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Background: The human UDP-glucuronosyltransferase 1A1 (UGT1A1) is a major phase-II drug metabolizing enzyme, catalyzing conjugation of e.g. bilirubin with glucuronic acid. It is inducible by rifampicin and is subject of hereditary variability due to a polymorphic TATA-box in the 5'-region of the UGT1A1 gene (UGT1A1*28). We aimed to investigate the impact of the genotype on UGT1A1 mRNA expression after rifampicin pre-treatment.Methods: 15 healthy Caucasian volunteers were included. The UGT1A1 TA repeat polymorphisms was determined from leukocyte DNA by capillary electrophoresis. Duodenal biopsies were obtained before and after 8 days of rifampicin treatment (600 mg/d p.o.). mRNA was isolated from duodenal biopsies, quantified by real-time RT-PCR and compared to 18S rRNA.Results: The basal UGT1A1 mRNA/18S rRNA expression level differed marginally (p=0.19). However, among 6 carriers with TA6/6 and 6 with TA6/7 genotype, ratios were about 5.1- or 3.7-fold elevated after rifampicin treatment compared to the basal level (p=0.028; 0.028 respectively). In contrast, UGT1A1 expression in TA7/7 homozygotes was not influenced by rifampicin (p=0.66).Conclusion: PXR-mediated UGT1A1 induction is genotype dependent, presumably caused by weakened DNA-protein interaction by an additional TA-repeat (TA7/7). Consequently, the extent of drug-interactions may vary inter-individually.Clinical Pharmacology & Therapeutics (2005) 79, P34–P34; doi: 10.1016/j.clpt.2005.12.123 [ABSTRACT FROM AUTHOR]

The experience of meaning has been found to be mapped onto spatial proximity whereby coherent-in contrast to incoherent-elements in a set are mentally represented as closer together in physical space. In a series of four experiments, we show that spatial representation of coherence is malleable and can employ other meaningful concrete dimensions of space that are made salient. When given task instructions cueing verticality, participants represented coherence in the upper vertical location when making judgements about the logical validity of realistic (Experiments 1 and 4) and unrealistic syllogistic scenarios (Experiment 3). When the task instruction made the spatial proximity between the stimuli materials and the participant salient (subjective proximity), participants represented coherence as spatially close to themselves (Experiment 2). We also found that being accurate in judging the validity of syllogisms was associated with representing coherence in the upper visual field or close to oneself. Overall, our findings show that identifying semantic links between an abstract concept and a given spatial dimension involves using that dimension to create spatial metaphoric mappings of the concept., Competing Interests: We declare we have no competing interests., (© 2024 The Author(s).)

The "good is up" metaphor, which links valence and verticality was found to influence affective judgement and to direct attention, but its effects on memory remain unclear with contradictory research findings. To provide a more accurate assessment of memory components involved in recognition, such as item memory and source-guessing biases, a standard source monitoring paradigm was applied in this research. A series of three experiments provided a conceptual replication and extension of Experiment 2 by Crawford et al., (2014) and yielded a consistent result pattern suggesting that the "good is up" metaphor biases participants' guessing of source location. That is, when source memory failed, participants were more inclined to guess the "up" location versus "down" location for positive items (and vice versa for negative items). It did, however, not affect source memory or item memory for valenced stimuli learned from metaphor-congruent versus incongruent locations (i.e., no metaphor-(in)congruent effects in memory). We suggest that the "good is up" metaphor may affect cognitive processes in a more subtle way than originally suggested., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

With mental models based on relational information, the present research shows that the semantics expressed by the relation can determine the structural properties of the constructed model. In particular, we demonstrate a reversal of the classical, well-replicated symbolic distance effect (SDE), as a function of relational semantics. The classical SDE shows that responses are more accurate, and faster, the wider the distance between queried elements on a mentally constructed rank order. We replicate this effect in a study using a relation that expresses a rank hierarchy ("older than," Experiment 4). In contrast, we obtain a clear reversal of the same effect for accuracy data when the relation expresses a number of equivalence classes ("is from the same city," Experiments 1-3). In Experiment 3, we find clear evidence of a reversed SDE for accuracy and latency in the above standard condition, and flat curves of means, across pair distances, for accuracy and latency in a condition that makes equivalence classes salient from the beginning. We discuss these findings in the context of a process model of equivalence class formation based on learned piecemeal information., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

