Relationship between ketamine-induced psychotic symptoms and NMDA receptor occupancy—a [123I]CNS-1261 SPET study

Rationale Ketamine induces effects resembling both positive and negative psychotic symptoms of schizophrenia. These are thought to arise through its action as an uncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. Objectives We used [¹²³I]CNS-1261 to study ketamine binding to NMDA receptors in healthy human controls in vivo and its relationship to positive and negative psychotic symptom induction. Materials and methods Ten healthy controls underwent two single-photon emission tomography scans with [¹²³I]CNS-1261. On each occasion, they received a bolus infusion of either ketamine or saline. The Brief Psychiatric Rating Scale (BPRS) was administered at the end of each scan. Predefined regions of interest were used to estimate change in volume of distribution of [¹²³I]CNS-1261 following ketamine administration. Two normalised-to-cortex binding indices were also used in order to study effects of ketamine on NMDA receptor availability by region, after correction for global and nonspecific effects. Results Ketamine-induced reduction in [¹²³I]CNS-1261 volume of distribution in all regions showed the strongest correlation with BPRS negative subscale (p < 0.01). With the normalised-to-cortex measures, NMDA receptor binding in middle inferior frontal cortex showed a significant correlation with BPRS negative subscale (BI1 r = 0.88, BI2 r = 95.9, p < 0.001). Conclusions [¹²³I]CNS-1261 binding was modulated by ketamine, a drug known to compete for the same site on the NMDA receptor in vitro. Ketamine may induce negative symptoms through direct inhibition of the NMDA receptor, and positive symptoms may arise through a different neurochemical pathway.     

Association between depressive behavior and absence of serotonin–dopamine interaction in the nucleus accumbens

RATIONALE: Current hypotheses on the etiology of depression attribute the disorder to alterations in serotonin and norepinephrine neurotransmission. However, the relationship between these alterations and depressive behavior is poorly understood. Conversely, an interaction between the serotonergic and dopaminergic systems in the nucleus accumbens has been established. Since motivation and hedonia have been associated with dopamine release in the nucleus accumbens, we decided to test its modulation by serotonin in relation to depressive-like behavior. OBJECTIVES AND METHODS: The extracellular dopamine levels in the nucleus accumbens were studied in vivo in Flinders Sensitive Line (FSL, a rat model of depressive behavior) and control rats, before and after antidepressant treatment. Rats were chronically treated with the antidepressants desipramine (5 mg/kg/day) and paroxetine (7.5 mg/kg/day) for 18 consecutive days. As a measure of depressive behavior we used a modified swim test. The release of dopamine in response to local serotonin application was monitored using the microdialysis technique. RESULTS: Serotonin (0.5 microM) facilitated dopamine release in the nucleus accumbens of control rats. In FSL rats, basal extracellular dopamine levels in the nucleus accumbens were 40% lower than in control rats and did not increase in response to serotonin stimulation. However, chronic antidepressant treatment of the FSL rats normalized the serotonin-dopamine interaction as well as their behavioral deficiencies. CONCLUSIONS: The inability of serotonin to stimulate dopamine release in the nucleus accumbens, thereby leading to anhedonia and lack of motivation, may therefore be an essential factor in the onset of depression and a target for modulation by antidepressant drugs.     

Plasma dopamine-β-hydroxylase activity and the pressor effect of dopamine infusion in man

Summary In order to study the function of dopamine--hydroxylase (DBH) in human plasma, dopamine, its natural substrate, was infused intravenously in 22 healthy volunteers. Their plasma DBH activities showed great interindividual variations (31–301 units/ml). The infusion rates of dopamine required to increase systolic blood pressure (BP) by 30 mm Hg differed considerably between the subjects, and ranged from 3,0 to 11,6 µg/kg/min. No correlation could be shown between the various dopamine doses and individual plasma levels of DBH. It was concluded, therefore, that plasma DBH in the blood stream was enzymatically inactive. Experiments with human plasma DBH in vitro also support this interpretation. Consequently, interindividual differences in the effects on BP during dopamine infusion cannot be due to pressor effects of noradrenaline synthesized by plasma DBH.The study was supported by the Deutsche Forschungsgemeinschaft     

Serotonin–glutamate and serotonin–dopamine reciprocal interactions as putative molecular targets for novel antipsychotic treatments: from receptor heterodimers to postsynaptic scaffolding and effector proteins

