Publications (73) View all
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Article: Human Precision-Cut Liver Slices as an ex Vivo Model to Study Idiosyncratic Drug-Induced Liver Injury
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ABSTRACT: Idiosyncratic drug-induced liver injury (IDILI) is a major problem during drug development and has caused drug withdrawal and black-box warnings. Because of the low concordance of the hepatotoxicity of drugs in animals and humans, robust screening methods using human tissue are needed to predict IDILI in humans. According to the inflammatory stress hypothesis, the effects of inflammation interact with the effects of a drug or its reactive metabolite, precipitating toxic reactions in the liver. As a follow-up to our recently published mouse precision-cut liver slices model, an ex vivo model involving human precision-cut liver slices (hPCLS), co-incubated for 24 h with IDILI-related drugs and lipopolysaccharide (LPS), was developed to study IDILI mechanisms related to inflammatory stress in humans and to detect potential biomarkers. LPS exacerbated the effects of ketoconazole and clozapine toxicity but not those of their non-IDILI-related comparators, voriconazole and olanzapine. However, the IDILI-related drugs diclofenac, carbamazepine, and troglitazone did not show synergistic toxicity with LPS after incubation for 24 h. Co-incubation of ketoconazole and clozapine with LPS decreased the levels of glutathione in hPCLS, but this was not seen for the other drugs. All drugs affected LPS-induced cytokine release, but interestingly, only ketoconazole and clozapine increased the level of LPS-induced TNF release. Decreased levels of glutathione and cysteine conjugates of clozapine were detected in IDILI-responding livers following cotreatment with LPS. In conclusion, we identified ketoconazole and clozapine as drugs that exhibited synergistic toxicity with LPS, while glutathione and TNF were found to be potential biomarkers for IDILI-inducing drugs mediated by inflammatory stress. hPCLS appear to be suitable for further unraveling the mechanisms of inflammatory stress-associated IDILI.Chemical Research in Toxicology 04/2013; · 3.78 Impact Factor -
Article: Bilitranslocase is Involved in the Uptake of Bromosulfophthalein in Rat and Human Liver
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ABSTRACT: Hepatic disposition of bromosulfophthalein (BSP), bilirubin and bile salts partially overlap, as these anions share both uptake and excretion mechanisms. Multiple organic anion transporters mediate hepatic BSP uptake, i.e. members of the SLCO and SLC22 gene families and bilitranslocase (TCDB #2.A.65.1.1). This study aimed at evaluating the relative contribution of bilitranslocase in BSP uptake in precision-cut human and rat liver slices. To this purpose, two different anti-sequence bilitranslocase antibodies were used as specific, functional inhibitors of bilitranslocase. The intact liver physiology was accurately reproduced in this BSP uptake assay, since uptake was strongly temperature-dependent and inhibited by hepatotropic organic anions, such as 50 nM bilirubin, 1 M nicotinic acid, 2 M digoxin, 5 M indocyanine green and 100 M taurocholate. The bilitranslocase antibodies inhibited BSP uptake both in rat and human liver slices. The combined use of bilitranslocase antibodies and taurocholate caused additive-type inhibition, confirming that bilitranslocase is not a bile salt transporter; by contrast, bilirubin caused no additive-type inhibition. In conclusion this data, indicate the role of the bilirubin transporter bilitranslocase as one of the transporters involved in the uptake of anions like BSP in parallel with other organic anion carriers. Moreover this data indicate the value of precision-cut liver slices for phenotypic drug uptake studies.Drug Metabolism Letters 03/2013; -
Article: Bilitranslocase is Involved in The Uptake of Bromosulfophthalein in Rat and Human Liver.
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ABSTRACT: Hepatic disposition of bromosulfophthalein (BSP), bilirubin and bile salts partially overlap, as these anions share both uptake and excretion mechanisms. Multiple organic anion transporters mediate hepatic BSP uptake, i.e. members of the SLCO and SLC22 gene families and bilitranslocase (TCDB #2.A.65.1.1). This study aimed at evaluating the relative contribution of bilitranslocase in BSP uptake in precision-cut human and rat liver slices. To this purpose, two different anti-sequence bilitranslocase antibodies were used as specific, functional inhibitors of bilitranslocase. The intact liver physiology was accurately reproduced in this BSP uptake assay, since uptake was strongly temperature-dependent and inhibited by hepatotropic organic anions, such as 50 nM bilirubin, 1 µM nicotinic acid, 2 µM digoxin, 5 µM indocyanine green and 100 µM taurocholate. The bilitranslocase antibodies inhibited BSP uptake both in rat and human liver slices. The combined use of bilitranslocase antibodies and taurocholate caused additive-type inhibition, confirming that bilitranslocase is not a bile salt transporter; by contrast, bilirubin caused no additive-type inhibition. In conclusion this data, indicate the role of the bilirubin transporter bilitranslocase as one of the transporters involved in the uptake of anions like BSP in parallel with other organic anion carriers. Moreover this data indicate the value of precision-cut liver slices for phenotypic drug uptake studies.Drug metabolism letters. 03/2013; -
Article: Pharmacokinetic-pharmacodynamic modeling of antipsychotic drugs in patients with schizophrenia Part I: The use of PANSS total score and clinical utility.
