ABSTRACT
The objective of the research was to establish the capability of the Intelisite capsule to deliver the probe drugs, theophylline and frusemide, in the form of split immediate release (IR) tablets, to the small intestine and colon. The two probe drugs were administered together in an open, random, three-way crossover study in eight healthy volunteers, comparing absorption following Intelisite delivery in the small bowel and colon to conventional IR dosing. Gamma scintigraphy was employed to monitor the gastrointestinal transit and activation of the Intelisite capsule. Standard pharmacokinetic parameters, and the percentage remaining in the capsules post defecation were determined. The Intelisite capsule was well tolerated in human volunteers and successfully activated on 15/16 occasions. Pharmacoscintigraphy showed internal marker release from the Intelisite capsule to be approximately 10-fold faster in the small intestine than in the colon. Theophylline and frusemide were both well absorbed following Intelisite activation in the small intestine, whereas complete colonic absorption was only observed in 1/7 subjects for theophylline, and 0/7 subjects for frusemide. The probe drugs were successfully delivered in particulate form from the Intelisite capsule in the small intestine and produced expected pharmacokinetic profiles. However drug release in the colon was incomplete and variable possibly due to: low water content, poor mixing, and a high loading dose.
Subject(s)
Colon/metabolism , Diuretics/pharmacokinetics , Furosemide/pharmacokinetics , Intestine, Small/metabolism , Phosphodiesterase Inhibitors/pharmacokinetics , Theophylline/pharmacokinetics , Adult , Area Under Curve , Capsules , Cross-Over Studies , Diuretics/blood , Furosemide/blood , Humans , Intestinal Absorption/physiology , Male , Phosphodiesterase Inhibitors/blood , Tablets , Theophylline/bloodABSTRACT
The synthesis, antibacterial activity and stability to human dehydropeptidase-1 (DHP-1) of three small series of carbapenems carrying carbon-linked substituents at C-2 are described. C-2 Ethenyl carbapenems showed moderate antibacterial activity but poor stability to DHP-1, C-2 Oxyiminomethyl carbapenems demonstrated variable activity and stability C-2 alpha-(Hydroxy)benzyl carbapenems were the most promising and showed good potency and DHP-1 stability.
Subject(s)
Carbapenems/chemical synthesis , Carbapenems/pharmacology , Humans , Structure-Activity RelationshipABSTRACT
A new series of carbapenems, having a saturated or partially unsaturated heterocycle at C-2, has been synthesised. The in vitro antibacterial activity of these compounds and their stability to human dehydropeptidase-1 (DHP-1) are described. The stereochemistry of the C-2 side-chain and the presence of a double bond in the heterocycle were shown to have significant effects on the stabilities of the compounds to DHP-1.