Danilo Wegner

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).

Influence of genetic polymorphisms on intestinal expression and rifampicin-type induction of ABCC2 and on bioavailability of talinolol.

Objectives To evaluate whether ABCC2 gene polymorphisms are associated with expression and/or function of the efflux pump. Methods We investigated the allele frequency of ABCC2 -24C>T, -23G>A, c.1249G>A, c.1446C>G, c.1457C>T, c.2302C>T, c.2366C>T, c.3542G>T, c.3561G>A, c.3563T>A, c.3972C>T, c.4348G>A, and 4544G>A in 374 nonrelated German healthy volunteers and determined the impact on duodenal mRNA and protein content of ABCC2. For functional analysis, the disposition of intravenously (30 mg) and orally administered talinolol (100 mg) was measured among 31 individuals. Moreover, the effects of rifampicin-type induction (600 mg, 8 days) of duodenal ABCC2 were quantified in 22 participants with regard to genetic polymorphisms. Results The allele frequencies were 18.3% (-24T), 21.1% (1249A), 1.4% (1446G), 0.1% (3542T), 4.5% (3563A), 34.2% (3972T), and 4.4% (4544A); carriers of -23G>A, 1457C>T, 2302C>T, 2366C>T, 3561G>A, and 4348G>A were not identified. The -24T allele was in strong linkage with 3972T, and 3563A with 4544A, whereas 1249A was weakly linked with other variant alleles. None of the single nucleotide polymorphisms investigated influenced significantly intestinal ABCC2 mRNA and protein content. The variant ABCC2 1249G>A (V417I), however, was associated with lower oral bioavailability (P=0.001), and increased residual clearance of intravenous talinolol (P=0.021). Intestinal ABCC2 mRNA and protein expression were upregulated by rifampicin treatment, a genetic influence could be detected in only four cases heterozygote for 3563T>A or 4544G>A. Conclusion The 1249G>A (V417I) polymorphism is obviously associated with higher activity of the intestinal transporter.

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).

Targeted adsorption of molecules in the colon with the novel adsorbent‐based Medicinal Product, DAV132: A proof of concept study in healthy subjects

During antibiotic treatments, active residuals reaching the colon profoundly affect the bacterial flora resulting in the emergence of resistance. To prevent these effects, we developed an enteric‐coated formulated activated‐charcoal based product, DAV132, meant to deliver its adsorbent to the ileum and neutralize antibiotic residues in the proximal colon. In a randomized, control, crossover study, the plasma pharmacokinetics of the probe drugs amoxicillin (500 mg) absorbed in the proximal intestine, and sulfapyridine (25 mg) metabolized from sulfasalazine in the cecum and rapidly absorbed, were compared after a single administration in 18 healthy subjects who had received DAV132, uncoated formulated activated charcoal (FAC) or water 16 and 8 hours before, concomitantly with the probe drugs, and 8 hours thereafter. The AUC0–96 h of amoxicillin was reduced by more than 70% when it was taken with FAC, but bioequivalent when it was taken with water or DAV132. By contrast, the AUC0–96 h of sulfapyridine was reduced by more than 90% when administered with either FAC or DAV132 in comparison with water. The results show that DAV132 can selectively adsorb drug compounds in the proximal colon, without interfering with drug absorption in the proximal small intestine, thereby constituting a proof of concept that DAV132 actually functions in humans.

Pharmacokinetics and pharmacodynamics of ch14.18/CHO in relapsed/refractory high-risk neuroblastoma patients treated by long-term infusion in combination with IL-2

ABSTRACT Ch14.18 manufactured in Chinese hamster ovary (CHO) cells is currently being evaluated in clinical trials. Short-term infusion (STI) (8–20 h/day; 4–5 days) of 100 mg/m2 ch14.18/CHO (dinutiximab β) per cycle in combination with cytokines is standard treatment of neuroblastoma (NB) patients. As pain is a limiting factor, we investigated a novel delivery method by continuous long-term infusion (LTI) of 100 mg/m2 over 10 days. 53 NB patients were treated with 5–6 cycles of 6 × 106 IU/m2 subcutaneous interleukin-2 (d 1-5, 8-12), LTI of 100 mg/m2 ch14.18/CHO (d 8-18) and 160 mg/m2 oral 13-cis-retinoic acid (d 22-35). Human anti-chimeric antibody (HACA), antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity were determined. With LTI, we observed a maximum concentration of ch14.18/CHO (Cmax) of 12.56 ± 0.68 µg/ml and a terminal half-life time (t1/2 β) of 32.7 ± 16.2 d. The clearance values for LTI and STI of 0.54 ± 0.13 and 0.41 ± 0.29 L/d m2 and area under the serum concentration-time curve (AUC) values of 189.6 ± 41.4 and 284.8 ± 156.8 µg×d/ml, respectively, were not significantly different. Importantly, we detected ch14.18/CHO trough concentration of ≥ 1 µg/ml at time points preceding subsequent antibody infusions after cycle 1, allowing a persistent activation of antibody effector mechanisms over the entire treatment period of 6 months. HACA responses were observed in 10/53 (19%) patients, similar to STI (21%), indicating LTI had no effect on the immunogenicity of ch14.18/CHO. In conclusion, LTI of ch14.18/CHO induced effector mechanisms over the entire treatment period, and may therefore emerge as the preferred delivery method of anti-GD2 immunotherapy to NB patients.

