Role of P-glycoprotein in the intestinal absorption and clinical effects of morphine

Kharasch, Evan D.; Hoffer, Christine; Whittington, Dale; Sheffels, Pamela

doi:10.1016/j.clpt.2003.08.011

Cited by 144 publications

(99 citation statements)

References 41 publications

(79 reference statements)

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“…Indeed, the administration of the P-gp inhibitor quinidine to healthy volunteers resulted in an increase in their plasma levels of methadone [42].…”

Section: Discussionmentioning

confidence: 99%

Role of P-glycoprotein in transplacental transfer of methadone

Nanovskaya

Nekhayeva

Karunaratne

et al. 2005

Biochemical Pharmacology

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Methadone is the therapeutic agent of choice for treatment of the pregnant opiate addict. However, little is known on the factors affecting its concentration in the fetal circulation during pregnancy and how it might relate to neonatal outcome. Therefore, a better understanding of the function of placental metabolic enzymes and transporters should add to the knowledge of the role of the tissue in the disposition of methadone and its relation to neonatal outcome. We hypothesized that the expression and activity of the placental efflux transporter P-glycoprotein (P-gp) would affect the transfer of methadone to the fetal circulation. Data obtained utilizing dual perfusion of placental lobule and monolayers of Be-Wo cell line indicated that methadone is extruded by P-gp. Transfer of methadone to the fetal circuit was increased by 30% in the presence of the P-gp inhibitor GF120918 while the transfer of paclitaxel, a typical substrate of the glycoprotein, was increased by 50%. In the Be-Wo cell line, methadone and paclitaxel uptake was also increased in the presence of the P-gp inhibitor cyclosporin A. Moreover, the expression of P-gp in placental brush-border membranes varied between term placentas. Taken together, these data strongly suggest that the concentration of methadone in the fetal circulation is affected by the expression and activity of P-gp. It is reasonable to speculate that placental disposition of methadone affects its concentration in the fetal circulation. If true, this may also be directly related to the incidence and intensity of neonatal abstinence syndrome (NAS).

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“…Indeed, the administration of the P-gp inhibitor quinidine to healthy volunteers resulted in an increase in their plasma levels of methadone [42].…”

Section: Discussionmentioning

confidence: 99%

Role of P-glycoprotein in transplacental transfer of methadone

Nanovskaya

Nekhayeva

Karunaratne

et al. 2005

Biochemical Pharmacology

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“…The present results showing that alfentanil is a P-gp substrate indicate that alfentanil-pupillometry studies may have the potential to detect alterations in P-gp activity. Previous pupillometry studies conducted with the P-gp substrates morphine, fentanyl, methadone, and loperamide have shown that inhibition of P-gp at the BBB by the P-gp inhibitor quinidine is modest (Kharasch et al, 2003(Kharasch et al, , 2004aSkarke et al, 2003). Because quinidine is one of the most potent compounds capable of inhibiting P-gp that is in clinical use, the likelihood of significant inhibition of P-gp at the BBB seems remote.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Alfentanil in P-Glycoprotein-Competent and P-Glycoprotein-Deficient Mice: P-Glycoprotein Efflux Alters Alfentanil Brain Disposition and Antinociception

Kalvass

Olson²,

Pollack³

2006

Drug Metab Dispos

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ABSTRACT:Previous studies have indicated that P-glycoprotein (P-gp) attenuates the central nervous system penetration and central activity of some opioids. The impact of P-gp-mediated efflux on the disposition and efficacy of the synthetic opioid alfentanil currently is unknown. In this study, P-gp-competent [mdr1a(؉/؉)] and P-gpdeficient [mdr1a(؊/؊)] mice were used to investigate the impact of P-gp-mediated efflux on the systemic pharmacokinetics, brain disposition, and central activity of alfentanil. Equipotent doses of alfentanil were administered to mdr1a(؉/؉) and mdr1a(؊/؊) mice (0.2 and 0.067 mg/kg, respectively), and the time course of brain and serum concentrations as well as antinociception were determined. A pharmacokinetic-pharmacodynamic (PK-PD) model was fit to the data and used to assess the impact of P-gp on parameters associated with alfentanil disposition and action. The mdr1a(؉/؉) mice were less sensitive to alfentanil than mdr1a(؊/؊) mice, requiring a 3-fold higher dose to produce similar antinociception. PK-PD modeling revealed no differences in alfentanil systemic pharmacokinetics between P-gp expressers and nonexpressers. However, the steady-state brain-to-serum concentration ratio (K p,brain,ss ) was ϳ3-fold lower in mdr1a(؉/؉) mice compared with mdr1a(؊/؊) mice (0.19 ؎ 0.01 versus 0.54 ؎ 0.04, respectively). Consistent with the ϳ3-fold lower K p,brain,ss , the antinociception versus serum concentration relationship in mdr1a(؉/؉) mice was shifted ϳ3-fold rightward compared with mdr1a(؊/؊) mice. However, there was no difference in the antinociception versus brain concentration relationship, or in the brain tissue EC 50 (11 ؎ 1.8 versus 9.2 ؎ 1.7 ng/g), between mdr1a(؉/؉) and mdr1a(؊/؊) mice. These results indicate that alfentanil is an in vivo P-gp substrate and are consistent with the hypothesis that P-gp-mediated efflux attenuates antinociception by reducing alfentanil K p,brain,ss .

