Rikard Sandström

Jejunal absorption and metabolism of R/S-verapamil in humans.

AbstractPurpose. The purpose of this human intestinal perfusion study was to investigate the transport and metabolism of R/S-verapamil in the human jejunum (in vivo). Methods. A regional single-pass perfusion of the jejunum was performed using a Loc-I-Gut® perfusion tube in 12 healthy volunteers. Each perfusion lasted for 200 min and was divided into two periods each of 100 min. The inlet concentrations of verapamil were 4.0 and 40 mg/1 in period one and two, respectively. Results. The effective jejunal permeability (Peff) of both R- and S-verapamil increased (p < 0.05) when the inlet concentration was increased consistent with saturation of an efflux mechanism. However, both R- and S-verapamil had high intestinal Peff, consistent with complete absorption. The Peff of antipyrine also increased, but there was no difference in the Peff for D-glucose in the two periods. The appearance of R/S-norverapamil in the intestinal perfusate leaving the jejunal segment was non-linear, presumably due to saturation of the CYP3A4 metabolism. Conclusions. The increased Peff in parallel with increased entering drug concentration is most likely due to saturable efflux by P-glycoprotein(s) in the human intestine.

Pharmacodynamics of carbamazepine-mediated induction of CYP3A4, CYP1A2, and Pgp as assessed by probe substrates midazolam, caffeine, and digoxin.

The aim of this study was to develop a model describing the carbamazepine autoinduction and the carbamazepine‐mediated induction of CYP3A4, CYP1A2, and P‐glycoprotein. Seven healthy volunteers were dosed with carbamazepine over 16 consecutive days. The CYP3A4, CYP1A2, and P‐glycoprotein activities were assessed, using midazolam, caffeine, and digoxin as probe substrates, on 12 occasions, covering the preinduced state and the onset and termination of the induction process. The data were evaluated using a mechanistic pharmacokinetic approach in NONMEM. The induction processes were described using turnover models, with carbamazepine and carbamazepine‐10,11‐epoxide as the driving force of the induction. The half‐lives of CYP3A4 and CYP1A2 were estimated to be 70 and 105 h, respectively. P‐glycoprotein was not affected by the carbamazepine treatment. The possibility of modeling the pharmacodynamics of enzyme induction using a turnover model was illustrated, and the time course of the process was estimated with good precision.

Jejunal permeability and hepatic extraction of fluvastatin in humans

The primary objective was to investigate the effective permeability and the hepatic extraction of fluvastatin, a new 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase inhibitor, during a jejunal perfusion in humans. The secondary objective was to investigate the relationship between human jejunal effective permeability values and physicochemical properties for four different drugs.

The absence of stereoselective P-glycoprotein-mediated transport of R/S-verapamil across the rat jejunum.

We have studied the potential stereoselective transport and metabolism of R/S‐verapamil in rat jejunum, in‐situ.

Concentration- and region-dependent intestinal permeability of fluvastatin in the rat.

The purpose of this study was to investigate the mechanisms of transport of fluvastatin across the intestinal mucosa in various regions of the intestine in the rat. In‐situ single‐pass perfusions of the jejunum, ileum and colon were performed and the effective permeability (Peff) of fluvastatin, antipyrine and D‐glucose were assessed in each region, at three different perfusate fluvastatin concentrations (1.6, 16 and 160 μM). The effect of lovastatin acid on the bi‐directional transport of fluvastatin across the ileal mucosa was also studied.

Enantiomeric separation of verapamil and norverapamil using Chiral-AGP® as the stationary phase

Simultaneous enantiomeric separation of verapamil and its main metabolite norverapamil was achieved using Chiral-AGP as the stationary phase. The optimized chromatographic system was obtained using statistical experimental design with partial least squares as regression method. The three variables studied were buffer pH, content of acetonitrile and column temperature. A high buffer pH favors enantioselectivity as well as the selectivity between (S)-verapamil and (R)-norverapamil. The concentration of the organic modifier in the mobile phase was a compromise as a high content of acetonitrile decreased enantioselectivity but increased the selectivity mentioned above. Increased column temperature increased the separation between (S)-verapamil and (R)-norverapamil with only a slight decrease in enantioresolution.