Thomas Giessmann

Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging

Aim : The gastrointestinal transit of sequentially administered capsules was investigated in relation to the availability of fluid along the intestinal lumen by magnetic resonance imaging.

The effects of the human MDR1 genotype on the expression of duodenal P-glycoprotein and disposition of the probe drug talinolol

A single‐nucleotide polymorphism (SNP) of the human multidrug‐resistance gene in wobble position of exon 26 reportedly predicts expression and function of P‐glycoprotein in human enterocytes and lymphocytes. Several other allelic variants of MDR1 have been identified, some of which lead to amino acid exchange with as yet unknown functional relevance.

Oral bioavailability of digoxin is enhanced by talinolol: Evidence for involvement of intestinal P‐glycoprotein

Recent data indicated that disposition of oral digoxin is modulated by intestinal P‐glycoprotein. The cardioselective β‐blocker talinolol has been described to be secreted by way of P‐glycoprotein into the lumen of the gastrointestinal tract after oral and intravenous administration. We therefore hypothesized that coadministration of digoxin and talinolol may lead to a drug‐drug interaction based on a competition for intestinal P‐glycoprotein.

Carbamazepine regulates intestinal P‐glycoprotein and multidrug resistance protein MRP2 and influences disposition of talinolol in humans

The antiepileptic drug carbamazepine is known to be an inducer of cytochrome P450 (CYP) 3A4 after binding to the nuclear pregnane X receptor. To evaluate whether it also regulates the multidrug transporter proteins P‐glycoprotein (P‐gp) and multidrug resistance protein MRP2 in humans, duodenal expression of multidrug resistance gene MDR1 messenger ribonucleic acid (mRNA) and MRP2 mRNA, content of P‐gp and MRP2, and disposition of the nonmetabolized P‐gp substrate talinolol after intravenous (30 mg) and long‐term oral administration (100 mg for 19 days) were assessed in 7 healthy subjects (age, 23–35 years; body weight, 64–93 kg) before and after comedication of carbamazepine (600 mg for 14–18 days).

CYP2D6 genotype and induction of intestinal drug transporters by rifampin predict presystemic clearance of carvedilol in healthy subjects

Clinical trials have indicated that the combined β‐ and α‐adrenergic receptor blocker carvedilol improves the survival rate in patients with advanced chronic heart failure. The objective of our study was the identification and quantification of factors that modulate steady‐state serum concentrations of carvedilol and its enantiomers and that may influence therapeutic efficacy and safety.

Irregular absorption profiles observed from diclofenac extended release tablets can be predicted using a dissolution test apparatus that mimics in vivo physical stresses

The prediction of the in vivo drug release characteristics of modified release oral dosage forms by in vitro dissolution tests is a prerequisite for successful product development. A novel dissolution test apparatus that mimics the physical conditions experienced by an oral formulation during gastrointestinal transit was developed. This included the simulation of pressure forces exerted by gut wall motility, shear forces generated during propagation, and loss of water contact when the dosage form is located in an intestinal air pocket. The new apparatus was evaluated using a diclofenac extended release (ER) tablet. The in vitro dissolution profiles were compared between the novel test apparatus and a conventional dissolution apparatus (USP II). These data were compared with the profiles of plasma concentration versus time that were obtained after the administration of an ER tablet to 24 healthy volunteers under fasting conditions. Multiple peaks were observed in individual plasma concentration-time profiles after the intake of the reference ER tablet. Standard dissolution testing showed typical characteristics of an almost continuous release for this formulation; however, dissolution testing with the novel apparatus suggested that the diclofenac release from the ER tablets would be extremely variable and dependent on the applied stress. The data suggest that the observed multiple peaks of plasma concentration after dosing of the ER diclofenac tablets are most probably caused by sensitivity to physical stress events during gastrointestinal transit.

Intestinal expression of P‐glycoprotein (ABCB1), multidrug resistance associated protein 2 (ABCC2), and uridine diphosphate–glucuronosyltransferase 1A1 predicts the disposition and modulates the effects of the cholesterol absorption inhibitor ezetimibe in humans

Ezetimibe is an inhibitor of the cholesterol uptake transporter Niemann‐Pick C1‐like protein (NPC1L1). Target concentrations can be influenced by intestinal uridine diphosphate–glucuronosyltransferases (UGTs) and the efflux transporters P‐glycoprotein (P‐gp) (ABCB1) and multidrug resistance associated protein 2 (MRP2) (ABCC2). This study evaluates the contribution of these factors to the disposition and cholesterol‐lowering effect of ezetimibe before and after induction of UGT1A1, P‐gp, and MRP2 with rifampin (INN, rifampicin).