The physical and functional interactions between serotonin–glutamate and serotonin–dopamine signaling have been suggested to be involved in psychosis pathophysiology and are supposed to be relevant for antipsychotic treatment. Type II metabotropic glutamate receptors (mGluRs) and serotonin 5-HT_2A receptors have been reported to form heterodimers that modulate G-protein-mediated intracellular signaling differentially compared to mGluR2 and 5-HT_2A homomers. Additionally, direct evidence has been provided that D₂ and 5-HT_2A receptors form physical heterocomplexes which exert a functional cross-talk, as demonstrated by studies on hallucinogen-induced signaling. Moving from receptors to postsynaptic density (PSD) scenario, the scaffolding protein PSD-95 is known to interact with N-methyl-d-aspartate (NMDA), D₂ and 5-HT₂ receptors, regulating their activation state. Homer1a, the inducible member of the Homer family of PSD proteins that is implicated in glutamatergic signal transduction, is induced in striatum by antipsychotics with high dopamine receptor affinity and in the cortex by antipsychotics with mixed serotonergic/dopaminergic profile. Signaling molecules, such as Akt and glycogen-synthase-kinase-3 (GSK-3), could be involved in the mechanism of action of antipsychotics, targeting dopamine, serotonin, and glutamate neurotransmission. Altogether, these proteins stand at the crossroad of glutamate–dopamine–serotonin signaling pathways and may be considered as valuable molecular targets for current and new antipsychotics. The aim of this review is to provide a critical appraisal on serotonin–glutamate and serotonin–dopamine interplay to support the idea that next generation schizophrenia pharmacotherapy should not exclusively rely on receptor targeting strategies.     

Does interaction between zinc and glutamate system play a significant role in the mechanism of antidepressant action?

In the central nervous system, zinc modulates predominantly the excitatory amino acid (glutamatergic) neurotransmission. Recent studies demonstrated that chronic antidepressant treatment, which is required for clinical improvement, reduced the reactivity/function of the glutamate/NMDA receptor complex and altered zinc concentration/interaction with this receptor type in the rodent brain. In the cerebral cortex: chronic antidepressant treatment "down-regulated" (reduced density/affinity) of the cortical (but not hippocampal) NMDA receptors measured by radioligand-receptor binding methods. Moreover, chronic imipramine treatment increased the ability of zinc ion to inhibit the NMDA receptor complex in the cerebral cortex but not in the hippocampus. In the hippocampus: chronic treatment with antidepressant drugs (imipramine or citalopram) increased the hippocampus/brain region ratio of zinc concentration, which may indicate redistribution of the rat brain zinc. On the other hand, electroconvulsive shocks induced robust increase of zinc concentration in the hippocampus (with a slight effect in the rest of brain). In spite of the lack of alterations in the hippocampal NMDA receptors (measured by receptor binding methods), inhibitory effect of the increased hippocampal zinc concentration induced by chronic antidepressant treatment, may be responsible for reduction in the function of that receptor complex also in the hippocampus. These data indicate a critical and complex role of the interaction between zinc and NMDA receptor complex in the mechanism of antidepressant treatment and strongly support the glutamate hypothesis of the mechanism of antidepressant action.     

Drug–drug interaction of rabeprazole and clopidogrel in healthy Chinese volunteers

Purpose

This study was aimed to determine the impact of rabeprazole (RBRZ) on the antiplatelet efficacy of clopidogrel (CPG) in healthy Chinese volunteers, and further to predict the effect of CYP2C19 genetic polymorphism on the efficacy of rabeprazole and clopidogrel.

Methods

The open-label, two period cross-over study was conducted in 20 healthy Chinese subjects with different CYP2C19 genotypes receiving clopidogrel, rabeprazole or the two drugs, respectively. All the volunteers were divided into two groups, poor metabolizers (PMs) and extensive metabolizers (EMs), depending on CYP2C19 genotypes. Blood samples were collected at baseline and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h after administration. The plasma concentrations of rabeprazole and clopidogrel were analyzed by LC-MS/MS and ADP-induced platelet aggregation was detected by the optical turbidimetric method.

Results

There were no significant differences in the mean plasma concentration–time curves of clopidogrel (CPG), the inactive metabolite clopidogrel carboxylic acid (CPG-CA), the active metabolite clopidogrel-MP-Derivative (MP-AM), and rabeprazole (RBRZ) according to the co-administration of CPG and RBRZ. There were no major changes in the pharmacokinetics of CPG and RBRZ. The maximal ADP-induced platelet aggregation (2 μmol/L) was decreased in EMs compared with PMs.