ABSTRACT People can support abstract reasoning by using mental models with spatial simulations. Such models are employed when people represent elements in terms of ordered dimensions (e.g. who is oldest, Tom, Dick, or Harry). We test and find that the process of forming and using such mental models can influence the liking of its elements (e.g. Tom, Dick, or Harry). The presumed internal structure of such models (linear-transitive array of elements), generates variations in processing ease (fluency) when using the model in working memory (see the Symbolic Distance Effect, SDE). Specifically, processing of pairs where elements have larger distances along the order should be easier compared to pairs with smaller distances. Elements from easier pairs should be liked more than elements from difficult pairs (fluency being hedonically positive). Experiment 1 shows that unfamiliar ideographs are liked more when at wider distances and therefore easier to process. Experiment 2 replicates this effect with non-words. Experiment 3 rules out a non-spatial explanation of the effect while Experiments 4 offers a high-powered replication. Experiment 5 shows that the spatial effect spontaneously emerges after learning, even without a task that explicitly focuses on fluency. Experiment 6 employed a shorter array, but yielded no significant results.

The present contribution argues that transitive reasoning, as exemplified in paradigms of linear order construction in mental space, is associated with spatial effects. Starting from robust findings from the early 70s, research so far has widely discussed the symbolic distance effect (SDE). This effect shows that after studying pairs of relations, e.g., "A > B," "B > C," and "D > E," participants are more correct, and faster in correct responding, the wider the "distance" between two elements within the chain A > B > C > D > E. The SDE has often been given spatial interpretations, but alternatively, non-spatial models of the effect are also viable on the empirical basis so far, which means the question about spatial contributions to the construction of analog representations of rank orders is still open. We suggest here that laterality effects can add the necessary additional information to support the idea of spatial processes. We introduce anchoring effects in terms of showing response advantages for congruent versus incongruent pairings of presentation location on a screen on the one hand, and the hypothetical spatial arrangement of the order in mental space, on the other hand. We report pertinent findings and discuss anchoring paradigms with respect to their internal validity as well as their being rooted in basic mechanisms of trained reading/writing direction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 von Hecker and Klauer.)

Investigates the hypothesis that spatial processes are involved in judgments on membership in a category. It is argued that membership versus nonmembership of an object or a concept, in a category, is spatially simulated in mental space by a minimal continuum with 2 levels, left for membership and right for nonmembership. In analogy to other embodied dimensions (e.g., time line or number line), the orientation of membership levels on the mental dimension is assumed to follow the acquired reading/writing schema, with procedural primacy implying dominance, hence leftward positioning of dominant elements. This rationale is tested in 7 experiments. A recognition memory paradigm (modified 2AFC paradigm, Experiment 1) revealed that participants were faster indicating the location of an old word on the screen when displayed left within a pair of words, indicating a spatial representation of category membership ("member" = left, "nonmember" = right). For category discrimination (Experiment 2) we found faster and more accurate performance when a target word is presented left as compared with right. This pattern is replicated in Experiments 4a and 4b, with different response alternatives. Discriminating categories in a stimulus-response compatibility paradigm (Experiment 3), participants were faster making correct responses with their left hand than with their right hand in target category trials. In contrast, no differences were found for distractor trials. Experiments 5a and 5b address the spatial bias in spontaneous sorting situations. Overall, this pattern of results across the 7 experiments provides evidence in support of a spatial simulation of category assignment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