Disposition and Antimuscarinic Effects of the Urinary Bladder Spasmolytics Propiverine: Influence of Dosage Forms and Circadian-Time Rhythms

Propiverine extended release is expected to be better tolerated compared to immediate release tablets because of slower drug release and reduced formation of active metabolites in the colon. CYP3A4 and ABCC2, the major variables in pharmacokinetics of propiverine, are less expressed in the colon. Therefore, disposition and pharmacodynamics of propiverine were measured in a double‐blind, double‐dummy, crossover study with administration of 15 mg immediate release 3 times daily for 7 days compared to 45 mg extended release once daily for 7 days in 24 healthy subjects. Twelve subjects also received 15 mg propiverine intravenously. Serum and urine propiverine levels were measured repeatedly following oral administration on day 7 for up to 72 hours and correlated to duodenal expression of CYP3A4, ABCB1, and ABCC2. Propiverine immediate release 3 times daily was not different to extended release once daily in areas under the serum concentration‐time curve (0–24 hours) and peak‐trough fluctuation. The areas under the serum concentration‐time curve of propiverine immediate release was circadian‐time‐dependent, with the lowest values during the night. Disposition of intravenous propiverine and propiverine immediate release administered in the night was influenced by intestinal expression of ABCC2. We concluded that oral absorption of propiverine is site‐dependent and influenced by dosage form and circadian‐time‐dependent elimination processes.

Extended-release but not immediate-release and subcutaneous methylnaltrexone antagonizes the loperamide-induced delay of whole-gut transit time in healthy subjects.

Methylnaltrexone (MNTX) is approved for subcutaneous treatment (MNTX‐SC) of opioid induced constipation. MNTX in oral immediate‐release (MNTX‐IR) and extended‐release (MNTX‐ER) dosage forms may antagonize the opioid induced delay in oro‐cecal transit time (OCT) as measured by using radiolabeled lactulose. Because lactulose acts laxative by its own and efficacy of MNTX on colon transit time (CTT) was unknown, the opioid antagonistic effects MNTX‐IR and MNTX‐ER (both 500 mg) relative to MNTX‐SC (12 mg) were evaluated in 15 healthy subjects with loperamide (LOP, 3 × 4 mg, 12 hourly) induced experimental constipation using the sulfasalazine/sulfapyridine method and radio‐opaque markers to measure OCT and whole gut transit time (WGT). MNTX‐ER significantly antagonized the LOP effects in 12 of our 15 subjects who responded to LOP with prolongation of WGT by 20.6–74.1 h (OCT by 0.50–10.5 h, CTT by 18.3–73.6 h). MNTX‐SC and MNTX‐IR were without significant influence. Compared to MNTX‐SC, bioavailability of MNTX‐IR and MNTX‐ER was 1.53–5.49 % and 0.11–1.24 %, respectively. MNTX‐SC and MNTX‐IR achieved active serum levels only for ∼3–5 h. MNTX‐ER antagonized the opioid‐induced delay of CTT most likely by local effects on µ‐opioid receptors in the colon.

Reference intervals for serum sphingosine-1-phosphate in the population-based Study of Health in Pomerania

BACKGROUND The bioactive signaling lipid sphingosine-1-phosphate (S1P) is a potential biomarker for cardiovascular disease (CVD). To date, no reference intervals for S1P have been defined. This study aims to establish a reference range for serum S1P in healthy individuals. METHODS We determined reference intervals for S1P levels according to gender and age in a sample of 1339 healthy participants of the Study of Health in Pomerania (SHIP)-TREND cohort after exclusion of subjects with CVD, diabetes mellitus, hypertension, metabolic syndrome, elevated liver enzymes, chronic kidney disease stadium III or IV, or body mass index (BMI)>30kg/m2. Serum S1P was measured by liquid chromatography-tandem mass spectrometry. RESULTS The median age of the participants was 41 (25th; 75th percentile 32; 51) years, 65% were women. The median serum concentration of S1P was 0.804 (0.694; 0.920) μmol/L. No association with gender and age was observed. The overall reference interval was 0.534-1.242μmol/L (2.5th; 97.5th percentile). Further exclusion of smokers, individuals with BMI>25kg/m2 or elevated lipid levels did not significantly affect median S1P concentrations. CONCLUSIONS This study provides reference intervals for serum S1P in healthy individuals. Total serum S1P concentrations vary irrespectively of age, gender, BMI or smoking status.

Data on subgroup specific baseline characteristics and serum sphingosine-1-phosphate concentrations in the Study of Health in Pomerania

In this data article, we provide subgroup specific baseline characteristics and serum sphingosine-1-phosphate (S1P) concentrations for healthy individuals within the Study of Health in Pomerania (SHIP)-TREND cohort. After exclusion of subjects with cardiovascular disease, diabetes mellitus, hypertension, metabolic syndrome, elevated liver enzymes and/or chronic kidney disease stadium III or IV, four subgroups were defined according to different limits for body mass index (BMI), alterations in blood lipid levels and smoking status. Tables show respective clinical and laboratory parameters stratified by gender. Serum S1P concentrations are also stratified by age groups. The data presented herein is related to the research article entitled “Reference intervals for serum sphingosine-1-phosphate in the population-based Study of Health in Pomerania” (E. Moritz, D. Wegner, S. Groß, M. Bahls, M. Dörr, S.B. Felix, T. Ittermann, S. Oswald, M. Nauck, N. Friedrich, R.H. Böger, G. Daum, E. Schwedhelm, B.H. Rauch, Clin Chim Acta. 468 (2017) 25–31) [1].