Conclusion

Co-administration of rabeprazol and clopidogrel did not affect the antiplatelet efficacy of clopidogrel. The CYP2C19 genetic polymorphism may impact the efficacy of clopidogrel.     

Protective effects of stigmasterol against ketamine‐induced psychotic symptoms: Possible behavioral,biochemical and histopathological changes in mice

Background

Stigmasterol, a naturally occurring phytoestrogen has been reported to possess many pharmacological activities. The aim of the present study was to screen the effect of stigmasterol against ketamine-induced mice model of psychosis.

The novel α7 nicotinic acetylcholine receptor agonist EVP-6124 enhances dopamine,acetylcholine, and glutamate efflux in rat cortex and nucleus accumbens

Background

Alpha7 and α4β2 nicotinic acetylcholine receptor (nAChR) agonists have been shown to improve cognition in various animal models of cognitive impairment and are of interest as treatments for schizophrenia, Alzheimer’s disease, and other cognitive disorders. Increased release of dopamine (DA), acetylcholine (ACh), glutamate (Glu), and γ-aminobutyric acid (GABA) in cerebral cortex, hippocampus, and nucleus accumbens (NAC) has been suggested to contribute to their beneficial effects on cognition.

Results

Using in vivo microdialysis, we found that EVP-6124 [(R)-7-chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide], a high-affinity α7 nAChR partial agonist, at 0.1 mg/kg, s.c., increased DA efflux in the medial prefrontal cortex (mPFC) and NAC. EVP-6124, 0.1 and 0.3 mg/kg, also increased efflux of ACh in the mPFC but not in the NAC. Similarly, EVP-6124, 0.1 mg/kg, but not 0.03 and 0.3 mg/kg, significantly increased mPFC Glu efflux. Thus, EVP-6124 produced an inverted U-shaped curve for DA and Glu release, as previously reported for other α7 nAChR agonists. The three doses of EVP-6124 did not produce a significant effect on GABA efflux in either region. Pretreatment with the selective α7 nAChR antagonist, methyllycaconitine (MLA, 1.0 mg/kg), significantly blocked cortical DA and Glu efflux induced by EVP-6124 (0.1 mg/kg), suggesting that the effects of EVP-6124 on these neurotransmitters were due to α7 nAChR agonism. MLA only partially blocked the effects of EVP-6124 on ACh efflux in the mPFC.

Conclusion

These results suggest increased cortical DA, ACh, and Glu release, which may contribute to the ability of the α7 nAChR agonist, EVP-6124, to treat cognitive impairment and possibly other dimensions of psychopathology.     

Flaxseed oil–trastuzumab interaction in breast cancer

Flaxseed oil (FO), which is rich in n?3 fatty acid, is commonly consumed by breast cancer patients because of its potential anti-cancer effects. Trastuzumab (TRAS) is the primary drug for epidermal growth factor receptor 2 (HER2) positive breast cancer. We investigated in athymic mice whether combining dietary FO (8%) with TRAS treatment (2.5 or 5 mg/kg body weight) can cause better or adverse effect on established human breast tumors overexpressing HER2 (BT-474). Control tumors significantly grew 187%, TRAS2.5 treated tumors did not change, while TRAS5, FO + TRAS2.5 and FO + TRAS5 treated tumors significantly regressed 75%, 89% and 84%, respectively, after 4 weeks treatment. Two weeks after stopping TRAS treatment while continuing on same diet, tumor size in FO + TRAS2.5 group was 87% lower than in TRAS2.5 group and was not different from TRAS5 group with or without FO. Combined TRAS2.5 treatment with FO caused a significantly lower tumor cell proliferation and higher apoptosis compared to TRAS2.5 treatment alone and showed similar effect to TRAS5 treatment with or without FO. Hence, FO did not interfere with TRAS but rather enhanced its tumor-reducing effects and combined FO and low dose TRAS was as effective as high dose TRAS treatment.     