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“…In addition, with the development and approval of anticancer drugs in oral dosage forms over the past few decades (107,108), the number of patients receiving oral anticancer drugs has recently increased (109,110). Therefore, when using these drugs concurrently, drug-drug interactions mediated through P-gp in the small intestine that influence the absorption and pharmacological effects of P-gp substrates given orally is of clinical concern (111,112).…”

Section: Influence Of Alterations In the Expression And Function Of Pmentioning

confidence: 99%

Mechanisms of P-Glycoprotein Alteration During Anticancer Treatment: Role in the Pharmacokinetic and Pharmacological Effects of Various Substrate Drugs

et al. 2014

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Abstract. In clinical pharmacotherapy, therapeutic benefits and adverse effects of medicines differ substantially between individuals and are often determined by their blood levels. Critical regulators influencing the pharmacokinetics and pharmacodynamics of drugs include drug transporters and drug-metabolizing enzymes. Among these, we have focused on P-glycoprotein (P-gp), a drug efflux transporter. A growing body of evidence indicates that the expression and functional activity of P-gp are altered under several pathological conditions, by exposure to substrate drugs of P-gp, and by ingestion of certain foods. In this critical review, we discuss the mechanisms by which anticancer drugs, most of which are P-gp substrates, alter the expression and functional activity of P-gp in tumors and normal tissues after chronic treatment. Accumulating evidence shows that various transcription factors, in addition to epigenetic and post-translational factors, modulate P-gp expression, which alters the pharmacokinetics and pharmacological effects of drugs. Therefore, it is important to consider individual patients with regard to drug-taking history, as well as levels of P-gp expression and function, when providing clinical pharmacotherapy.Keywords: P-glycoprotein, anticancer drug, drug-drug interaction, opioid, cancer *Corresponding author. stoku@pharm.Kobegakuin.ac.jp Published online in J-STAGE on July 2, 2014 doi: 10.1254/jphs.14R01CRInvited article 243 Changes in P-gp by Anticancer Treatment targeted anticancer drugs acting on specific genes or their products has grown rapidly. In fact, combination treatment with molecularly targeted drugs and cytotoxic chemotherapy against cancers such as acute leukemia or lymphatic malignancy improved therapeutic outcome in comparison to conventional anticancer chemotherapy (8, 9). However, solid tumors often have greater inherent resistance and are less sensitive to anticancer drugs (10). Furthermore, chronic exposure to anticancer drugs frequently leads to multi-drug resistance where the therapeutic effects of these drugs on tumors is largely reduced (11). The development of resistance to anticancer chemotherapy remains one of the major obstacles in effective pharmacological therapy for cancer using current treatment strategies (12).Research revealing the role of drug transporters in cancer began with the discovery of P-glycoprotein (P-gp). In 1976, during research to elucidate the mechanism by which cancer cell lines acquire multi-drug resistance, Juliano et al. discovered that P-gp is over-expressed on the surface membranes of multi-drug resistant cancer cells (13). Subsequent studies have demonstrated that P-gp is present in cancer tissue (11,14), as well as in normal tissues such as small intestine, where it regulates drug absorption, and liver and kidney, where it modulates drug clearance (15). These results suggest that P-gp determines blood levels of its substrate drugs. Furthermore, P-gp is now considered to be an extremely important factor in the pharmacokinetics of drugs bec...

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Role of P-glycoprotein in the intestinal absorption and clinical effects of morphine

Cited by 144 publications

References 41 publications

Role of P-glycoprotein in transplacental transfer of methadone

Role of P-glycoprotein in transplacental transfer of methadone

Pharmacokinetics and Pharmacodynamics of Alfentanil in P-Glycoprotein-Competent and P-Glycoprotein-Deficient Mice: P-Glycoprotein Efflux Alters Alfentanil Brain Disposition and Antinociception

Mechanisms of P-Glycoprotein Alteration During Anticancer Treatment: Role in the Pharmacokinetic and Pharmacological Effects of Various Substrate Drugs

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