Drug Metabolism and Drug Interactions最新文献

During the last century a large number of documents (regulations, ethical codes, treatises, declarations, conventions) were published on the subject of ethics and clinical trials, many of them focusing on the protection of research participants. More recently various proposals have been put forward to relax some of the constraints imposed on research by these documents and regulations. It is important to distinguish between risks deriving from direct interventions on human subjects and other types of risk. In Italy the Data Protection Authority has acted in the question of research using previously collected health data and biological samples to simplify the procedures regarding informed consent. The new approach may be of help to other researchers working outside Italy.

Background: The metabolism of tyrosine kinase inhibitors (TKIs) is mainly mediated via hepatic route, but the mechanism responsible for their hepatocellular accumulation is still unknown. This study was designed to understand the contribution of organic anion transporting polypeptides (OATPs) in the hepatic uptake of selected TKIs - pazopanib, canertinib, erlotinib, vandetanib and nilotinib.

Methods: Michaelis-Menten (MM) kinetic parameters for TKIs were determined by concentration-dependent cellular accumulation of selected TKIs using Chinese hamster ovary cells - wild type as well as transfected with humanized OATP-1B1 and OATP-1B3 transporter proteins.

Results: The MM constant (Km) values of OATP-1B1 for nilotinib and vandetanib are 10.14±1.91 and 2.72±0.25 μM, respectively, and Vmax values of OATP-1B1 for nilotinib and vandetanib were 6.95±0.47 and 75.95±1.99 nmol/mg protein per minute, respectively. Likewise, Km values of OATP-1B3 for canertinib, nilotinib and vandetanib were 12.18±3.32, 7.84±1.43 and 4.37±0.79 μM, respectively, and Vmax values of OATP-1B3 for canertinib, nilotinib and vandetanib were 15.34±1.59, 6.75±0.42 and 194.64±10.58 nmol/mg protein per minute, respectively. Canertinib did not exhibit any substrate specificity toward OATP-1B1. Also, erlotinib and pazopanib did not exhibit any substrate specificity toward OATP-1B1 and -1B3.

Conclusions: Because selected TKIs are the substrates of OATP-1B1 and -1B3 expressed in hepatic tissue, these compounds can be regarded as molecular targets for transporter-mediated drug-drug interactions (DDIs). Any alteration in the function of these hepatic OATPs might account for the pharmacokinetic variability of TKIs.

Phase I and II drug metabolizing enzymes (DMEs) play an important role in biotransformation of endogenous and exogenous compounds including drugs currently used in pharmacoterapy. Moreover, the genetic variability of DMEs causes important interindividual differences in drug and metabolite exposure, drug response, and risk of adverse drug reactions. We reviewed pharmacogenetics/pharmacogenomics (PGx) studies that evaluated the influence of polymorphisms in the CYPs genes - mainly CYP1, CYP2 and CYP3 gene families - and in the phase II genes - TPMT, NAT2, GSTs and UGTs - on therapeutic response in Brazilian cohorts. Ethnic admixture of Brazilians resulted in a population characterized by a unique genetic profile, in which ancestry informative markers change continuously among ethnic groups. Therefore, some of the PGx biomarkers have a different distribution among Brazilians and PGx data from well-defined ethnic groups are not applicable to Brazilian populations. PGx data focused on phase I and phase II DMEs from Brazilian studies are needed in order to establish the influence of the genetic diversity on therapeutic response to clinically relevant drugs in a population with a composition from a complex genetic admixture. These studies and their impact are discussed in this review.

Background: The aim of this study was to investigate etomidate administration with or without flumazenil in autistic children who underwent intrathecal transplantation of stem cells by lumbar puncture.

Methods: Forty autistic children aged 2-12, who were scheduled for stem cell transplantation via lumbar puncture under anesthesia, were randomized for a double-blind study. The children were randomly assigned to two groups: the flumazenil group (group F, n=20) and the etomidate group (group E, n=20). All children received 0.2 mg/kg of etomidate. In the case of inadequate anesthesia, patients received repeated doses of 0.1 mg/kg of etomidate until reaching deep sedation. After operation, children in group F were given flumazenil (0.01 mg/kg) and children in group E received placebo. Heart rate (HR), mean arterial pressure, oxygen saturation, respiratory rate, the Ramsay sedation score (RSS), and recovery time of all children were continuously monitored and recorded during the entire procedure.