The gut–brain interaction in opioid tolerance

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Investigation of Cortical Glutamate–Glutamine and γ-Aminobutyric Acid in Obsessive–Compulsive Disorder by Proton Magnetic Resonance Spectroscopy

Glutamatergic abnormalities in corticostriatal brain circuits are thought to underlie obsessive–compulsive disorder (OCD). Whether these abnormalities exist in adults with OCD is not clear. We used proton magnetic resonance spectroscopy (¹H MRS) to test our hypothesis that unmedicated adults with OCD have reduced glutamate plus glutamine (Glx) levels in the medial prefrontal cortex (MPFC) compared with healthy controls. Levels of γ-aminobutyric acid (GABA) were also explored. Twenty-four unmedicated adults with OCD and 22 matched healthy control subjects underwent ¹H MRS scans at 3.0 T. Resonances of both Glx and GABA were obtained using the standard J-editing technique and assessed as ratios relative to voxel tissue water (W) in the MPFC (the region of interest) and the dorsolateral prefrontal cortex (DLPFC) to explore the regional specificity of any finding. In the MPFC, Glx/W did not differ by diagnostic group (p=0.98) or sex (p=0.57). However, GABA/W was decreased in OCD (2.16±0.46 × 10⁻³) compared with healthy controls (2.43±0.45 × 10⁻³, p=0.045); moreover, age of OCD onset was inversely correlated with MPFC GABA/W (r=−0.50, p=0.015). MPFC GABA/W was higher in females than in males. In the DLPFC, there were no main effects of diagnosis or gender on Glx/W or GABA/W. These data indicate that unmedicated adults with OCD do not have Glx abnormalities in a MPFC voxel that includes the pregenual anterior cingulate cortex. However, they may have decreased MPFC GABA levels. How GABA abnormalities might contribute to corticostriatal dysfunction in OCD deserves further study.     

Clinical disposition,metabolism and in vitro drug–drug interaction properties of omadacycline

1.?Absorption, distribution, metabolism, transport and elimination properties of omadacycline, an aminomethylcycline antibiotic, were investigated in vitro and in a study in healthy male subjects.

2.?Omadacycline was metabolically stable in human liver microsomes and hepatocytes and did not inhibit or induce any of the nine cytochrome P450 or five transporters tested. Omadacycline was a substrate of P-glycoprotein, but not of the other transporters.

3.?Omadacycline metabolic stability was confirmed in six healthy male subjects who received a single 300?mg oral dose of [¹⁴C]-omadacycline (36.6 μCi). Absorption was rapid with peak radioactivity (～610 ngEq/mL) between 1–4?h in plasma or blood. The AUC_last of plasma radioactivity (only quantifiable to 8?h due to low radioactivity) was 3096 ngEq?h/mL and apparent terminal half-life was 11.1?h. Unchanged omadacycline reached peak plasma concentrations (～563?ng/mL) between 1–4?h. Apparent plasma half-life was 17.6?h with biphasic elimination. Plasma exposure (AUC_inf) averaged 9418?ng?h/mL, with high clearance (CL/F, 32.8?L/h) and volume of distribution (Vz/F 828?L). No plasma metabolites were observed.

4.?Radioactivity recovery of the administered dose in excreta was complete (>95%); renal and fecal elimination were 14.4% and 81.1%, respectively. No metabolites were observed in urine or feces, only the omadacycline C4-epimer.     

Dabigatran–dronedarone interaction in a spontaneous reporting system

ObjectivesTo investigate the risk of bleeding events associated with concurrent administration of dabigatran–dronedarone compared with dabigatran standalone therapy using the Food and Drug Administration Adverse Event Reporting System (FAERS) database and to identify the characteristics of patients with bleeding events associated with concurrent use of dabigatran and dronedarone.DesignRetrospective data mining analysis.SettingUnited States, from the dabigatran approval date (October 19, 2010) through the fourth quarter of 2011.PatientsCases from FAERS with bleeding events (combined in a single term based on adverse event reports such as hemorrhage and rectal hemorrhage) as the adverse event.InterventionCases listing concomitant use of the terms Pradaxa, dabigatran, or dabigatran etexilate with Multaq or dronedarone as the suspect drug from FAERS and cases listing dabigatran and dronedarone as standalone therapies were extracted for analysis.Main outcome measureRisk of bleeding among those using dabigatran–dronedarone concomitantly compared with those using dabigatran standalone therapy.Results108 dabigatran–dronedarone interaction reports and 14,913 reports concerning bleeding events were extracted from FAERS. Of 108 dabigatran–dronedarone interaction cases, 51 were associated with bleeding events. The odds ratio (OR) for risk of bleeding in patients using dabigatran and dronedarone concomitantly compared with those using neither of the suspect drugs was 13.80 (95% CI 9.45–20.14). The OR for risk of bleeding in patients using only dabigatran compared with those using neither of the suspect drugs was 16.06 (15.00–17.19).ConclusionThe likelihood of reporting bleeding events to FAERS among patients using dabigatran only was similar to that among patients using dabigatran and dronedarone concomitantly.     

