Chiral Pharmacokinetics and Metabolite Profile of Prolonged-release Ketamine Tablets in Healthy Human Subjects.

BACKGROUND: The anesthetic ketamine after intravenous dosing is nearly completely metabolized to R- and S-stereoisomers of the active norketamine (analgesic, psychoactive) and 2,6-hydroxynorketamine (potential analgesic, antidepressant) as well as the inactive dehydronorketamine. Oral administration favors the formation of 2,6-hydroxynorketamines via extensive presystemic metabolism. The authors hypothesized that plasma exposure to 2,6-hydroxynorketamines relative to the psychoactive ketamine is greater after prolonged-release ketamine tablets than it is after intravenous ketamine. METHODS: Pharmacokinetics of ketamine after intravenous infusion (5.0 mg) and single-dose administrations of 10, 20, 40, and 80 mg prolonged-released tablets were evaluated in 15 healthy white human subjects by means of a controlled, ascending-dose study. The stereoisomers of ketamine and metabolites were quantified in serum and urine by validated tandem mass-spectrometric assays and evaluated by noncompartmental pharmacokinetic analysis. RESULTS: After 40 mg prolonged-release tablets, the mean ± SD area under the concentrations-time curve ratios for 2,6-hydroxynorketamine/ketamine were 18 ± 11 (S-stereoisomers) and 30 ± 16 (R-stereoisomers) compared to 1.7 ± 0.8 and 3.1 ± 1.4 and after intravenous infusion (both P < 0.001). After 10 and 20 mg tablets, the R-ratios were even greater. The distribution volumes at steady state of S- and R-ketamine were 6.6 ± 2.2 and 5.6 ± 2.1 l/kg, terminal half-lives 5.2 ± 3.4 and 6.1 ± 3.1 h, and metabolic clearances 1,620 ± 380 and 1,530 ± 380 ml/min, respectively. Bioavailability of the 40 mg tablets was 15 ± 8 (S-isomer) and 19 ± 10% (R-isomer) and terminal half-life 11 ± 4 and 10 ± 4 h. About 7% of the dose was renally excreted as S-stereoisomers and 17% as R-stereoisomers. CONCLUSIONS: Prolonged-release ketamine tablets generate a high systemic exposure to 2,6-hydroxynorketamines and might therefore be an efficient and safer pharmaceutical dosage form for treatment of patients with chronic neuropathic pain compared to intravenous infusion.

Pharmacokinetic Drug-Drug Interactions Between Trospium Chloride and Ranitidine Substrates of Organic Cation Transporters in Healthy Human Subjects.

Trospium chloride, a muscarinic receptor blocker, is poorly absorbed with different rates from areas in the jejunum and the cecum/ascending colon. To evaluate whether organic cation transporter (OCT) 1, OCT2 and multidrug and toxin extrusion (MATE) 1 and MATE2-K are involved in pharmacokinetics, competitions with ranitidine, a probe inhibitor of the cation transporters, were evaluated in transfected HEK293 cells. Furthermore, a drug interaction study with trospium chloride after intravenous (2 mg) and oral dosing (30 mg) plus ranitidine (300 mg) was performed in 12 healthy subjects and evaluated by noncompartmental analysis and population pharmacokinetic modeling. Ranitidine inhibited OCT1, OCT2, MATE1, and MATE2-K with half maximal inhibitory concentration values of 186 ± 25 µM, 482 ± 105 µM, 134 ± 37 µM, and 35 ± 11 µM, respectively. In contrast to our hypothesis, coadministration of ranitidine did not significantly decrease oral absorption of trospium. Instead, renal clearance was lowered by ∼15% (530 ± 99 vs 460 ± 120 mL/min; P < .05). It is possible that ranitidine was not available in competitive concentrations at the major colonic absorption site, as the inhibitor is absorbed in the small intestine and undergoes degradation by microbiota. The renal effects apparently result from inhibition of MATE1 and/or MATE2-K by ranitidine as predicted by in vitro to in vivo extrapolation. However, all pharmacokinetic changes were not of clinical relevance for the drug with highly variable pharmacokinetics. Intravenous trospium significantly lowered mean absorption time and relative bioavailability of ranitidine, which was most likely caused by muscarinic receptor blocking effects on intestinal motility and water turnover.

Effects of the P-Glycoprotein Inhibitor Clarithromycin on the Pharmacokinetics of Intravenous and Oral Trospium Chloride: A 4-Way Crossover Drug-Drug Interaction Study in Healthy Subjects.

