablets, capsules and suspension in healthy volunteers.

The efficacy of several formulations of activated charcoal (AC) was compared by measuring the intestinal absorption of a solution of 1 g paracetamol administered 2 min before administration of 5 g AC as suspension (200 ml), tablets (40 of 125 mg) or capsules (25 of 200 mg). The suspension medium without AC was used as the control treatment. Based on the results of a pilot experiment, an 8 subject panel was used in a two 4 x 4 Latin square design. All treatments with AC resulted in a statistically significant decrease in paracetamol absorption compared to the control treatment. The suspension was considerably and significantly more effective than the tablets or capsules. Treatment with tablets was slightly but significantly more effective than capsules. The intake of large numbers of tablets and capsules was difficult. In the hospital AC suspensions are available. For first aid elsewhere, at home, at the working place or in the general practitioner's surgery a preservable and easily redispersible AC formulation would be preferable to the present solid forms.

Pharmacokinetic interactions between indomethacin and paracetamol in the rat.

The influence of concurrent administration of paracetamol with indomethacin on the plasma concentrations of these drugs was studied in rats. Orally administered paracetamol reduced the plasma levels of indomethacin during the first 2 hours after oral administration. Later, 16 and 24 hours after administration of indomethacin, the plasma levels exceeded the control values due to the concurrent oral administration of paracetamol. These data suggest that paracetamol delayed the absorption of indomethacin. In contrast the plasma concentrations of paracetamol were not influenced substantially by indomethacin. When paracetamol was co-administered subcutaneously with oral indomethacin, the plasma levels of the latter drug were not influenced. It is concluded that the protective effect of paracetamol against the gastric injuring side effect of indomethacin, which also occurs with subcutaneous administration of paracetamol, cannot be solely due to lowered plasma concentrations of indomethacin.

Determination of amygdalin and its major metabolite prunasin in plasma and urine by high pressure liquid chromatography.

A method is described for the determination of amygdalin and prunasin in plasma ultrafiltrate and urine. Both compounds are separated by high pressure liquid chromatography on a reversed phase column and subsequently detected at 215 nm. The identity of an amygdalin metabolite with prunasin was confirmed by mass spectrometry.

The pharmacokinetics of prunasin, a metabolite of amygdalin.

The pharmacokinetics of prunasin have been investigated in the dog. The results are compared with results obtained with amygdalin. The volume of distribution and the clearance of prunasin are larger than those of amygdalin. The oral bioavailability of prunasin is approximately 50%, whereas amygdalin is hardly absorbed unchanged.

The pharmacokinetics of amygdalin.

Amygdalin (D-mandelonitrile-beta-D-gentiobioside) is a cyanogenic glycoside claimed to show anti-cancer activity, sold under the incorrect name "Laetrile". For a sensible discussion of its alleged activity and its established toxicity it is necessary that its fate in the organism is known. The pharmacokinetics of amygdalin have been investigated in the Beagle dog after both intravenous and oral administration. The excretion of amygdalin has also been studied in the rat. Amygdalin concentrations were determined by high performance liquid chromatography in plasma ultrafiltrate and urine. The pharmacokinetics of amygdalin after intravenous administration were compared with those of diatrizoate, a model substance for extracellular volume and glomerular filtration. The amygdalin clearance is significantly larger than that of diatrizoate. The volumes of distribution of both substance are the same. After oral administration only a few percents of the amygdalin dose are systemically available. A part of the oral dose is recovered from the urine as prunasin (D-mandelonitrile-beta-D-glucoside).

The determination of propiopromazine in animal tissue.

A thin-layer chromatographic method for the determination of the veterinary tranquillizer propiopromazine (Combelen) in slaughter pigs is described. Propiopromazine residue depletion from the kidney occurs with different rates in sows and in castrated boars. In the liver residues increase over at least 24 h after intramuscular administration, in accordance with the distribution pattern of phenothiazine tranquilizers.

Interactions of aspirin with acetaminophen and caffeine in rat stomach: pharmacokinetics of absorption and accumulation in gastric mucosa.

To study the pharmacokinetic interactions between aspirin (250 mg/kg) and simultaneously administered oral acetaminophen (125 mg/kg) or caffeine (50 mg/kg) in male rats, noninterfering GLC assays for these drugs were developed. Acetaminophen and caffeine both retarded the appearance of salicylate in plasma. During the elimination phase, acetaminophen enhanced plasms salicylate levels whereas caffeine did not. Aspirin reduced the plasms levels of both acetaminophen and caffeine during absorption and elimination. Regardless of whether the drugs had been administered separately or in combination, higher concentrations of salicylate, acetaminophen, and caffeine were found in the glandular part of the stomach compared to the nonglandular part (rumen). In both parts, the absorption of acetaminophen increased in the presence of aspirin. Simultaneous administration of aspirin with caffeine did not influence the absorption of either drug in the glandular and ruminal parts. The inhibitory action of acetaminophen and the potentiating action of caffeine on the erosive activity of aspirin are not due to any effects of these drugs on salicylate accumulation in glandular tissue.

Treatment of experimental imipramine and desipramine poisoning in the rat.

The influence of orally administered activated charcoal on organ concentrations of parenteral imipramine and desipramine was investigated. Ancillary distribution experiments indicated that the gastroenteral cycle of these substances might be more important than the enterohepatic cycle. Nevertheless the effectiveness of repeated activated charcoal dosage in lowering antidepressant concentrations of visceral organs is unpredictable. This is interpreted as a consequence of predominant binding of these drugs in the tissues, in contrast to drugs like acetosal and the barbiturates, which are distributed more evenly in the body water. The conclusion is, that activated charcoal has only limited value as an anitdotal adsorbent in imipramine or desipramine poisoning.