Penbutolol: β-Adrenoceptor interaction and the time course of plasma concentrations explain its prolonged duration of action in man

Summary -adrenoceptor binding of (—) penbutolol and its active metabolite 4-hydroxy-penbutolol to rat reticulocyte membranes was shown in the presence of native human plasma. Due to the high plasma protein binding (90%) the apparent K_i-values of penbutolol were shifted 100-fold to the right after inclusion of plasma in the assay; the K_i was 40–70 ng/ml. That value is comparable to the IC₅₀-values calculated from clinical studies. The interaction of 4-hydroxy-penbutolol with -adrenoceptors was not affected to the same extent by inclusion of plasma protein binding 80%, apparent K_i-value 7 ng/ml. Thus, the active metabolite of penbutolol displays higher potency at -adrenoceptors in vitro due to its lesser degree of plasma protein binding. A prediction procedure for antagonist activity after penbutolol administration using -adrenoceptor interaction and plasma concentration kinetics suggests that, in addition to a rapid elimination process from human plasma, a slow elimination phase of penbutolol (or an active metabolite) is necessary to explain the long duration of action observed in clinical studies after a single oral dose. Inhibition in vitro of -adrenoceptor binding by plasma samples obtained after oral administration of 40 mg penbutolol to 3 healthy volunteers indicated a biphasic concentration-time profile of the antagonist in plasma and was in accordance with the time course of the reported reduction in exercise tachycardia. Finally, plasma concentrations of penbutolol equivalents derived from the receptor assay were in the range of penbutolol concentrations detected by physico-chemical methods.It is concluded that the time course of antagonism against -adrenoceptor-mediated effects after a single oral dose of penbutolol in man can readily be explained by its biphasic elimination kinetics from human plasma together with the properties of the -adrenoceptor interaction detectable in vitro.This work is dedicated to Professor Dr. K. Greeff on occasion of his 65th birthday     

Differential actions of dopamine agonists and antagonists on the γ-butyrolactone-induced increase in mouse brain dopamine

-Butyrolactone (GBL) increased the dopamine concentration in the forebrain of the mouse. Apomorphine dose-dependently antagonized the GBL effect, while piribedil was less effective. Haloperidol prevented the antagonism of GBL by apomorphine but pimozide was ineffective in blocking apomorphine. After chronic treatment with haloperidol or pimozide, there was no alteration of the maximum GBL-induced increase in dopamine nor was there any significant change in the antagonism by apomorphine, although a trend toward increased sensitivity to apomorphine was noted in the group withdrawn from haloperidol. These results suggest that in the mouse, haloperidol is a more effective antagonist of presynaptic dopamine autoreceptors than pimozide, while apomorphine is a better presynaptic agonist than piribedil.     

Biotransformation and pharmacokinetics of sulfinpyrazone (Anturan®) in man

Summary The absorption, biotransformation and elimination of sulfinpyrazone, 1,2-diphenyl-3,5-dioxo-4-(2-phenylsufinylethyl)-pyrazolidine, have been studied by administration of single 200 mg oral doses of a¹⁴C-labelled preparation to two male volunteers. Absorption from the gastro-intestinal tract was rapid and complete and the plasma concentration of unchanged drug reached maximum values of 22.67 and 13.04 µg/ml, respectively, after 1 – 2 hours. The elimination half-life in the two subjects, calculated from the decline between 3 and 8 hours, was 2.7 and 2.2 hours. The integrated concentration of unchanged sulfinpyrazone in plasma, estimated from the area under the concentration curves (AUC), was almost as high as that of total¹⁴C-substances, so the proportion of metabolized drug in plasma was low. In no case did the AUC of the three specifically determined metabolites, i.e. the sulphone G 31 442, the para-hydroxy-compound G 32 642 and the 4-hydroxy-compound GP 52 097, exceed 4% of the sulfinpyrazone value. More than 95% of whole blood radioactivity was confined to plasma. The oral dose was rapidly and completely excreted, since within 4 days more than 95% was recovered, 85% from urine and 10% from faeces. A large proportion of the dose was excreted as unchanged drug in the two volunteers: 51 and 54% of total urinary radioactivity was present as sulfinpyrazone; 8.2 and 8.8% was present as para-hydroxy-metabolite, 2.7 and 3.0% as sulphone-metabolite, and 0.6 and 0.8% as 4-hydroxy-metabolite. About 30% of urinary radioactivity consisted of highly polar metabolites. Spectroscopy of them showed that they were the C--glucuronides of sulfinpyrazone (28%) and the corresponding sulfone (2%). In these metabolites the C(4) of the pyrazolidine ring was directly attached to glucuronic acid, and thus they represent a new type of biosynthetic conjugate.     