The quaternary ammonium compound trospium chloride is poorly absorbed from 2 "absorption windows" in the jejunum and cecum/ascending colon, respectively. To confirm whether intestinal P-glycoprotein (P-gp) is involved, a 4-period, crossover drug interaction study with trospium chloride after intravenous (2 mg) and oral administration (30 mg) without and after comedication of clarithromycin (500 mg), an inhibitor for P-gp, was initiated in 12 healthy subjects. Pharmacokinetics of trospium was evaluated using gas chromatography-mass spectrometry, noncompartmental evaluation, and pharmacokinetic modeling. Trospium chloride was poorly absorbed after oral administration (absolute bioavailability, ∼8%-10%). About 30% of the bioavailable dose fraction was absorbed from the "narrow window". Comedication with clarithromycin increased steady-state distribution volumes by ∼27% (P < .01). Bioavailability was not increased as hypothesized. The geometric mean ratios (90% confidence interval) for area under the plasma concentration-time curve, maximum concentration, and renal clearance accounted for 0.75 (0.56-1.01), 0.64 (0.45-0.89), and 1.00 (0.90-1.13), respectively. The amount of trospium absorbed from the "narrow window" was reduced in all subjects but from the "wider window" in only 9 of them. Bioavailability was strongly predicted by the maximum absorption rate of trospium in the distal "window" (rs2  = 0.910, P < .0001). In conclusion, the P-gp inhibitor clarithromycin significantly increases distribution volumes but not oral absorption of trospium. The amount absorbed from the "narrow window" was lowered in all subjects. However, the extent of all influences seems not to be of clinical relevance.

Muscle Injury After Intramuscular Administration of Diclofenac: A Case Report Supported by Magnetic Resonance Imaging.

Intramuscular injection of diclofenac is still frequently practiced, although there is ample evidence that the risk of local tissue intolerability is highly underestimated. The aim of this study was to evaluate local toxicity in a patient using magnetic resonance imaging. A patient who gave written informed consent received a medically indicated intramuscular administration of diclofenac 75 mg/2 mL. Simultaneously with magnetic resonance imaging of the depot, a clinical-chemical evaluation and quantification of diclofenac in plasma was performed. A manifold enhancement of the T2-weighted magnetic resonance signal was observed in a muscle area of approximately 60 mL volume, with maximum signal intensity 30 min after injection, the time of maximum diclofenac plasma exposure. Plasma creatine kinase activity was elevated approximately sixfold within 8 h and normalized within 1 week, whereas the magnetic resonance enhancement disappeared within 5 weeks. Interestingly, the patient did not complain about any clinical symptoms at the injection site. Asymptomatic tissue injury after intramuscular injection of diclofenac, caused by intramuscular dosing, can be reliably evaluated by magnetic resonance imaging and should be applied early during the development of parenteral dosage forms. Clinical Trials Registration Number: BB130/16 (Ethics Committee of the University Medicine Greifswald).

Trospium chloride is absorbed from two intestinal "absorption windows" with different permeability in healthy subjects.

Intestinal P-glycoprotein is regio-selectively expressed and is a high affinity, low capacity efflux carrier for the cationic, poorly permeable trospium. Organic cation transporter 1 (OCT1) provides lower affinity but higher capacity for trospium uptake. To evaluate regional intestinal permeability, absorption profiles after gastric infusion of trospium chloride (30mg/250ml=[I]2) for 6h and after swallowing 30mg immediate-release tablets in fasted and fed healthy subjects, were evaluated using an inverse Gaussian density function to model input rate and mean absorption time (MAT). Trospium chloride was slowly absorbed (MAT ∼10h) after gastric infusion involving two processes with different input rates, peaking at about 3h and 7h. Input rates and MAT were influenced by dosage form and meal. In conclusion, trospium is absorbed from two "windows" located in the jejunum and cecum/ascending colon, whose uptake capacity might result from local abundance and functional interplay of P-glycoprotein and OCT1.

Resolving the physiological conditions in bioavailability and bioequivalence studies: Comparison of fasted and fed state.