We examined whether people can simultaneously apply 2 cognitive strategies in social categorizations. Specifically, we tested whether stereotypes concerning social power of gender categories interact with metaphoric power-space links. Based on the conceptual blending perspective suggesting that semantically consistent concepts acquire each other's properties, we predicted the following: Given that stereotypes create expectations linking gender with power, and metaphorically power is linked with vertical space, the conceptual blend of gender-power-space would invoke representations of male targets at the top vertical position when categorizing them as powerful, while female targets at the bottom when categorizing them as powerless. Across 6 studies, we show that the concept of gender is simulated spatially when people attribute power to male, but not female, targets. The predicted power-gender blending involved simulations of men judged as powerful when presented in upper location as opposed to women judged as powerful in upper location and men judged as powerful in lower location. Our hypothesis was further corroborated using pupillometry to assess preconscious processing, whereby stereotypically inconsistent orientations of gender and power evoked pupillary markers indicative of surprise. Our studies suggest that gender-power stereotypic expectations interact with the power-space metaphor in social categorizations. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The robustness of effects indicating a spatial component associated with abstract reasoning is tested. Judgements regarding hierarchical orderings tend to be faster and more accurate when the dominant element in any pair from the order (e.g., the older, richer) is presented on the left of the screen as compared with the right ( left-anchoring effect ). This signature effect is investigated in three conditions (Experiment 1), each implementing a different timing regime for the elements in each pair, during learning. Thereby, the construction of a mental representation of the ordering was exposed to a potentially competing spatial simulation, that is, the well-known "mental timeline" with orientation from left (present) to right (future). First, the left-anchoring effect for order representations remained significant when timeline information was congruent with the presumed left-anchoring process, that is, the dominant element in a pair was always presented first. Second, the same effect remained also significant when the timeline-related information was random, that is, the dominant element being presented either first or second. Third, the same effect was found to be still significant, when the timeline-related information was contrary to the left-anchoring process, that is, the dominant element being presented always second. Experiment 2 replicates the target effect under random timeline information, controlling for colour as a stimulus feature. The results are discussed in the context of a theoretical model that integrates basic assumptions about acquired reading/writing habits as a scaffold for spatial simulation and primacy/dominance representation within such spatial simulations.

Three studies examined the role of need for affect (NFA) and need for cognition (NFC) in intergroup perception. We hypothesized that NFA predicts a preference for stereotypically warm groups over stereotypically cold groups, whereas NFC predicts a preference for stereotypically competent groups over stereotypically incompetent groups. Study 1 supported these hypotheses for attitudes toward stereotypically ambivalent groups, which are stereotyped as high on one of the trait dimensions (e.g., high warmth) and low on the other (e.g., low competence), but not for stereotypically univalent groups, which are seen as high or low on both dimensions. Studies 2 and 3 replicated this pattern for stereotypically ambivalent groups, and yielded provocative evidence regarding several putative mechanisms underlying these associations. Together, these findings help integrate and extend past evidence on attitude-relevant individual differences with research on intergroup perception.

The Indian caste system is a complex social structure wherein social roles like one's profession became 'hereditary,' resulting in restricted social mobility and fixed status hierarchies. Furthermore, we argue that the inherent property of caste heightens group identification with one's caste. Highly identified group members would protect the identity of the group in situations when group norms are violated. In this paper, we were interested in examining the consequence of caste norm violation and how an individual's status is mentally represented. High caste norms are associated with moral values while the lower caste norms are associated with immorality. We predicted a 'black sheep effect,' that is, when high caste individuals' group identity (caste norm violation condition) is threatened their salient high caste identity would increase, thereby resulting in devaluing the status of their fellow in-group member if the latter is perceived as perpetrator. We presented participants with a social conflict situation of a victim and a perpetrator that is ' Caste norm consistent' (Lower caste individual as a perpetrator and higher caste individual as a victim) and vice versa 'Caste norm inconsistent' condition (higher caste individual as perpetrator and lower caste individual as a victim). Then, participants had to choose from nine pictorial depictions representing the protagonists in the story on a vertical line, with varying degrees of status distance. Results showed evidence for the black sheep effect and, furthermore, revealed that no other identity (religious, national, and regional) resulted in devaluing the status of fellow in-group member. These results help us understand the 'black sheep' effect in the context of moral norms and status representation and are discussed in the framework of the Indian society.