Biotransformation and pharmacokinetics of acenocoumarol (Sintrom®) in man

Summary The absorption, biotransformation and elimination of the anticoagulant acenocoumarol, 3-[- (4-nitrophenyl)--acetylethyl]-4-hydroxycoumarin, have been studied by oral administration of 12 mg of a¹⁴C-labelled preparation to two male volunteers. Absorption from the gastro-intestinal tract was rapid and the plasma concentration of unchanged drug reached a maximum of 169 and 412 ng/ml, respectively, after 3 hours. The elimination half-life in the two subjects, calculated from the decline between 6 and 24 h, was 8.7 and 8.2 hours. A constant proportion of 98.7% of the drug was bound in vitro to serum proteins over a concentration range of 0.021–8.34 µg/ml, with little interindividual variation. The major portion of the binding was to human serum albumin (97.5%) at two classes of binding sites: association constant K₁=1.04×10⁵ l/mole (n₁=1) and K₂=5.55×10³ l/mole (n₂=4). In addition to unchanged acenocoumarol, four metabolites were determined in plasma by isotope dilution techniques: the amino-, acetamido-, alcohol₁- and alcohol₂-metabolites. Of them, the amino-metabolite showed the highest concentration, namely 278 ng/ml, after 6 h in Subject A, and 163 ng/ml after 10 hours in Subject B. Judged from the integrated concentrations, the compounds analyzed accounted for 76 and 89%, respectively, of the total radioactivity in plasma. All the metabolites detected in plasma showed anticoagulant activity when tested in mice. The quantities of the metabolites excreted in urine from 0–120 hours were (Subject A/Subject B): acenocoumarol 0.3/0.2%, amino-metabolite 12.3/7.7%, acetamido-metabolite 19.0/11.1%, alcohol₁-metabolite 4.6/9.0%, alcohol₂-metabolite 1.7/4.4%, 6-hydroxy-metabolite 6.9/18.3% and 7-hydroxy-metabolite 14.0/22.2%.     

Comparative β-adrenoceptor blocking effect and pharmacokinetics of bucindolol and propranolol in man

Summary The -adrenoceptor blocking properties and pharmacokinetics of bucindolol 150 mg were compared to those of propranolol 80 mg and a placebo in a double-blind trial in 6 healthy volunteers. Heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressures and peak expiratory flow rate (PEFR) at rest and during vigorous exercise, and plasma renin activity (PRA) at rest, were measured before and at intervals up to 24 h after oral administration of the drugs. Bucindolol reduced exercise tachycardia and decreased exercise PEFR, thus behaving as a non-selective -adrenoceptor blocking drug. In contrast to propranolol, bucindolol did not reduce resting HR and PRA, probably because of its intrinsic sympathomimetic activity. It decreased resting DBP in relation to its peripheral vasodilator properties. The effects of bucindolol developed as early as 30 min after administration and lasted up to 24 h, whereas its T_max and T_1/2 were 1.6 and 3.6 h respectively. Comparison of the time courses of plasma bucindolol and the cardiac -adrenoceptor blockade strongly suggests that in man bucindolol undergoes an extensive first-pass effect, leading to the formation of one or more active metabolites.     

Drug metabolism and liver disease: a drug–gene–environment interaction

Despite the central role of the liver in drug metabolism, surprisingly there is lack of certainty in anticipating the extent of modification of the clearance of a given drug in a given patient. The intent of this review is to provide a conceptual framework in considering the impact of liver disease on drug disposition and reciprocally the impact of drug disposition on liver disease. It is proposed that improved understanding of the situation is gained by considering the issue as a special example of a drug–gene–environment interaction. This requires an integration of knowledge of the drug’s properties, knowledge of the gene products involved in its metabolism, and knowledge of the pathophysiology of its disposition. This will enhance the level of predictability of drug disposition and toxicity for a drug of interest in an individual patient. It is our contention that advances in pharmacology, pharmacogenomics, and hepatology, together with concerted interests in the academic, regulatory, and pharmaceutical industry communities provide an ideal immediate environment to move from a qualitative reactive approach to quantitative proactive approach in individualizing patient therapy in liver disease.