In the present study temperature, pH and pressure profiles of nine healthy human volunteers were investigated after ingestion of the SmartPill® under conditions simulating the fasted state treatment in bioavailability and bioequivalence studies. In a previously published study the same subjects received the SmartPill® under fed conditions as recommended by the FDA. Since large non-digestible objects are mainly emptied during phase III of the interdigestive migrating motor complex, the gastric residence time of the SmartPill® was found to be clearly shorter under fasting conditions. Intragastric pH values during the initial 5min were similar with an identical median value of pH 4.6. Interestingly, the median lowest observed intragastric pH value in fasted state was about one pH unit higher than that under fed conditions. Highest pressure activity was observed within the stomach, in relation to gastric emptying. In fasted state, pressure values upon gastric emptying varied strongly between 30mbar and 304mbar, whereas after fed state ingestion values of at least 240mbar could always be observed. The data showed highly variable gastrointestinal parameters even under fasting conditions which must be considered when evaluating clinical studies and developing biorelevant in vitro test methods especially for large non-disintegrating dosage forms.

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.

Effects of anxiety sensitivity and expectations on the modulation of the startle eyeblink response during a caffeine challenge.

RATIONALE: The way in which the tendency to fear somatic arousal sensations (anxiety sensitivity), in interaction with the created expectations regarding arousal induction, might affect defensive responding to a symptom provocation challenge is not yet understood. OBJECTIVES: The present study investigated the effect of anxiety sensitivity on autonomic arousal, startle eyeblink responses, and reported arousal and alertness to expected vs. unexpected caffeine consumption. METHODS: To create a match/mismatch of expected and experienced arousal, high and low anxiety sensitive participants received caffeine vs. no drug either mixed in coffee (expectation of arousal induction) or in bitter lemon soda (no expectation of arousal induction) on four separate occasions. Autonomic arousal (heart rate, skin conductance level), respiration (end-tidal CO2, minute ventilation), defensive reflex responses (startle eyeblink), and reported arousal and alertness were recorded prior to, immediately and 30 min after beverage ingestion. RESULTS: Caffeine increased ventilation, autonomic arousal, and startle response magnitudes. Both groups showed comparable levels of autonomic and respiratory responses. The startle eyeblink responses were decreased when caffeine-induced arousal occurred unexpectedly, e.g., after administering caffeine in bitter lemon. This effect was more accentuated in high anxiety sensitive persons. Moreover, in high anxiety sensitive persons, the expectation of arousal (coffee consumption) led to higher subjective alertness when administering caffeine and increased arousal even if no drug was consumed. CONCLUSIONS: Unexpected symptom provocation leads to increased attention allocation toward feared arousal sensations in high anxiety sensitive persons. This finding broadens our understanding of modulatory mechanisms in defensive responding to bodily symptoms.

Metabolic activation and analgesic effect of flupirtine in healthy subjects, influence of the polymorphic NAT2, UGT1A1 and GSTP1.

AIMS: The rare association of flupirtine with liver injury is most likely caused by reactive quinone diimines and their oxidative formation may be influenced by the activities of N-acetyltransferases (NAT) that conjugate the less toxic metabolite D13223, and by glucuronosyltransferases (UGT) and glutathione S-transferases (GST) that generate stable terminal glucuronides and mercapturic acid derivatives, respectively. The influence of genetic polymorphisms of NAT2, UGT1A1 and GSTP1 on generation of the terminal mercapturic acid derivatives and analgesic effects was evaluated to identify potential genetic risk factors for hepatotoxicity of flupirtine. METHODS: Metabolic disposition of flupirtine was measured after intravenous administration (100 mg), after swallowing an immediate-release (IR) tablet (100 mg) and after repeated administration of modified release (MR) tablets (400 mg once daily 8 days) in 36 selected healthy subjects. Analgesic effects were measured using pain models (delayed onset of muscle soreness, electric pain). RESULTS: Flupirtine IR was rapidly but incompletely absorbed (∼ 72%). Repeated administration of flupirtine MR showed lower bioavailability (∼ 60%). Approximately 12% of bioavailable flupirtine IR and 8% of bioavailable flupiritine MR was eliminated as mercapturic acid derivatives into the urine independent of the UGT1A1, NAT2 and GSTP1 genotype. Carriers of variant GSTP1 alleles showed lower bioavailability but increased intestinal secretion of flupirtine and increased efficiency in experimental pain. Flupirtine was not a substrate for ABCB1 and ABCC2. CONCLUSIONS: Formation of mercapturic acid derivatives is a major elimination route for flupirtine in man. However, the theoretically toxic pathway is not influenced by the frequent polymorphisms of UGT1A1, NAT2 and GSTP1.

Anxiety sensitivity and expectation of arousal differentially affect the respiratory response to caffeine.