Memory performance in linear order reasoning tasks (A > B, B > C, C > D, etc.) shows quicker, and more accurate responses to queries on wider (AD) than narrower (AB) pairs on a hypothetical linear mental model (A - B - C - D). While indicative of an analogue representation, research so far did not provide positive evidence for spatial processes in the construction of such models. In a series of 7 experiments we report such evidence. Participants respond quicker when the dominant element in a pair is presented on the left (or top) rather than on the right (or bottom). The left-anchoring tendency reverses in a sample with Farsi background (reading/writing from right to left). Alternative explanations and confounds are tested. A theoretical model is proposed that integrates basic assumptions about acquired reading/writing habits as a scaffold for spatial simulation, and primacy/dominance representation within such spatial simulations. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Four experiments examined spatial correlates of the experience of coherence, that is, the extent to which propositions "fit together." Experiment 1 demonstrates for Heiderian triads (i.e., sets of liking/disliking relations between 3 fictitious persons) that name pairs from balanced triads, such as 2 friends commonly disliking a third person (high coherence) are seen as closer to each other in physical space as compared to name pairs from unbalanced triads, such as 2 persons disliking each other and having a common friend (low coherence). This pattern of results is conceptually replicated in 2 further experiments for categorical syllogisms. Two terms in conclusions from valid syllogisms (high coherence) were seen as spatially closer to each other than when 2 terms came from invalid syllogisms (low coherence). In the final 2 experiments, similar closeness effects are demonstrated for word pairs from scenarios that "made sense" in terms of causal connectedness (latent causality) as opposed to word pairs from scenarios perceived as causally unconnected. These findings are discussed in the context of spatial binding theories, applied psychology, and embodied cognition in general, and their methodological implications are highlighted. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

The capacity to learn new information and manipulate it for efficient retrieval has long been studied through reasoning paradigms, which also has applicability to the study of social behavior. Humans can learn about the linear order within groups using reasoning, and the success of such reasoning may vary according to affective state, such as depression. We investigated the neural basis of these latter findings using functional neuroimaging. Using BDI-II criteria, 14 non-depressed (ND) and 12 mildly depressed volunteers took part in a linear-order reasoning task during functional magnetic resonance imaging. The hippocampus, parietal, and prefrontal cortices were activated during the task, in accordance with previous studies. In the learning phase and in the test phase, greater activation of the parietal cortex was found in the depressed group, which may be a compensatory mechanism in order to reach the same behavioral performance as the ND group, or evidence for a different reasoning strategy in the depressed group.

We challenge the idea that a cognitive perspective on therapeutic change concerns only memory processes. We argue that inclusion of impairments in more generative cognitive processes is necessary for complete understanding of cases such as depression. In such cases what is identified in the target article as an "integrative memory structure" is crucially supported by processes of mental model construction.

Why do some autobiographical events feel as if they happened yesterday, whereas others feel like ancient history? Such temporal distance perceptions have surprisingly little to do with actual calendar time distance. Instead, psychologists have found that people typically perceive positive autobiographical events as overly recent, while perceiving negative events as overly distant. The origins of this temporal distance bias have been sought in self-enhancement strivings and mood congruence between autobiographical events and chronic mood. As such, past research exclusively focused on the evaluative features of autobiographical events, while neglecting semantic features. To close this gap, we introduce a semantic congruence model. Capitalizing on the Big Two self-perception dimensions, Study 1 showed that high semantic congruence between recalled autobiographical events and trait self-perceptions render the recalled events subjectively recent. Specifically, interpersonally warm (competent) individuals perceived autobiographical events reflecting warmth (competence) as relatively recent, but warm (competent) individuals did not perceive events reflecting competence (warmth) as relatively recent. Study 2 found that conscious perceptions of congruence mediate these effects. Studies 3 and 4 showed that neither mood congruence nor self-enhancement account for these results. Study 5 extended the results from the Big Two to the Big Five self-perception dimensions, while affirming the independence of the semantic congruence model from evaluative influences., (PsycINFO Database Record (c) 2013 APA, all rights reserved.)

