Concise review: Clinical relevance of drug drug and herb drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein).

Learning Objectives After completing this course, the reader will be able to: Identify important sources of variability in drug exposure caused by drug interactions mediated by P-glycoprotein.Describe how unwanted drug–drug interactions may lead to unexpected serious toxicity or undertreatment.Prevent these interactions by individualizing pharmacotherapy; this means selecting noninteracting drugs or adapting the dose of (the) interacting drug(s). CME Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.co

Role of Membrane Transporters, P-Glycoprotein and Mrp1, in The Placental Transfer of Drugs With Special Reference to Saquinavir and Quetiapine

Drug transporting membrane proteins are expressed in various human tissues and blood-tissue barriers, regulating the transfer of drugs, toxins and endogenous compounds into or out of the cells. Various in vitro and animal experiments suggest that P-glycoprotein (P-gp) forms a functional barrier between maternal and fetal blood circulation in the placenta thereby protecting the fetus from exposure to xenobiotics during pregnancy. The multidrug resistance-associated protein 1 (MRP1) is a relatively less studied transporter protein in the human placenta. The aim of this study series was to study the role of placental transporters, apical P-gp and basal MRP1, using saquinavir as a probe drug, and to study transfer of quetiapine and the role of P-gp in its transfer in the dually perfused human placenta/cotyledon. Furthermore, two ABCB1 (encoding P-gp) polymorphisms (c.3435C>T, p.Ile1145Ile and c.2677G>T/A, p.Ala893Ser/Thr) were studied to determine their impact on P-gp protein expression level and on the transfer of the study drugs. Also, the influence of the P-gp protein expression level on the transfer of the study drugs was addressed. Because P-gp and MRP1 are ATP-dependent drug-efflux pumps, it was studied whether exogenous ATP is needed for the function of ATP-dependent transporter in the present experimental model. The present results indicated that the addition of exogenous ATP was not necessary for transporter function in the perfused human placental cotyledon. Saquinavir and quetiapine were both found to cross the human placenta; transplacental transfer (TPTAUC %) for saquinavir was <0.5% and for quetiapine 3.7%. Pharmacologic blocking of P-gp led to disruption of the blood-placental barrier (BPB) and increased the placental transfer of P-gp substrate, saquinavir, into the fetal circulation by 6- to 8-fold. In reversed perfusions P-gp, MRP1 and possibly OATP2B1 had a negligible role in the fetal-to-maternal transfer of saquinavir. The TPTAUC % of saquinavir was about 100-fold greater from the fetal side to the maternal side compared with the maternal-to-fetal transfer. P-gp activity is not likely to modify the placental transfer of quetiapine. Higher P-gp protein expression levels were associated with the variant allele 3435T, but no correlation was found between the TPTAUC % of saquinavir and placental P-gp protein expression. The present results indicate that P-gp activity drastically affects the fetal exposure to saquinavir, and suggest that pharmacological blockade of the P-gp activity during pregnancy may pose an increased risk for adverse fetal outcome. The blockade of P-gp activity could be used in purpose to obtain higher drug concentration to the fetal side, for example, in prevention (to decrease virus transfer to fetal side) or in treating sick fetus.Siirretty Doriast

Efflux transporters of the placenta

This is the author's accepted manuscript, post peer review. For the published version, please see the link in this record.The use of pharmaceuticals during pregnancy is often a necessity for the health of the mother. Until recently, the placenta was viewed as a passive organ through which molecules are passed indiscriminately between mother and fetus. In reality, the placenta contains a plethora of transporters, some of which appear to be specifically dedicated to removal of xenobiotics and toxic endogenous compounds. Drug efflux transporters such as P-glycoprotein (P-gp), several multidrug resistant associated proteins (MRPs) and breast cancer resistant protein (BCRP) may provide mechanisms that protect the developing fetus. Bile acid transporters may also play a role in exporting compounds back into the maternal compartment. Steroid hormones directly influence the level of expression and function in some of these transporters. Investigating the link between the hormones of pregnancy and these drug efflux transporters is one possible key in developing strategies to deliver drugs to the mother with minimal fetal risk.This research was supported by NIH grants P01HD-3-9878 and N01DA-4-7405

Frequency of G2677T/A and C3435T polymorphisms of MDR1 gene in preeclamptic women

Objective: Preeclampsia (PE) belongs to main causes of mortality rates of mothers, fetuses and new born children. Polymorphism of MDR1 gene is connected with reduction of P-glycoprotein expression in placenta and increased fetal exposure to xenobiotics. The aim of the study was to determine the frequency of C3435T and G2677T/A polymorphisms of MDR1 gene in pregnant women with preeclampsia. Materials and methods: The study consisted of 180 Polish women including 60 women with PE and 120 healthy pregnant women. Determination of C3435T and G2677T/A polymorphisms of MDR1 gene was performed using PCR-RFLP method. Results: No significant association between genotypes of the examined polymorphisms and the clinical parameters of pregnant women with PE was observed. However the interesting tendency to higher prevalence of mutated 2677A allele of G2677T/A MDR1 polymorphism in PE group has been shown (2,50 vs. 0,83% in controls, OR=3,05, ns). Conclusions: The results of this study suggest no significant effect of examined C3435T and G2677T/A MDR1 polymorphisms in PE pathogenesis. However given the noteworthy results related to mutated 2677A allele of G2677T/A MDR1 polymorphism in preeclamptic women further studies seem to be needed. Nevertheless, the frequency of investigated polymorphisms was consistent with the distribution in other Caucasian populations

A medical molecular genetics of Orofacial clefting: Role of ABC Transporter Polymorphisms in Disease Risk

Master'sMASTER OF SCIENC

Studies on the human MDR1, MRP1, and MRP2 ABC transporters: functional relevance of the genetic polymorphisms in the MDR1 and MRP1 gene

http://www.ester.ee/record=b1812718*es