RATIONALE: This study aimed to test how expectations and anxiety sensitivity influence respiratory and autonomic responses to caffeine. OBJECTIVES: The current study investigated the effects of expected vs. unexpected caffeine ingestion in a group of persons prone to the anxiety-provoking effect of caffeine (high anxiety sensitive persons, that is, persons scoring at least one SD above the mean on the Anxiety Sensitivity Index (Peterson and Reiss 1992)) as compared to low-anxious controls. METHODS: Autonomic arousal (heart rate, skin conductance level), respiratory responding (expired CO2, minute ventilation), and subjective report were assessed in high and low anxiety sensitive participants immediately after beverage consumption and at absorption peak (30 min post-consumption) in four separate sessions during which either coffee (expectation of caffeine) or bitter lemon soda (no expectation of caffeine) was crossed with 4 mg/kg caffeine vs. no drug. RESULTS: High and low anxiety sensitive persons showed comparable autonomic arousal and symptom reports to caffeine which was modulated by expectation, i.e., greater for coffee. Respiratory responding (CO2 decrease, minute ventilation increase) was more accentuated when caffeine was both expected and administered in the low anxiety sensitive group but more accentuated when caffeine was unexpectedly administered in the high anxiety sensitive group. Autonomic arousal and respiratory effects were observable within a few minutes after caffeine administration and were most pronounced at maximum absorption. CONCLUSIONS: The results highlight the modulating role of expectancies in respiratory responding to caffeine in low vs. high anxiety sensitive persons and might have important implications for the better understanding of unexpected panic attacks.

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.

Visualization of hepatic uptake transporter function in healthy subjects by using gadoxetic acid-enhanced MR imaging.

PURPOSE: To determine if genetic polymorphisms of liver-specific human organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 influence cellular uptake of gadoxetic acid in vitro and if functionally relevant polymorphisms are confounders for liver enhancement by gadoxetic acid in healthy subjects. MATERIALS AND METHODS: This study received ethics approval, and all subjects provided written informed consent. Cellular uptake of gadoxetic acid by OATP1B1 and OATP1B3 and their frequent genetic variants was measured by using stable transfected embryonic kidney HEK293 cells. Liver signal intensity at gadoxetic acid-enhanced MR imaging and pharmacokinetics of gadoxetic acid were evaluated in 36 healthy carriers of SLCO1B1/1B3 wild-type alleles (n = 10), SLCO1B1*1b/*1b (n = 8), SLCO1B1*15/*15 (n = 7), SLCO1B1*5/*15 (n = 1), SLCO1B1*1a/*5 (n = 6), and SLCO1B3*4/*4 (n = 4) by using T1-weighted MR imaging and liquid chromatography tandem mass spectrometry. RESULTS: Transport activity for gadoxetic acid was increased in cells transfected with SLCO1B1c.388A>G (12.8 pmol/[mg·min]6 3.53, P = .001) but decreased in cells with SLCO1B1c.388A>G/521T>C (3.11 pmol/[mg·min] ± 0.918, P = .004) compared with cells with nonvariant transporter (6.32 pmol/[mg·min] ± 2.73). Compared with activity of cells transfected with the nonvariant SLCO1B3 (7.43 pmol/[mg·min] ± 2.43), SLCO1B3c.699G>A was a gain-of-function variant (15.1 pmol/[mg·min] ± 5.52, P = .002), whereas SLCO1B3c.334T>G (0.364 pmol/[mg·min] ± 0.125, P = .0001) and SLCO1B3c.1564G>T (0.295 pmol/[mg·min] ± 0.247, P = .0001) were variants with lower function. Liver enhancement with gadoxetic acid was reduced in subjects with OATP1B1*1a/*5 compared with wild-type subjects and those with OATP1B1*1b/*1b (area under enhancement curve, 3-480 minutes in arbitrary units [au]; 20.7 au ± 6.85 vs 36.5 au ± 8.08 [P = .006] vs 34.6 au ± 8.92 [P = .026]). The OATP1B3*4 polymorphism was not of functional relevance. No pharmacokinetic characteristics of gadoxetic acid were influenced by genetic polymorphisms of OATP1B1 and OATP1B3. CONCLUSION: Liver-specific OATP1B1 and OATP1B3 are uptake carriers for gadoxetic acid in subjects. Genetic polymorphisms of OATP1B1 are signal confounders in gadoxetic acid-enhanced liver MR imaging.