The defocused attention hypothesis (von Hecker and Meiser, 2005) assumes that negative mood broadens attention, whereas the analytical rumination hypothesis (Andrews and Thompson, 2009) suggests a narrowing of the attentional focus with depression. We tested these conflicting hypotheses by directly measuring the perceptual span in groups of dysphoric and control subjects, using eye tracking. In the moving window paradigm, information outside of a variable-width gaze-contingent window was masked during reading of sentences. In measures of sentence reading time and mean fixation duration, dysphoric subjects were more pronouncedly affected than controls by a reduced window size. This difference supports the defocused attention hypothesis and seems hard to reconcile with a narrowing of attentional focus., (Copyright © 2011 Elsevier B.V. All rights reserved.)

In a variant of the negative priming (NP) procedure, the larger of two presented animals is to be named in each trial. Eight animals of different sizes are used, which allows a manipulation of conceptual task difficulty in terms of pair distance (difficult: one step, versus easy: three steps) on the series. Distances are varied for prime pairs and probe pairs orthogonally. NP effects were found for easy (wide) probe distances (Experiments 1 and 2) and, additionally, for easy (wide) prime distances (Experiment 2). This pattern is interpreted in terms of different theories of NP, which emphasize either forward-acting (prime to probe) or backward-acting (probe to prime) processes. The present results are most compatible with a backward-acting mechanism defined by the episodic retrieval perspective; they are less compatible with a forward-acting inhibition perspective. The results have implications for resource requirements of retrieval-based accounts of NP.

Objective: Anticholinesterase compounds like organophosphorous and carbamates account for the majority of poisonings by the insecticides class agents. While the toxicokinetic depends on the extent of exposure and also on the chemical structure of the agent, the clinical symptoms range from the classic cholinergic syndrome to flaccid paralysis and intractable seizures. The carbamate ester pirimicarb (Pirimor), a toxic N-dimethylcarbamate pesticide, is used as insecticide. Our case presents the first poisoning associated with clinical and analytical findings., Patient: A 68-year-old male ingested an unknown amount of pirimicarb and developed cholinergic symptoms immediately, accompanied by seizures., Interventions: He was admitted in the Intensive Care Unit (ICU) and received intensive care including intubation for hypoxemia following seizures and drug therapy of hypertensive dysregulation. No Atropine but benzodiazepines were administered. The patient recovered in the ICU after 3 days and was discharged after a week., Measurements and Results: Pirimicarb stomach, blood, and urine levels were determined on admission and during hospitalisation. Using an one-compartment model the pesticide elimination was estimated and its terminal half-life in plasma, t1/2, was found to be 3.8 hours. The butyryl cholinesterase (BChE) activity was at the lower level of detection on the admission and recovered during the following 24 hours.

The current research challenges the widespread truism that recalling a positive self necessarily increases self-esteem, whereas recalling a negative self necessarily decreases self-esteem. Four experiments demonstrate that chronically happy people show a relative increase in self-esteem by recalling either a positive or a negative self. Chronically sad people, however, show a relative decrease in self-esteem by recalling either a positive or a negative self. These effects are due to divergent perceptions of mood congruence between the recalled self and the current self. Specifically, happy people perceive high mood congruence between a recalled positive self and the current self but low mood congruence between a recalled negative self and the current self. In contrast, sad people perceive high mood congruence between a recalled negative self and the current self but low mood congruence between a recalled positive self and the current self. Independent of chronic mood, mood congruence leads to perceptions of temporal recency, whereas mood incongruence leads to perceptions of temporal distance. In line with the inclusion-exclusion model of social judgment, perceived temporal recency elicits assimilation effects on self-esteem, whereas perceived temporal distance elicits contrast effects on self-esteem., ((c) 2008 APA, all rights reserved)

