Pharmacokinetics of gefitinib in humans: the influence of gastrointestinal factors.

PURPOSE: To investigate whether differences in plasma pharmacokinetic profiles of gefitinib between healthy subjects having normal (N; t(1/2)>20h) and altered (A; t(1/2)<20h) pharmacokinetic (PK) profiles might be explained by inter-individual variability in gastric emptying and/or precipitation/dissolution of gefitinib in the proximal small intestine. METHODS: One hundred healthy male subjects were screened to enable identification of subjects with the two PK profiles. Twenty five subjects from the screening were subsequently enrolled in an intubation study where a 250mg gefitinib dispersion preparation (IRESSA AstraZeneca) was administered directly into the stomach. Intestinal fluid samples were withdrawn continuously for 180min post-dose using the Loc-I-Gut catheter positioned in the jejunum. The crystalline form of gefitinib was determined using Raman microscopy. RESULTS: There were no differences between normal and altered subjects with regard to gastric emptying or the precipitation/dissolution of gefitinib in jejunal fluid. Due to difficulties in crystalline identification in the jejunal fluid samples, only the same crystalline form as the dosed form was identified. CONCLUSIONS: There was no pronounced difference in gastric emptying, precipitation and re-dissolution of gefitinib in proximal human jejunum between normal and altered subjects. Other mechanism(s) are also likely to be important in explaining the inter-individual differences in plasma exposure to gefitinib, such as polymorphism in various metabolic enzymes and/or transport proteins. However, the difference between altered and normal subjects cannot be easily explained and it is likely a multifactorial explanation including low jejunal pH, increased expression of enzymatic and transporter activity and rapid small intestine transit.

Biliary secretion of rosuvastatin and bile acids in humans during the absorption phase.

AIM: The aim of this study was to investigate the biliary secretion of rosuvastatin in healthy volunteers using an intestinal perfusion method after administration of 10mg rosuvastatin dispersion in the intestine. METHODS: The Loc-I-Gut tube was positioned in the distal duodenum/proximal jejunum and a semi-open segment was created by inflating the proximal balloon in ten volunteers. A dispersion of 10mg rosuvastatin was administered below the inflated balloon and bile was collected proximally of the inflated balloon. Bile and plasma samples were withdrawn every 20 min during a 4h period (absorption phase) and additional plasma samples were collected 24 and 48 h post-dose. RESULTS: The study showed that there is a substantial and immediate transport of rosuvastatin into the human bile, with the maximum concentration appearing 42 min after dosing, 39,000+/-31,000 ng/ml. Approximately 11% of the administered intestinal dose was recovered in the bile after 240 min. At all time points the biliary concentration exceeded the plasma concentration, and the average bile to plasma ratio was 5200+/-9200 (range 89-33,900, median 2000). We were unable to identify any bile-specific metabolites of rosuvastatin in the present study. CONCLUSION: Rosuvastatin is excreted via the biliary route in humans, and the transport and accumulation of rosuvastatin in bile compared to that in plasma is rapid and extensive. This intestinal perfusion technique offers a successful way to estimate the biliary secretion for drugs, metabolites and endogenous substances during the absorption phase in healthy volunteers.

A clinical single-pass perfusion investigation of the dynamic in vivo secretory response to a dietary meal in human proximal small intestine.

PURPOSE: To investigate the gastrointestinal secretory and enzymatic responses to a liquid meal during in vivo perfusion of the proximal human jejunum. METHODS: Human intestinal fluid was collected from the proximal jejunum by single-pass in vivo perfusion (Loc-I-Gut). The fluid was quantitatively collected at 10-min intervals during 90 min while perfusing a nutritional drink at 2 mL/min. Quantification of lipids in the fluid leaving the segment was performed by using novel chromatographic methods. RESULTS: The overall bile acid concentration varied between 0.5 and 8.6 mM with a peak level 40 min after the start of the liquid meal perfusion. The total concentration of phospholipids was between 0.1 and 3.9 mM and there was a rapid degradation of phosphatidylcholine to lysophosphatidylcholine. The tri-, di-, monoglycerides and free fatty acid levels increased sharply in the beginning and reached steady-state levels between 7 and 9.5 mM. CONCLUSIONS: There is a rapid secretion of bile in response to food. Most of the dietary lipids are found in the form of their degradation products in vivo in human jejunum. This novel in vivo characterization, based on direct and high-recovery sampling of intestinal fluids, forms a basis for further development of improved in vitro drug dissolution test media.

The effects of food on the dissolution of poorly soluble drugs in human and in model small intestinal fluids.

PURPOSE: This study was conducted to determine the effect of food on drug solubility and dissolution rate in simulated and real human intestinal fluids (HIF). METHODS: Dissolution rate obtained via the rotating disk method and saturation solubility studies were carried out in fed and fasted state HIF, fed dog (DIF), and simulated (FeSSIF) intestinal fluid for six aprotic low solubility drugs. The intestinal fluids were characterized with respect to physical-chemical characteristics and contents. RESULTS: Fed HIF provided a 3.5- to 30-times higher solubility compared to fasted HIF and FeSSIF, whereas fed DIF corresponded well (difference of less than 30%) to fed HIF. The increased solubility of food could mainly be attributed to dietary lipids and bile acids. The dissolution rate was also 2 to 7 times higher in fed HIF than fasted HIF. This was well predicted by both DIF and FeSSIF (difference of less than 30%). CONCLUSIONS: Intestinal solubility is higher in fed state compared to fasted state. However, the dissolution rate does not increase to the same extent. Dog seems to be a good model for man with respect to dissolution in the small intestine after intake of a meal, whereas FeSSIF is a poorer means of determining intestinal saturation solubility in the fed state.