ABSTRACT
Brexpiprazole, a serotonin-dopamine activity modulator, is indicated for the treatment of schizophrenia and also adjunctive therapy to antidepressants for the treatment of Major Depressive Disorder. To determine the drug-drug interaction risk for cytochrome P450, and SLC and ABC transporters, brexpiprazole and its metabolite, DM-3411 were assessed in this in vitro investigation.Brexpiprazole exhibited weak inhibitory effects (IC50 >13 µmol/L) on CYP2C9, CYP2C19, CYP2D6 and CYP3A4 activities, but had moderate inhibitor activity on CYP2B6 (IC50 8.19 µmol/L). The ratio of systemic unbound concentration (3.8 nmol/L) to the Ki value was sufficiently low. DM-3411 had comparable inhibitory potentials with brexpiprazole only for CYP2D6 and CYP3A4. The mRNA expressions of CYP1A2, CYP2B6 and CYP3A4 were not changed by the exposure of brexpiprazole to human hepatocytes.Brexpiprazole and DM-3411 exhibited weak or no inhibitory effects for hepatic and renal transporters (OATPs, OATs, OCTs, MATE1, and BSEP), except for MATE-2K (0.156 µmol/L of DM-3411), even for which the ratio to systemic unbound concentration (5.3 nmol/L) was sufficiently low.Brexpiprazole effected the functions of P-gp and BCRP with IC50 values of 6.31 and 1.16 µmol/L, respectively, however, the pharmacokinetic alteration was not observed in the clinical concomitant study on P-gp and BCRP substrates.These in vitro data suggest that brexpiprazole is unlikely to cause clinically relevant drug interactions resulting from the effects on CYPs or transporters mediating the absorption, metabolism, and/or disposition of co-administered drugs.
Subject(s)
Depressive Disorder, Major , Pharmaceutical Preparations , ATP Binding Cassette Transporter, Subfamily G, Member 2 , Dopamine , Drug Interactions , Humans , Neoplasm Proteins , Quinolones , Serotonin , ThiophenesABSTRACT
1. Penciclovir, ganciclovir, creatinine, para-aminohippuric acid (PAH), ketoprofen, estrone 3-O-sulfate (E3S), dehydroepiandrosterone 3-O-sulfate (DHEAS) and cyclic guanosine monophosphate (cGMP) were screened as substrates of human liver organic anion transporters OAT2 and OAT7. 2. For OAT7, high uptake ratios (versus mock transfected HEK293 cells) of 29.6 and 15.3 were obtained with E3S and DHEAS. Less robust uptake ratios (≤3.6) were evident with the other substrates. OAT2 (transcript variant 1, OAT2-tv1) presented high uptake ratios of 30, 13, â¼35, â¼25, 8.5 and 9 with cGMP, PAH, penciclovir, ganciclovir, creatinine and E3S, respectively. No uptake was observed with DHEAS. 3. Although not a substrate of either transporter, ketoprofen did inhibit transfected OAT2-tv1 (IC50 of 17, 22, 23, 24, 35 and 586 µM; creatinine, ganciclovir, penciclovir, cGMP, E3S and prostaglandin F2α, respectively) and penciclovir uptake (IC50 = 27 µM; >90% inhibition) by plated human hepatocytes (PHH). 4. It is concluded that penciclovir and ketoprofen may serve as useful tools for the assessment of OAT2 activity in PHH. However, measurement of OAT7 activity therein will prove more challenging, as high uptake rates are evident with E3S and DHEAS only and both sulfoconjugates are known to be substrates of organic anion transporting polypeptides.
Subject(s)
Organic Anion Transporters, Sodium-Independent/metabolism , Acyclovir/analogs & derivatives , Acyclovir/pharmacology , Adult , Estrone/analogs & derivatives , Estrone/metabolism , Female , Guanine , HEK293 Cells , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Ketoprofen/pharmacology , Organic Anion Transporters, Sodium-Independent/antagonists & inhibitors , Organic Anion Transporters, Sodium-Independent/genetics , Peptides/metabolism , Proteomics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Substrate Specificity/drug effects , TransfectionABSTRACT
Delamanid (Deltyba, OPC-67683) is the first approved drug in a novel class of nitro-dihydro-imidazooxazoles developed for the treatment of multidrug-resistant tuberculosis. Patients with tuberculosis require treatment with multiple drugs, several of which have known drug-drug interactions. Transporters regulate drug absorption, distribution, and excretion; therefore, the inhibition of transport by one agent may alter the pharmacokinetics of another, leading to unexpected adverse events. Therefore, it is important to understand how delamanid affects transport activity. In the present study, the potencies of delamanid and its main metabolites as the substrates and inhibitors of various transporters were evaluated in vitro Delamanid was not transported by the efflux ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp; MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), solute carrier (SLC) transporters, organic anion-transporting polypeptides, or organic cation transporter 1. Similarly, metabolite 1 (M1) was not a substrate for any of these transporters except P-gp. Delamanid showed no inhibitory effect on ABC transporters MDR1, BCRP, and bile salt export pump (BSEP; ABCB11), SLC transporters, or organic anion transporters. M1 and M2 inhibited P-gp- and BCRP-mediated transport but did so only at the 50% inhibitory concentrations (M1, 4.65 and 5.71 µmol/liter, respectively; M2, 7.80 and 6.02 µmol/liter, respectively), well above the corresponding maximum concentration in plasma values observed following the administration of multiple doses in clinical trials. M3 and M4 did not affect the activities of any of the transporters tested. These in vitro data suggest that delamanid is unlikely to have clinically relevant interactions with drugs for which absorption and disposition are mediated by this group of transporters.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , ATP-Binding Cassette Transporters/metabolism , Antitubercular Agents/pharmacology , Neoplasm Proteins/metabolism , Nitroimidazoles/pharmacology , Organic Anion Transporters/metabolism , Oxazoles/pharmacology , Solute Carrier Proteins/metabolism , Tuberculosis, Multidrug-Resistant/drug therapy , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 11 , Animals , Biological Transport, Active/drug effects , Cell Line , Drug Interactions/physiology , HEK293 Cells , Humans , Kidney Tubules, Proximal/cytology , Nitroimidazoles/metabolism , Octamer Transcription Factor-1/metabolism , Oxazoles/metabolism , SwineABSTRACT