This research investigated the hypothesis that metacognitive inferences in source memory judgements are based on the recognition or nonrecognition of an event together with perceived or expected differences in the recognizability of events from different sources. The hypothesis was tested with a multinomial source-monitoring model that allowed separation of source-guessing tendencies for recognized and unrecognized items. Experiments 1A and 1B manipulated the number of item presentations as relevant source information and revealed differential guessing tendencies for recognized and unrecognized items, with a bias to attribute unrecognized items to the source associated with poor item recognition. Experiments 2A and 2B replicated the findings with a manipulation of presentation time and extended the analysis to subjective differences in item recognition. Experiments 3A and 3B used more natural source information by varying type of acoustic signal and demonstrated that subjective theories about differences in item recognition are sufficient to elicit differential source-guessing biases for recognized and unrecognized items. Together the findings provide new insights into the cognitive processes underlying source memory decisions, which involve episodic memory and reconstructive tendencies based on metacognitive beliefs and general world knowledge.

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 authors suggest that depressed mood is associated with a defocused mode of attention, allowing irrelevant information to be noticed and processed more than in nondepressed states. Working on a source monitoring task, subclinically depressed college students selected with the Beck Depression Inventory (A. T. Beck, 1967; D. Kammer, 1983) had better memory for irrelevant stimulus aspects than nondepressed control students. However, depressed students' performance on the relevant stimulus aspects was unimpaired. These results are in conflict with a capacity reduction view of depressed mood and support the hypothesized altered, defocused mode, in which attentional resources are more evenly allocated across various aspects of the materials. The results are discussed within the framework of adaptive functions of emotional states., (Copyright (c) 2005 APA, all rights reserved.)

The performance of older adults and depressed people on linear order reasoning is hypothesized to be best explained by different theoretical models. Whereas depressed younger adults are found to be impaired in generative inference making, older adults are well capable of making such inferences but exhibit problems with working memory (Experiments 1 and 2). Restriction of the available study time impairs reasoning by nondepressed control participants and. as such, proves to be a good model of older adults' but not depressed participants' limitations (Experiment 3). These results are replicated comparing depressed and older participants with a control group in the same study, providing increased power and linking the results to additional control measures of processing speed and working memory (Experiment 4)., (((c) 2004 APA, all rights reserved))

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.

Objective: Thyroid function alters the pharmacokinetics of many drugs; one example is the cardiac glycoside digoxin. Because digoxin disposition is affected by intestinal expression of P-glycoprotein, we hypothesized that thyroid hormones may regulate P-glycoprotein and influence disposition of P-glycoprotein substrates., Methods: Duodenal expression of P-glycoprotein measured by reverse transcriptase-polymerase chain reaction of MDR1 messenger ribonucleic acid (mRNA) and by immunohistochemical examination was studied in 8 healthy volunteers (4 men and 4 women; age range, 22-29 years; body weight, 59-89 kg) before and after coadministration with levothyroxine (200 microg orally for 17 days), which resulted in suppression of thyroid-stimulating hormone. The pharmacokinetics of the P-glycoprotein substrate talinolol was assessed after intravenous (30 mg) and oral (100 mg) administration., Results: Duodenal MDR1 mRNA expression and immunoreactive P-glycoprotein were increased 1.4-fold (not significant; P =.078) and 3.8-fold (P <.01), respectively, after administration of levothyroxine. The changes in P-glycoprotein expression were associated with minor alterations in talinolol half-life after both oral and intravenous administration., Conclusions: Expression of intestinal P-glycoprotein in humans appears to be influenced by thyroid hormones. The functional consequences need to be addressed in patients with hyperthyroidism.