Propranolol selectively blocks the enhanced parietal old/new effect during long-term recollection of unpleasant pictures: a high density ERP study.

Evidence from both animal and human research suggests that the formation of emotional memories is triggered by the beta-adrenergic system. To confirm whether modulation of central beta-adrenergic transmission is specifically involved in the neural signature of memory performance, the pre-encoding effect of propranolol (80 mg) on event-related potentials (ERPs) was measured in a placebo-controlled, double-blind, parallel-group study in 46 male healthy subjects using high density EEG and source imaging analysis during encoding and retrieval (after 1 week) of IAPS pictures of unpleasant, neutral and pleasant contents; for recognition 90 old pictures were randomly mixed with 90 new pictures. During retrieval correctly remembered old pictures elicited a significantly larger positive voltage change over the centro-parietal cortex than new pictures. Propranolol significantly reduced this old/new difference of the mean ERP amplitudes (500-800 ms) for unpleasant but not for neutral and pleasant memories. This effect correlated with salivary alpha-amylase activity, a surrogate for central adrenergic stimulation. In conclusion, propranolol selectively blocked the neural signature of unpleasant memories by mechanisms in which the parietal cortex seems to be specifically involved.

Oral absorption of propiverine solution and of the immediate and extended release dosage forms: influence of regioselective intestinal elimination.

PURPOSE: The muscarine receptor antagonist propiverine in immediate release tablet form (IR) undergoes presystemic elimination mediated by CYP450 enzymes and intestinal efflux transporters. The aim of our study with propiverine IR and extended release (ER) was to determine whether propiverine disposition is dose linear, to compare the pharmacokinetics of propiverine in oral solution with IR and ER and to show how absorption rate is associated with bioavailability. METHODS: The pharmacokinetics of propiverine administered as intravenous propiverine (15 mg), 10, 15, and 30 mg propiverine IR, an oral propiverine solution (15 mg) and 10, 15, 30, and 45 mg propiverine ER were measured in two randomized, controlled, single-dose, five-period, cross-over studies, with each case involving a study cohort of ten healthy Caucasian subjects. RESULTS: Disposition of propiverine IR and ER was not dose-related. The bioavailability of ER was 64.5 +/- 16.1% compared to 50.3 +/- 13.4% (non-significant) after administration of the IR and propiverine solution (42.6 +/- 14.8%, p < 0.05). The mean absorption time (MAT) of ER (14.2 +/- 4.79 h) was significantly longer than that of the solution and IR (3.94 +/- 4.14 and 0.38 +/- 3.79 h, respectively; both p < 0.05). The bioavailability of propiverine was significantly correlated to the MAT (r = 0.521, p < 0.001). Renal excretion of the metabolite M-23 after propiverine ER administration (6.7 +/- 2.7%) was significantly lower than that after administration of the oral solution (10 +/- 2.2%) and of IR (9.8 +/- 2.7%; both p < 0.05). CONCLUSIONS: The bioavailability of propiverine appears to be dependent on the intestinal site of dissolution and, consequently, on the extent of presystemic intestinal elimination.

Simvastatin does not influence the intestinal P-glycoprotein and MPR2, and the disposition of talinolol after chronic medication in healthy subjects genotyped for the ABCB1, ABCC2 and SLCO1B1 polymorphisms.

AIMS: To evaluate whether simvastatin influences (i) the intestinal expression of P-glycoprotein (P-gp) and MRP2, and (ii) the disposition of the beta(1)-selective blocker talinolol, a substrate of these transporter proteins. METHODS: The disposition of talinolol after intravenous (30 mg) and single or repeated oral administration (100 mg daily) was monitored before and after chronic treatment with simvastatin (40 mg daily) in 18 healthy subjects (10 males, eight females, body mass index 19.0-27.0 kg m(-2)) genotyped for ABCB1, ABCC2 and SLCO1B1 polymorphisms. The steady-state pharmacokinetics of simvastatin was evaluated before and after repeated oral talinolol administration. The duodenal expression of ABCB1 and ABCC2 mRNA before and after simvastatin treatment was quantified using real-time reverse transcriptase-polymerase chain reaction (TaqMan. RESULTS: Simvastatin did not influence the expression of duodenal ABCB1 and ABCC2. There was no significant pharmacokinetic interaction between simvastatin and talinolol. Duodenal ABCB1 mRNA content was significantly correlated with the AUC(0-infinity) (r = 0.627, P = 0.039) and C(max) (r = 0.718, P = 0.013) of oral talinolol. The ABCB1 and ABCC2 gene polymorphisms did not influence simvastatin and talinolol disposition. The half-life of the latter was significantly shorter in the nine carriers with a SLCO1B1*1b allele compared with the seven subjects with the wild-type SLCO1B1*1a/*1a genotype (12.2 +/- 1.6 h vs. 14.5 +/- 1.4 h, P = 0.01). CONCLUSIONS: Simvastatin does not influence the intestinal expression of P-gp and MRP2 in man. There was no pharmacokinetic interaction between talinolol and simvastatin during their chronic co-administration to healthy subjects.

