The roles of P‐glycoprotein and intracellular metabolism in the intestinal absorption of methadone: in vitro studies using the rat everted intestinal sac

Zhou

Journal of Ethnopharmacology

et al. 2005

Paeonia lactiflora Pall. (Ranunculaceae) root and Sinomenium acutum Rehder and Wilson (Menispermaceae) stem are two herbs widely used in Chinese medicine to treat rheumatoid arthritis. While, in theory, either herb could be used alone, in practice, Chinese medicine practitioners prescribe them together. Studies on pharmacokinetic interaction between the active constituents of these two herbs (paeoniflorin and sinomenine, respectively) provide empirical evidence to support their clinical practice. A single dose of paeoniflorin (150 mg/kg) alone and with sinomenine hydrochloride (90 mg/kg) was administered by gastric gavage to unrestrained conscious male Sprague-Dawley rats (n = 6, 250-300 g). Blood samples were collected periodically via a jugular vein before and after dosing from 10 min to 12 h. A high-performance liquid chromatographic (HPLC) assay was developed to determine the plasma concentrations of paeoniflorin. Non-compartmental pharmacokinetic profiles were constructed by using the software PK Solutions 2.0. The pharmacokinetic parameters were compared using unpaired Student t-test. After co-administration of sinomenine, the peak plasma concentration of paeoniflorin was elevated (P < 0.01), the peak time was delayed (P < 0.01), the AUC 0-t was increased (P < 0.001), the mean residence time (MRT) was prolonged (P < 0.01), the C L was decreased (P < 0.01) and the V d was reduced (P < 0.05). These results indicate that sinomenine hydrochloride at 90 mg/kg significantly improved the bioavailability of paeoniflorin in rats.

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Influence of co-administrated sinomenine on pharmacokinetic fate of paeoniflorin in unrestrained conscious rats

Zhou

Journal of Ethnopharmacology

et al. 2005

Biochemical Pharmacology

“…In an in vivo investigation utilizing knockout mice for MDR1 gene revealed higher concentrations of methadone in the brain of these animals [34] and increased analgesia [35]. In another model system, addition of verapamil to the everted rat intestine increased the transfer of methadone by 60% [36]. Accordingly, it was reasonable to assume that the unidirectional activity of P-gp could contribute to the role of the placenta as a functional barrier between maternal and fetal blood and consequently protecting the developing fetus from environmental toxins, xenobiotics, and drugs such as methadone.…”

Section: Discussionmentioning

confidence: 98%

Role of P-glycoprotein in transplacental transfer of methadone

Nanovskaya

Nekhayeva

Karunaratne

et al. 2005

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).

Biological & Pharmaceutical Bulletin

“…Everted Sac Method According to the method of Barr and Reigelman, 11) an intestinal everted sac was prepared from drug free mice ileum to investigate whether KA has direct effect on the Rho123 uptake via P-gp. The 10 cm length of everted sac was preincubated with KA (1.0 mg/ml) at 37°C for 30 min in 50-ml glass test-tubes containing 10 ml of Krebs-Henselit buffer (pH 6.0) with supplying 95% O 2 -5% CO 2 .…”

Section: Preparation Of Standard and Test Solutionsmentioning

confidence: 99%

Evaluation of Carbamazepine Pharmacokinetic Profiles in Mice with Kainic Acid-Induced Acute Seizures

Nishimura

Honda²,

Sugioka³

et al. 2008

Approximately 30% of epileptic patients do not respond to the usual antiepileptic drugs (AEDs), representing a major problem associated with increased morbidity and mortality. 1) The underlying mechanisms are not completely understood; it has been believed that mechanisms leading to AEDs resistance are most likely complex network phenomena including development of tolerance to antiepileptic drugs' action or alterations in drug targets based on pharmacogenomic factor. 2) Among various transporters, P-glycoprotein (P-gp) has been identified as being important regulators of bioavailabily of drugs, which is located in the endothelial cells of the blood-brain barrier and/or the small intestine, and its outwardly directed active efflux mechanisms from the blood to intestinal lumen or cerebral cell to the blood appear to act as a second line defense mechanism. P-gp, gene product of the multidrug resistance 1 (MDR1 gene ), limiting brain accumulation and intestinal absorption of many lipophilic drugs. [3][4][5][6] Because of lipophilic properties, some AEDs have been established as a substrate of P-gp, and P-gp participates in the regulation of their extracellular brain concentrations. 7) In case of carbamazepine (one of major AEDs), however, there are contradictions among the papers on the relationship between P-gp function and CBZ disposition. One reports concluded that CBZ is not a substrate for P-gp using mdr1a/1b(Ϫ/Ϫ) knockout mice or P-gp transfected cell lines, 8,9) and the other reports concluded that CBZ is appropriate substrate for P-gp using P-gp transfected cell lines or normal rats with a microdialysis method. 2,7) In addition, study on pharmacoresistance in patients with epilepsy using a radio-labeled P-gp substrate (verapamil) and positron-emission tomography (PET) method showed that regionally enhanced P-gp activity in brain might contribute to drug resistance in some patients with temporal lobe epilepsy. 10) These reports indicate that there is complexity to explain the relationship between CBZ therapy and drug resistance through the P-gp function, and it is not known to what extent the P-gp is involved in the transport of CBZ in a living body in epileptic patients. Therefore, it is important that confirmation of Pgp function during seizure in the living organism should be conducted to relief contradictions among those literatures. (Wayne NJ, U.S.A.) and Nikko Chemical Co., Ltd. (Tokyo, Japan). As a primary antibody for P-glycoprotein (P-gp), C219 antibody was purchased from Calbiochemi, Co. (CA, U.S.A.). As a secondary antibody, anti-mouse IgG, immunestar HRP chemiluminescent (ECL) kit was purchased from Bio-Rad Laboratory, Inc. (CA, U.S.A.). All other chemicals were of the highest grade available. MATERIALS AND METHODS MaterialsAnimals All animal experiments were performed in accordance with the Guidelines for Animal Experiments of Kyoto Pharmaceutical University. Male ddy mice (6 weeks old, 28-35 g) were purchased from Japan SLC Inc. (Hamamatsu, Japan), and housed in a temperature and humiditycontrol...