Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The taurocholate (TC) maximal secretory rate (SRm) in the isolated perfused liver is increased in postpartum rats and ovariectomized rats treated with ovine prolactin (oPRL). The present studies were designed to characterize the mechanism(s) by which oPRL increases TC transport in the liver. oPRL (300 micrograms/day i.v. for 7 days) increased the SRm 1.6-fold from 185 to 364 nmol.min-1.mg protein-1 in the perfused rat liver and the maximal rate of transport for ATP-dependent transport 1.7-fold from 66 to 109 nmol.min-1.mg protein-1 in canalicular liver plasma membrane (cLPM) vesicles without changing the Michaelis constant (5-6 microM). The oPRL-mediated increases in biliary excretion in the perfused liver and ATP-dependent TC transport in cLPM vesicles were significantly inhibited by cycloheximide treatment (2 mg/kg). oPRL (300 micrograms/day iv for 7 days) increased expression of Ca(2+)-Mg(2+)-ecto-adenosinetriphosphatase mRNA sixfold and increased protein expression two- to threefold, but had no effect on the expression of P-glycoprotein (mdr1b and mdr2) mRNA. Thus the increase in ATP-dependent transport in cLPM vesicles due to oPRL treatment accounts for the increased TC SRm in the perfused liver. The oPRL-mediated increased TC transport may be associated with increased expression of proteins related to bile acid transport.
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PMID:Prolactin increases ATP-dependent taurocholate transport in canalicular plasma membrane from rat liver. 903 75

An in vitro study has suggested that risperidone is a substrate of P-glycoprotein, which is coded by MDR1gene. The rate of P-glycoprotein efflux transport can mediate brain penetration of lipophilic drugs. We therefore studied the effects of major polymorphisms of MDR1 gene on plasma concentrations of prolactin. Subjects included 175 schizophrenic patients (68 males, 107 females) who were receiving 3 mg of risperidone twice daily for at least 4 weeks. Sample collections were conducted 12 h after the bedtime dosing. The plasma concentrations of prolactin in females were significantly higher than in males (54.3+/-27.2 versus 126.8+/-70.2 ng/ml, p<0.001). There was no difference in mean (+/-SD) plasma concentration of prolactin between C3435T genotypes [C/C, C/T, T/T; 62.3+/-33.3, 49.4+/-15.6, 53.2+/-33.2 ng/ml, ns] or G2677T/A genotypes [G/G, G/T or A, T or A/T or A; 58.0+/-27.7, 58.5+/-35.0, 46.1+/-20.7 ng/ml, ns] in males nor between C3435T genotypes (123.6+/-65.0, 127.8+/-79.2, 130.4+/-49.7 ng/ml, ns) or G2677T/A genotypes (123.3+/-67.0, 97.7+/-71.2, 144.9+/-69.9 ng/ml, ns) in females. Multiple regression analyses including plasma drug concentration and age revealed that plasma concentration of prolactin correlated with gender (standardized beta=0.540, p<0.001) and negatively with age (standardized beta=-0.183, p<0.01). No correlations were found between prolactin concentration and MDR1 genotypes. These findings suggest that prolactin concentrations in females are much higher than in males but the major MDR1 variants are not associated with the plasma concentration of prolactin.
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PMID:Association between major Multidrug Resistance 1 (MDR1) gene polymorphisms and plasma concentration of prolactin during risperidone treatment in schizophrenic patients. 1805 26

To understand the drivers in the biological system response to dopamine D2 receptor antagonists, a mechanistic semiphysiologically based (PB) pharmacokinetic-pharmacodymanic (PKPD) model was developed to describe prolactin responses to risperidone (RIS) and its active metabolite paliperidone (PAL). We performed a microdialysis study in rats to obtain detailed plasma, brain extracellular fluid (ECF), and cerebrospinal fluid (CSF) concentrations of PAL and RIS. To assess the impact of P-glycoprotein (P-gp) functioning on brain distribution, we performed experiments in the absence or presence of the P-gp inhibitor tariquidar (TQD). PK and PKPD modeling was performed by nonlinear mixed-effect modeling. Plasma, brain ECF, and CSF PK values of RIS and PAL were well described by a 12-compartmental semi-PBPK model, including metabolic conversion of RIS to PAL. P-gp efflux functionality was identified on brain ECF for RIS and PAL and on CSF only for PAL. In the PKPD analysis, the plasma drug concentrations were more relevant than brain ECF or CSF concentrations to explain the prolactin response; the estimated EC50 was in accordance with reports in the literature for both RIS and PAL. We conclude that for RIS and PAL, the plasma concentrations better explain the prolactin response than do brain ECF or CSF concentrations. This research shows that PKPD modeling is of high value to delineate the target site of drugs.
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PMID:Target-Site Investigation for the Plasma Prolactin Response: Mechanism-Based Pharmacokinetic-Pharmacodynamic Analysis of Risperidone and Paliperidone in the Rat. 2783 41