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 beta(1)-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 microg/ml vs. 315 +/- 122 microg/ml, p < 0.05) and shifted the second peak of talinolol to shorter t(max) 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.

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

BACKGROUND AND METHODS: 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). RESULTS: Carbamazepine medication was associated with increased urinary excretion of D-glucaric acid and induction of carbamazepine elimination. Creatinine clearance was not affected. Duodenal expression of both MDR1 mRNA and MRP2 mRNA and the MPR2 protein was significantly induced, whereas the P-gp content was not affected. MDR1 mRNA expression and MPR2 mRNA expression were correlated ( r = 0.873, P <.001). After carbamazepine, metabolic clearance of intravenous talinolol was significantly increased. Residual clearance was significantly decreased in dependence on MDR1 mRNA expression ( r = -0.647, P =.012) and MRP2 mRNA expression ( r = -0.613, P =.020). Oral absorption of talinolol was significantly lower after carbamazepine comedication (53.2% +/- 15.5% versus 62.1% +/- 13.0%, P =.018), and renal clearance and metabolic clearance were significantly increased, correlated in each case with MDR1 mRNA ( r = 0.612, P =.020, and r = 0.554, P =.040, respectively) and MRP2 mRNA ( r = 0.596, P =.025, and r = 0.565, P =.035, respectively). CONCLUSIONS: Aside from induction of CYP3A4, carbamazepine acts as an inducer of intestinal MDR1 mRNA, MRP2 mRNA, and MRP2 protein content.

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

BACKGROUND: Clinical trials have indicated that the combined beta- and alpha-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. METHODS: The influence of genetic variants of cytochrome P450 (CYP) 2D6 and CYP2C9 and of transporter proteins (P-glycoprotein, multidrug resistance protein 2 [MRP2]) on the disposition of carvedilol and its enantiomers after intravenous (5 mg) and long-term oral administration (25 mg for 7 days) was assessed in 12 healthy subjects. The intestinal expression of P-glycoprotein and MRP2 was analyzed by quantitative real-time polymerase chain reaction and immunohistochemical techniques. RESULTS: The area under the serum concentration-time curve (AUC) values of carvedilol were significantly (P <.05) increased in 6 subjects with CYP2D6 deficiency, with effects being more pronounced for R(+)-carvedilol (230 +/- 72.6 ng. h/mL versus 93.9 +/- 64.6 ng. h/mL in extensive metabolizers) than for S(-)-carvedilol (62.9 +/- 21.1 ng. h/mL versus 32.7 +/- 14.5 ng. h/mL). The AUC and fecal excretion of intravenous carvedilol were correlated with the intestinal expression of MDR1 messenger ribonucleic acid (mRNA) (r = -0.67, P =.001; r = 0.83, P =.002) and MRP2 mRNA (r = -0.74, P <.001; r = 0.70, P =.025). Furthermore, we measured the disposition of long-term oral carvedilol after comedication of the pregnane X receptor ligand rifampin (INN, rifampicin) (600 mg, 9 days), which up-regulates both P-glycoprotein and MRP2 but not CYP2D6. Rifampin decreased the AUC of carvedilol to an extent independent of the CYP2D6 genotype (poor metabolizers, 341 +/- 147 ng. h/mL versus 126 +/- 41.7 ng. h/mL; extensive metabolizers, 173 +/- 102 ng. h/mL versus 74 +/- 41.4 ng. h/mL; both P <.05). The AUC was significantly correlated with intestinal expression of MDR1 mRNA (r = -0.671, P =.001) and MRP2 mRNA (r = -0.595, P <.006). CONCLUSIONS: Variable plasma concentrations of carvedilol during long-term administration are predicted by CYP2D6 genotype and intestinal expression of P-glycoprotein and MRP2.