A common belief is that one tablet or suppository containing, e.g. 100 mg of a drug can be substituted, without any changes in the therapeutic effect, with two units of the same brand containing 50 mg of the drug. In the present study a single dose of paracetamol was administered to healthy volunteers as (a) two tablets of 500 mg, (b) two suppositories of 500 mg, and (c) one suppository of 1000 mg. There were statistically significant differences in all bioavailability parameters (t(max), C(max) and AUC) between the three treatments. The relative bioavailability of the 500 mg suppositories was 77% and that of the 1000 mg suppositories 66%. The absorption rate from suppositories was markedly lower than from the tablets. Especially low absorption rate was obtained with the suppository of 1000 mg. The two strengths, although having the same trade name, were not therefore bioequivalent.
Gastrointestinal absorption of bisphosphonates is highly variable from individual to individual (between-subject variation) and from day to day (within-subject variation), a fact that creates problems both in research and in clinical use of these drugs. We conducted a randomized, two-period cross-over pharmacokinetic (phase I) study to assess the relative bioavailability of two different clodronate preparations: an 800 mg tablet and a 400 mg capsule. Urinary excretion of clodronate correlates with gastrointestinal absorption. To minimize the confounding effect of the high variability of gastrointestinal absorption, we chose as the primary parameter the cumulative amount of clodronate excreted into urine (A e0-t ) during 9 days (7 days of treatment, 2 days of follow-up). The 90% confidence interval calculated for the population medians of A e0-t was 0.83-1.09, well within the 90% confidence interval stipulated for bioequivalence for the area under the curve values (0.80 -1.25). This new procedure for pooling urinary excretion data offered a clear advantage over previous methods, and thus could presumably be used to study other drugs as well that are not metabolized and may show highly variable gastrointestinal absorption. (J Bone Miner Res 1997;12:66-71) INTRODUCTION C LODRONATE (dichloromethylene bisphosphonate) belongs to the bisphosphonates, compounds structurally related to the naturally occurring pyrophosphate, which regulates mineralization of bone matrix. In bisphosphonates, the P-O-P bond of pyrophosphate is replaced by a P-C-P bond, which makes them resistant to enzymatic hydrolysis. Clodronate, like other bisphosphonates, because it inhibits osteoclastic bone resorption, is used clinically in the therapy of hypercalcemia and bone resorption due to malignancy. (1,2) Clodronate, with its high water solubility and extensive ionization, is poorly penetrative through biological membranes. This leads to poor absorption from the gastrointestinal tract, a common characteristic of all bisphosphonates; clodronate's bioavailability is about 2% of the oral dose. The plasma protein binding of the drug is low, i.e., about 30%. (3) The peak serum concentration after a single oral dose is reached in 0.5 h, which may point to site-specific absorption in the (upper) gastrointestinal tract. Absorption occurs to some extent in the stomach and to a larger extent in the small intestine. It is greatly diminished when the drug is given with meals, especially in the presence of calcium and iron.(1,2) Elimination of clodronate from serum is characterized by two clearly distinguished phases: the distribution phase with a half-life of about 2 h (4,5) and a very slow second elimination phase, (3,5,6) which results from its strong binding to bone. (3,6) About 20 -30% of the intravenously administered dose remains in the body (in bone). (3,4,6) When bisphosphonates are given in clinically effective doses, there seems to be no saturation in their total skeletal uptake in humans.(1,2) The bone-unbound portion of the absorbed or...
The object of this study was to examine whether prolonged-release hard gelatin capsule formulations could be developed for dogs. Different viscosity grades of hydroxypropyl methylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC) were used to control drug release. Furosemide was chosen because of its wide use in the management of heart failure in dogs. In vitro, selecting different viscosity grades allowed good control of drug release, whereas in vivo the difference between formulations was clearly smaller. Although all formulations gave prolonged release, both inter- and intra-individual variation in the plasma concentration-time curves was high. It is difficult to develop prolonged-release formulations for drugs such as furosemide with highly variable pharmacokinetic properties. However, hard gelatin capsules containing hydrophilic polymers could still be a suitable choice for some drugs.
Furosemide is a problematic drug in a prolonged‐release product because its absorption is site specific, taking place mainly in the upper parts of the alimentary tract. The aim of the study reported here was to develop prolonged‐release furosemide formulations for dogs. The type of preparation selected was a hydroxypropyl methylcellulose (HPMC) matrix tablet. Evaluation was based on dissolution studies, on in vivo disintegration studies in the canine stomach and on bioavailability studies in Beagle dogs. The variables tested were the viscosity grade of the polymer, the amount of polymer and presence or absence of an alkaline compound (potassium carbonate) in the formulation. When potassium carbonate was included, furosemide was absorbed so slowly that drug administration once daily would give plateau drug plasma concentrations, even though the elimination half‐life of furosemide is only about one hour.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.