Results: After anesthesia, blood pressure and HR measurements were not significantly changed in both groups compared with the baseline. There were no respiratory depression, bradycardia, hypotension, nausea, and vomiting. Five patients complained of pain on the site of injection. Myoclonus occurred in seven patients. Recovery time in group F was significantly shorter than in group E (p<0.001), and after the injection of flumazenil, RSS in group F significantly decreased than in group E. There were no significant differences in operation time. Physician satisfaction in both groups was similar.

Conclusions: Etomidate resulted in stable hemodynamic responses and relatively less adverse effects, and flumazenil antagonized the anesthetic effect of etomidate; thus, etomidate with flumazenil is suitable for performing stem cell transplantation in autistic children.

Background: Raloxifene is a selective estrogen receptor (ER) modulator (SERM) used for the treatment of osteoporosis. However, its efficacy and also its safety vary greatly among treated patients, and it might be influenced by the individuals' genetic background. As the receptor activator of the nuclear factor κB (RANK) ligand (RANKL)/RANK/osteoprotegerin (OPG) system is essential for osteoclastogensis and Wnt signaling pathway for osteoblastogenesis, we decided to evaluate the raloxifene treatment in regard to selected polymorphisms in key genes of these two main bone regulatory pathways.

Methods: Fifty-six osteoporotic postmenopausal women treated with raloxifene were genotyped for 11 polymorphisms located in six genes: -290C>T, -643C>T, and -693G>C in tumor necrosis factor receptor superfamily member 11 (TNFSF11), +34694C>T, +34901G>A, and +35966insdelC in tumor necrosis factor receptor superfamily member 11A (TNFRSF11A), K3N and 245T>G in tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), A1330V in LRP5, I1062V in LRP6, and -1397_-1396insGGA in SOST. For evaluation of treatment efficacy, bone mineral density (BMD) and biochemical markers of bone turnover were measured.

Results: One-year change in total hip BMD was associated with +34901G>A in TNFRSF11A (p=0.040), whereas, for lumbar spine BMD, the association was shown for -1397_-1396insGGA in SOST (p=0.015). C-terminal crosslinking telopeptides of type I collagen (CTX) concentrations showed significant association with -643C>T single nucleotide polymorphism (SNP) in TNFSF11 (p=0.049) and +34694C>T in TNFRSF11A (p=0.022). No other association was found between 1-year change in BMDs or biochemical markers and the studied SNPs.

Conclusions: We have shown that, in postmenopausal osteoporotic women treated with raloxifene, the efficacy of raloxifene treatment might be influenced by +34901G>A in TNFRSF11A gene and -1397_-1396insGGA in the SOST gene as well as -643C>T in TNFSF11 gene and +34694C>T in TNFRSF11A gene. However, these findings need additional functional and clinical confirmation for potential pharmacogenetic use in the future.

Background: The aim of this study was to investigate the effect of silymarin pretreatment on domperidone oral bioavailability in humans.

Methods: The rats were pretreated with silymarin for 7 days. The transport of domperidone across the rat intestine (duodenum, jejunum, ileum, and colon) was studied by using in vitro everted and non-everted sac methods. Samples were collected at preset time points and replaced with buffer. The drug content in the samples was estimated. The first part of the study included oral administration of 10 mg domperidone tablet alone, and blood was sampled from the antecubital vein. The second part of the study was conducted after a washout period of 2 weeks. Five hundred milligrams of silymarin was administered twice daily for 6 days. On day 7, one tablet each of 10 mg domperidone and 500 mg silymarin were administered concomitantly.

Results: In the everted sac and non-everted sac study with silymarin pretreatment, domperidone transport increased from the duodenum, jejunum, ileum, and colon. The silymarin pretreatment increased the bioavailability of domperidone. There was a statistically significant difference in the pharmacokinetic parameters Cmax, T1/2, AUC0-∞, and AUC0-24.

Conclusions: The significant difference in absorption of domperidone on pretreatment with silymarin is due to the inhibition of P-glycoprotein and CYP3A. Silymarin, which inhibits CYP3A4, should be contraindicated for domperidone.