Disposition of ezetimibe is influenced by polymorphisms of the hepatic uptake carrier OATP1B1

Objectives Genetic variability in hepatic uptake was recently shown to influence the disposition and cholesterol-lowering effects of statins. Ezetimibe, an inhibitor of the intestinal cholesterol uptake protein Niemann-Pick C 1 like 1, is another drug for which genetic polymorphisms of hepatic organic anion transporting polypeptides (OATPs) are expected to be of clinical relevance because ezetimibe undergoes intensive enterohepatic circulation for which hepatic uptake transporters may be rate-limiting determinants. Methods Using OATP1B3-, OATP2B1-, and OATP1B1-transfected HEK cells, including the OATP1B1 variants OATP1B1*1b and OATP1B1*5, we measured the uptake of ezetimibe and its glucuronide and we analyzed the competition with the common OATP-substrate bromosulfophthalein. Disposition and sterol-lowering effects of 20-mg ezetimibe were measured in 35 healthy participants genotyped for OATP1B1, ABCB1, ABCC2, and UGT1A1. Results Ezetimibe glucuronide inhibited bromosulfophthalein uptake in all OATP-transfected cells (50% inhibitory concentration (IC50): 0.14–0.26 μmol/l) whereas ezetimibe was 30–100 times less potent. Only the glucuronide was accumulated significantly in cells expressing OATP1B1 and OATP2B1. Its uptake in cells expressing OATP1B1*1b and *5 was reduced. In-vivo studies showed there was a gene-dose-dependent decrease in the area under the curve of ezetimibe in participants with the OATP1B1*1b protein (*1a/*1a, N=12, 112±66 ng×h/ml vs. *1a/*1b, N=8, 88±39 ng×h/ml vs. *1b/*1b, N=5, 55±18 ng×h/ml; Jonkheere–Terpstra, P=0.041) and a tendency for increased glucuronide exposure (704±296 vs. 878±369 vs. 1059±363 ng×h/ml; P=0.092). Fecal ezetimibe excretion was significantly decreased whereas renal glucuronide excretion was increased in carriers of *1b/*1b. Fecal excretion was also diminished in carriers of OATP1B1*5 and *15. The sterol-lowering effect of ezetimibe was not influenced by OATP1B1 polymorphisms. Conclusion Pharmacokinetics of ezetimibe is influenced by OATP1B1 polymorphisms in healthy participants after single dose administration.

The talinolol double-peak phenomenon is likely caused by presystemic processing after uptake from gut lumen.

Purpose.Evaluation of the double-peak phenomenon during absorption of the β1-selective blocker talinolol relative to paracetamol, which is well absorbed from all parts of the gut, and relative to vitamin A, which is absorbed via the lymphatic pathway.Methods.Talinolol was given with paracetamol and retinyl palmitate in fast-disintegrating, enteric-coated, and rectal soft capsules to 8 fasting male healthy subjects (21–29 years, 68–86 kg). To evaluate whether the talinolol double-peak is associated with processes of food absorption, a breakfast was served 1 h after administration of a fast disintegrating capsule.Results.Bioavailability of talinolol in enteric-coated and rectal capsules was significantly reduced by about 50% and 80%, respectively, despite unchanged bioavailability of paracetamol. Double-peaks appeared after 2–3 h and 4–6 h with talinolol given as fast-liberating capsules. Food increased the maximum concentrations significantly (223 ± 76 μg/ml vs. 315 ± 122 μg/ml, p ‹ 0.05) and shifted the second peak of talinolol to shorter tmax values (3.8 ± 1.2 h vs. 2.1 ± 0.6 h, p ‹ 0.05), which was associated with faster absorption of retinyl palmitate. Pharmacokinetic model fits showed that about half of the oral talinolol dose given with and without meal is drained from the intestine via a presystemic storage compartment.Conclusions.The double-peak phenomenon of talinolol is likely caused by a presystemic storage compartment, which represents the complex interplay of heterogeneous uptake and kick-back transport processes along the intestinal-hepatic absorption pathway.

Disposition and sterol‐lowering effect of ezetimibe are influenced by single‐dose coadministration of rifampin, an inhibitor of multidrug transport proteins

The disposition and sterol‐lowering effect of ezetimibe are associated with long‐lasting enterosystemic circulation, which is initiated by secretion of ezetimibe and its glucuronide via intestinal P‐glycoprotein (P‐gp) (ABCB1) and the multidrug resistance‐associated protein 2 (MRP2) (ABCC2) into gut lumen. Hepatic uptake and secretion may contribute to recycling. To obtain deeper insight into the intestinal and hepatic processes, the disposition of ezetimibe was studied in the presence of rifampin (INN, rifampicin), a modulator of P‐gp, MRP2, and hepatic organic anion (uptake) transporting polypeptides (OATPs) (SLCOs).