Pharmaceutical Research, Vol. 16. No. 7, 1999 Research Paper Regional Differences in Quinine Absorption from the Undisturbed Human Colon Assessed Using a Timed Release Delivery System distal sites (1,2), but in normal clinical use colonic contents may have an important modifying effect. Wc therefore aimed to study absorption by measuring the permeation of probe marker molecules from different regions of the distal gut, using a delivery system, the Pulsincap™ (3), which allowed selective delivery to various regions of the undisturbed gut. John M. Hebden,' Clivc G. Wilson, 2 Robin C. Spiller, 1 ' 4 Peter J. Gilchrist, 2 Elaine Blackshaw, 3 Malcolm E. Frier, 3 and Alan C. Perkins 3 Received March II. 1999; accepted April 12, 1999 Purpose. To investigate the regional absorption characteristics of'thc distal gut using two markers of permeability, quinine (a transcellular probe) and "CrEDTA (a paracellular probe). Methods. The permeability markers were delivered to the undisturbed gastrointestinal tract in 39 healthy volunteers using an oral timed- release delivery vehicle which allowed pulsed release within a particu- lar site of the gut. Site of release was identified using gamma scintigra- phy. Absorption of quinine and "CrEDTA was assessed by measuring the percent excretion in the urine using HPLC and gamma counting respectively. Serial plasma samples allowed time-concentration curves for quinine to be plotted. Results. There was a significant trend for diminished absorption with more distal delivery of the transcellular probe, quinine, which was: 6.26 ± 0.87% (small intestine, n = 10); 4.65 ± 0.93% (ascending colon, n = 16); and 2.59 ± 0.52% (transverse colon, n = 10) of the ingested dose excreted respectively (p < 0.001). No such gradient was seen with the paracellular marker. "CrEDTA. Conclusions. These results suggest that delayed release formuations shoud aim for release in the distal small bowel and proximal colon if absorption is to be miximised. Absorption by the transcellular toutc diminishes in the more distal colon, a fact which has implications for delayed or sustained release formulations. KEY WORDS: transcellular; paracellular: absorption: gas- trointestinal. INTRODUCTION It has long been the aim of the pharmaceutical industry to achieve delayed absorption of drug to treat nocturnal and early morning exacerbations of disease, e.g., asthma, rheuma- toid disease, and cardiovascular disease. Such formulations taken at bedtime are inevitably situated in the distal small bowel or proxi mal colon by the early hours of the momi ng. Knowledge of the effect of site of release on absorption characteristics in the undisturbed colon is therefore highly relevant in designing such preparations. Previous studies using a cleansed colon have suggested little intrinsic difference in absorption between proximal and 1 Division of Gastroenterology. University Hospital Nottingham, Not- tingham, UK. 1 Department of Pharmaceutical Sciences. University of Strathclydc, Glasgow, UK. 3 Department of Medical Physics, University Hospital Nottingham, Nottingham, UK. 4 To whom correspondence should be addressed. METHODS Subjects Thirty-nine healthy volunteers (23 male; 16 females), age range 20-40, were recruited into the study. All subjects were free from gastrointestinal disease, and were not taking any laxatives or drugs known to affect gut motility. All were asked to refrain from excess alcohol, curries, and aspirin or non- steroidal antiinflammatory drugs during the course of the study. Females were required to have a negative pregnancy test on the morning of the study day. The study was approved by Nottingham University Ethical Committee and the Association of Radioactive Substances Advisory Committee at the Depart- ment of Health. Study Protocol Phase I In the initial phase of the study, 11 healthy volunteers (6 males; 5 females; age range 20-29) were recruited into a two way crossover study in which they were dosed with either a 5 hour (part A) or 15 hour (part B) release delivery capsule in an attempt to selectively target permeability probes to the proximal colon or distal colon respectively. There was a 2 week washout period, and the volunteers were required to adhere to a 20 gm fibre diet for 2 days before each of the study days. In part A, subjects ingested the 5 hour release delivery system at 0800 h following an overnight fast, and then consumed a stan- dard 200 kcal breakfast of toast, butter and jam once the capsule was seen to empty from the stomach. A standard 600 kcal lunch and 1000 kcal meal were provided at 1300 h and 1800 h respectively. Blood samples were taken prior to, and at 30 minute intervals after the predicted release time (1300 h), and urine was collected in the 3 hour period leading up to the expected release time, and for the 0-20 hour period following the expected release time. In part B, subjects were dosed at 2200 h on the evening prior to the study day, so that the predicted time of release would be the same as in part A (i.e., 1300 hrs). An identical meal pattern, blood and urine sampling protocol was followed. Phase 2 This comprised 12 healthy volunteers who were dosed on a separate occasion with a 5 hr release Pulsincap™, and 16 healthy volunteers who were dosed with a 6 hr release Pulsin- cap™ . These 28 healthy volunteers(I7M; 11F, age range 20-40) followed an identical protocol to phase I part A. Pulsincap™ Delivery Capsule The Pulsincap™ delivery capsule consists of a water insol- uble body with a hydrogel plug inserted at its open end, which 1087 I)724.874l/<W/07(IO-IOK7SIA.(KI/ll » IW" Plenum PuMahin|;C<»p.>rali<«i