Spanning over 2000 years, the Jewish population has a long history of migration, population bottlenecks, expansions, and geographical isolation, which has resulted in a unique genetic architecture among the Jewish people. As such, many Mendelian disease genes and founder mutations for autosomal recessive diseases have been discovered in several Jewish groups, which have prompted recent genomic studies in the Jewish population on common disease susceptibility and other complex traits. Although few studies on the genetic determinants of drug response variability have been reported in the Jewish population, a number of unique pharmacogenetic variants have been discovered that are more common in Jewish populations than in other major racial groups. Notable examples identified in the Ashkenazi Jewish (AJ) population include the vitamin K epoxide reductase complex subunit 1 (VKORC1) c.106G>T (p.D36Y) variant associated with high warfarin dosing requirements and the recently reported cytochrome P450 2C19 (CYP2C19) allele, CYP2C19*4B, that harbors both loss-of-function [*4 (c.1A>G)] and increased-function [*17 (c.-806C>T)] variants on the same haplotype. These data are encouraging in that like other ethnicities and subpopulations, the Jewish population likely harbors numerous pharmacogenetic variants that are uncommon or absent in other larger racial groups and ethnicities. In addition to unique variants, common multi-ethnic variants in key drug metabolism genes (e.g., ABCB1, CYP2C8, CYP2C9, CYP2C19, CYP2D6, NAT2) have also been detected in the AJ and other Jewish groups. This review aims to summarize the currently available pharmacogenetics literature and discuss future directions for related research with this unique population.

Background: The purpose of this study is to identify the effect of binary and ternary combinations of anti-HIV protease inhibitors (PIs) on the expression of metabolizing enzyme (CYP3A4) and efflux transporters [multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP)] in a model intestinal cell line (LS-180).

Methods: LS-180 cells were treated with various combinations of PIs (amprenavir, indinavir, saquinavir and lopinavir), and the mRNA expression levels of metabolizing enzyme and efflux transporters were measured using quantitative reverse transcription polymerase chain reaction. The alteration of gene expression was further correlated to the expression of nuclear hormone receptor PXR. Uptake of fluorescent and radioactive substrates was carried out to study the functional activity of these proteins. Cytotoxicity and adenosine triphosphate (ATP) assays were carried out to measure stress responses.

Results: Binary and ternary combinations of PIs appeared to modulate the expression of CYP3A4, MRP2, P-gp and BCRP in a considerable manner. Unlike the individual PIs, their binary combinations showed much greater induction of metabolizing enzyme and efflux proteins. However, such pronounced induction was not observed in the presence of ternary combinations. The observed trend of altered mRNA expression was found to correlate well with the change in expression levels of PXR. The gene expression was found to correlate with activity assays. Lack of cytotoxicity and ATP activity was observed in the treatment samples, suggesting that these alterations in expression levels were probably not stress responses.

Conclusions: In the present study, we demonstrated that combinations of drugs can have serious consequences toward the treatment of HIV infection by altering their bioavailability and disposition.

Background: To evaluate potential drug-drug interactions with the atypical antipsychotic lurasidone.

Methods: Seven phase I studies were conducted to investigate the effects of repeated dosing of ketoconazole, diltiazem, rifampin, or lithium on the pharmacokinetics (PK) of single oral doses of lurasidone, or the effects of repeated dosing of lurasidone on the PK of digoxin, midazolam, or the oral contraceptive norgestimate/ethinyl estradiol. Two 6-week, phase III studies included evaluation of the potential for interaction between lurasidone and lithium or valproate. Maximum serum or plasma concentration (Cmax) and area under the concentration-time curve (AUC) were calculated.

Results: Concomitant ketoconazole administration resulted in a 6.8-fold increase in lurasidone Cmax and a 9.3-fold increase in lurasidone AUC; concomitant diltiazem administration resulted in 2.1- and 2.2-fold increases, respectively. Rifampin decreased lurasidone Cmax and AUC (one-seventh and one-fifth of lurasidone alone, respectively). Steady-state dosing with lurasidone increased Cmax and AUC0-24 (AUC from time 0 to 24 h postdose) of digoxin by 9% and 13%, respectively, and of midazolam by 21% and 44%, respectively. There were no significant interactions between lurasidone and lithium, valproate, ethinyl estradiol, or norelgestromin (the major active metabolite of norgestimate).

Conclusions: Lurasidone PK is altered by strong cytochrome P450 (CYP) 3A4 inhibitors or inducers, and coadministration is contraindicated; whereas moderate CYP3A4 inhibitors have less effect, and lurasidone dosage restrictions are recommended. No dose adjustment for lurasidone is needed when administered with lithium or valproate. Dose adjustment is not required for lithium, valproate, digoxin (a P-glycoprotein substrate), or midazolam or oral contraceptives (CYP3A4 substrates) when coadministered with lurasidone.