The antidiabetic drugs glibenclamide, repaglinide, and nateglinide are well-known substrates for hepatic uptake transporters of the organic anion transporting polypeptide (OATP) family and metabolizing enzymes of the cytochrome P450 (CYP) 2C subfamily. The systemic exposure of these drugs varies substantially among individuals, impacted by genetic polymorphisms of transporters and metabolizing enzymes as well as drug-drug interactions. The use of the conventional in vitro-in vivo extrapolation (IVIVE) method was found to underestimate their hepatic intrinsic clearance (CLint,all); the clinically observed CLint,all values were ≥10-fold higher than the predicted values from in vitro data. In order to improve the accuracy in predicting CLint,all of these drugs, the following modifications were implemented; i) the extended clearance concept was applied during IVIVE processes, ii) albumin was added to metabolic assays using human liver microsomes (to minimize the impact of intrinsic inhibitors on kinetic parameters for CYP2C-mediated metabolism) and to hepatic uptake assays (to accommodate the enhanced hepatic uptake observed with albumin-bound drugs), and iii) differing rates of efflux and influx via diffusion were used. The IVIVE method with these modifications yielded the predicted CLint,all values from in vitro data in closer agreement with the CLint,all values observed in vivo; the fold differences between the predicted and observed CLint,all values reduced from 13-15 to 5.9-6.7. Our current approach offers an improvement in the prediction of CLint,all and further investigations are warranted to enhance the prediction accuracy of IVIVE.
Subject(s)
Albumins/metabolism , Cytochrome P-450 Enzyme System/metabolism , Hypoglycemic Agents/pharmacokinetics , Liver-Specific Organic Anion Transporter 1/metabolism , Liver/metabolism , Models, Biological , Carbamates/pharmacokinetics , Glyburide/pharmacokinetics , HEK293 Cells , Hepatocytes/metabolism , Humans , Liver-Specific Organic Anion Transporter 1/genetics , Metabolic Clearance Rate , Microsomes, Liver/metabolism , Nateglinide/pharmacokinetics , Piperidines/pharmacokinetics , Solute Carrier Organic Anion Transporter Family Member 1B3/genetics , Solute Carrier Organic Anion Transporter Family Member 1B3/metabolismABSTRACT
This study aimed to construct a physiologically based pharmacokinetic (PBPK) model of rifampicin that can accurately and quantitatively predict complex drug-drug interactions (DDIs) involving its saturable hepatic uptake and auto-induction. Using in silico and in vitro parameters, and reported clinical pharmacokinetic data, rifampicin PBPK model was built and relevant parameters for saturable hepatic uptake and UDP-glucuronosyltransferase (UGT) auto-induction were optimized by fitting. The parameters for cytochrome P450 (CYP) 3A and CYP2C9 induction by rifampicin were similarly optimized using clinical DDI data with midazolam and tolbutamide as probe substrates, respectively. For validation, our current PBPK model was applied to simulate complex DDIs with glibenclamide (a substrate of CYP3A/2C9 and hepatic organic anion transporting polypeptides (OATPs)). Simulated results were in quite good accordance with the observed data. Altogether, our constructed PBPK model of rifampicin demonstrates the robustness and utility in quantitatively predicting CYP3A/2C9 induction-mediated and/or OATP inhibition-mediated DDIs with victim drugs.
Subject(s)
Cytochrome P-450 CYP2C9/metabolism , Cytochrome P-450 CYP3A/metabolism , Rifampin/pharmacokinetics , Computer Simulation , Drug Interactions , Enzyme Induction/drug effects , Glucuronosyltransferase/metabolism , Glyburide/pharmacokinetics , Glyburide/pharmacology , Humans , Models, Biological , Rifampin/pharmacologyABSTRACT
Hyperlactate production is related to disorders of the large intestine such as inflammatory bowel diseases. Lactate, an intermediate in hindgut fermentation, is metabolized to SCFA. Megasphaera elsdenii can convert lactate to butyrate, a physiologically important organic acid for the hindgut mucosa. This experiment was conducted to determine whether M. elsdenii normalizes hyperlactate production and stimulates butyrate production in the rat large intestine. Specific pathogen-free Sprague-Dawley male rats (n = 12) were fed a fructooligosaccharide (FOS)-supplemented (100 g/kg), semipurified diet to induce lactate production. Lactate excretion in all rats was >30 mmol/kg fresh feces on d 2 of FOS-feeding. The rats were divided into two groups on the morning of d 4. One group (n = 5) was dosed orally with M. elsdenii JCM1772T (1.3 x 10(13) cells) for 3 d. The other group was treated with a vehicle solution. Fecal lactate was significantly lower in rats administered M. elsdenii than in controls. An increase in fecal butyrate compensated for the decrease in lactate. The number of cecal epithelial cells was greater in rats administered M. elsdenii than in controls. M. elsdenii has the potential to normalize hyperlactate accumulation in the large intestine, and lactate-utilizing butyrate producers may be useful probiotics when hyperlactate fermentation in the large intestine is a problem.