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ABSTRACT: BACKGROUND: To develop a pharmacokinetic-pharmacodynamic (PK-PD) model using individual-level data of Positive and Negative Syndrome Scale (PANSS) total score to characterize the antipsychotic drug effect taking into account the placebo effect and dropout rate. In addition, a clinical utility (CU) criterion that describes the usefulness of a drug therapy was calculated using the efficacy of the drug and dropout rates. METHODS: Data from 12 clinical trials in schizophrenia patients was used to quantify the effects of the antipsychotic drugs (APs), namely, haloperidol, risperidone, olanzapine, ziprasidone and paliperidone. Compartmental PK models were used to describe the time course of plasma drug concentrations. The combination of an Emax and the Weibull model was used to describe the drug and placebo effects. The steady-state drug concentrations were assumed to be the drivers of the exposure-response relationship. An exponential model was utilized to identify the predictors of probability of dropout. Simulations were performed to check the predictability of the model, and to calculate the CU of the drugs based on PANSS scores and dropout rates. RESULTS: The maximal drug effect (Emax) was highest for olanzapine whilst it was lowest for ziprasidone. Higher observed PANSS scores resulted in a greater likelihood of dropout. Taking into account the efficacy and the drop-out rate, all APs possessed a comparable CU at the therapeutic doses. The resulting PK-PD model parameters were used to compute the effective concentration and dose required to produce a clinically meaningful 30% drop in PANSS score from the baseline. CONCLUSIONS: The developed PK-PD model and the associated CU score allow the evaluation of the time course of the PANSS scores of the different APs and a proper comparison of their clinically relevant treatments effects.Biological Psychiatry 03/2013; · 8.28 Impact Factor -
Article: Pharmacokinetic-pharmacodynamic modelling of antipsychotic drugs in patients with schizophrenia: Part II: The use of subscales of the PANSS score.
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ABSTRACT: BACKGROUND AND OBJECTIVES: The superiority of atypical antipsychotics (also known as second-generation antipsychotics (SGAs)) over typical antipsychotics (first generation antipsychotics (FGAs)) for negative symptom control in schizophrenic patients is widely debated. The objective of this study was to characterize the time course of the scores of the 3 subscales (positive, negative, general) of the Positive and Negative Syndrome Scale (PANSS) after treatment of patients with antipsychotics, and to compare the control of negative symptom by SGAs versus a FGA (haloperidol) using pharmacokinetic and pharmacodynamic (PKPD) modelling. In addition, to obtain insight in the relationship between the clinical efficacy and the in vitro and in vivo receptor pharmacology profiles, the D2 and 5-HT2A receptor occupancy levels of antipsychotics were related to the effective concentrations. METHODS: The PKPD model structure developed earlier (part I) was used to quantify the drug effect using the 3 PANSS subscales. The maximum drug effect sizes (Emax) of oral SGAs (risperidone, olanzapine, ziprasidone, and paliperidone) across PANSS subscales were compared with that of haloperidol, while accounting for the placebo effect. Using the estimates of PKPD model parameters, the effective concentrations (Ceff) needed to achieve 30% reduction in the PANSS subscales were computed. Calculated effective concentrations were then correlated with receptor pharmacology profiles. RESULTS: Positive symptoms of schizophrenia responded well to all antipsychotics. Olanzapine showed a better effect towards negative symptoms than the other SGAs and haloperidol. Dropout modelling results showed that the probability of a patient dropping out from a trial was associated with all subscales, but was more strongly correlated with the positive subscale than with the negative or the general subscales. Our results suggest that different levels of D2 or 5-HT2A receptor occupancy are required to achieve improvement in PANSS subscales. CONCLUSIONS: This PKPD modelling approach can be helpful to differentiate the effect of antipsychotics across the different symptom domains of schizophrenia. Our analysis revealed that olanzapine seems to be superior in treating the negative symptoms compared to other non-clozapine SGAs. The relationship between receptor pharmacology profiles of the antipsychotics and their clinical efficacy is not yet fully understood.Biological Psychiatry 03/2013; · 8.28 Impact Factor
