ABSTRACT
BACKGROUND: Recent US Food and Drug Administration (FDA) draft guidance on pharmacokinetic drugdrug interactions (DDIs) has highlighted the clinical importance of ABC transporters B1 or P-glycoprotein (P-gp), hepatic organic anion-transporting polypeptide transporters and breast cancer resistant protein because of their broad substrate specificity and the potential to be involved in DDIs. This guidance has indicated that digoxin, dabigatran etexilate and fexofenadine are P-gp substrate drugs and has defined P-gp inhibitors as those that increase the AUC of digoxin by â§1.25-fold in clinical DDI studies. However, when substrate drugs of both CYPs and P-gp are involved in DDIs, it remains that the mechanisms of DDIs will be quite ambiguous in assessing how much the CYPs and/or drug transporters partially contribute to DDIs. OBJECTIVE: Since there are no detailed manuscripts that summarizes P-gp interactions unrelated to CYP metabolism, this article reviews the effects of potent P-gp inhibitors and P-gp inducers on the pharmacokinetics of P-gp substrate drugs, including digoxin, talinolol, dabigatran etexilate, and fexofenadine in human studies. In addition, the present outcome were to determine the PK changes caused by DDIs among P-gp substrate drugs without CYP metabolism in human DDI studies. CONCLUSION: Our manuscript concludes that the PK changes of the DDIs among P-gp drugs unrelated to CYP metabolism are less likely to be serious, and it appears to be convincing that the absences of clinical effects caused to the PK changes by the P-gp inducers is predominant compared with the excessive effects caused to those by the P-gp inhibitors.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Dabigatran/pharmacokinetics , Digoxin/pharmacokinetics , Propanolamines/pharmacokinetics , Terfenadine/analogs & derivatives , Animals , Cytochrome P-450 Enzyme System/metabolism , Drug Interactions , Humans , Terfenadine/pharmacokineticsABSTRACT
Background This study developed a novel high-performance liquid chromatography (HPLC) method for the simultaneous quantification of clozapine and its active metabolite, N-desmethylclozapine, in human plasma and investigated the effects of various factors, including genetic polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A5, ABCB1 and ABCG2, on the steady-state plasma trough concentrations (C0) of clozapine and N-desmethylclozapine in Japanese patients with schizophrenia. Methods Forty-five patients had been receiving fixed doses of clozapine for at least four weeks. The CYP2D6 ( CYP2D6*2, CYP2D6*5, CYP2D6*10), CYP3A5 ( CYP3A5*3), ABCB1 (1236C > T, 2677G > T/A, 3435C > T) and ABCG2 (421 C > A) genotypes were identified by polymerase chain reaction. Results The within- and between-day coefficients of variation (CV) were less than 11.0%, and accuracy was within 9.0% over the linear range from 10 to 2500 ng/mL for both analytes, and their LOQs were each 10 ng/mL. The median C0/dose (C0/D) ratios of clozapine were significantly higher in patients with the ABCG2 421 A allele than in those with the 421 C/C genotype ( P = 0.010). However, there were no significant differences in C0/D ratios of clozapine and N-desmethylclozapine among ABCB1, CYP2D6 or CYP3A5 genotypes. In multiple regression analysis, including polymorphisms, age, body weight and biochemical data of patients, the ABCG2 polymorphism alone was correlated with the C0/D ratios of clozapine ( R2 = 0.139, P = 0.016). Conclusions Among the various CYPs and drug transporters, BCRP appeared to most strongly influence clozapine exposure. Knowledge of the patient's ABCG2 421 C > A genotype before initiating therapy may be useful when making dosing decisions aimed at achieving optimal clozapine exposure.
Subject(s)
ATP-Binding Cassette Transporters/genetics , Blood Chemical Analysis/methods , Clozapine/analogs & derivatives , Clozapine/blood , Cytochrome P-450 Enzyme System/genetics , Polymorphism, Genetic , Schizophrenia/blood , Adolescent , Adult , Aged , Chromatography, High Pressure Liquid , Clozapine/pharmacokinetics , Female , Genotype , Humans , Japan , Male , Middle Aged , Schizophrenia/genetics , Schizophrenia/metabolism , Young AdultABSTRACT
The stereoselective pharmacokinetics of fexofenadine are associated with OATP2B1-mediated transport, and grapefruit juice (GFJ) is an inhibitor of OATP2B1. Therefore, in this study, we aimed to investigate whether and to what extent GFJ ingestion affected the pharmacokinetics of fexofenadine enantiomers in healthy subjects. In a randomized, two-phase, open-label, crossover study, 14 subjects received 60 mg of racemic fexofenadine simultaneously with water or GFJ. Ingestion of GFJ significantly decreased the areas under the plasma concentration-time curve (AUC0-24) for (R)- and (S)-fexofenadine by 39% and 52%, respectively. Subsequently, GFJ increased the mean R/S ratio of the AUC0-24 from 1.58 to 1.96 (P < 0.05). Although GFJ greatly reduced the amounts of (R)- and (S)-fexofenadine excreted into the urine (Ae0-24) by 52% and 61%, respectively, the mean R/S ratios of Ae0-24 and the renal clearances of both enantiomers were unchanged between the control and GFJ phases. GFJ, an OATP2B1 inhibitor, significantly reduced the plasma concentrations of fexofenadine enantiomers, exhibiting clinically moderate effects. The present results suggested that changes in OATP2B1 activity by GFJ may alter the stereoselective pharmacokinetics of fexofenadine and that reduced intestinal OATP2B1 activity may affect the stereoselectivity of fexofenadine.
Subject(s)
Anti-Allergic Agents/pharmacokinetics , Beverages , Citrus paradisi , Organic Anion Transporters/antagonists & inhibitors , Organic Anion Transporters/metabolism , Terfenadine/analogs & derivatives , Adult , Anti-Allergic Agents/chemistry , Area Under Curve , Cross-Over Studies , Female , Food-Drug Interactions , Humans , Male , Stereoisomerism , Terfenadine/chemistry , Terfenadine/pharmacokinetics , Young AdultABSTRACT
PURPOSE: We examined the effect of a single apple juice intake on the pharmacokinetics of fexofenadine enantiomers in healthy Japanese subjects. METHODS: In a randomized two phase, open-label crossover study, 14 subjects received 60 mg of racemic fexofenadine simultaneously with water or apple juice. For the uptake studies, oocytes expressing organic anion-transporting polypeptide 2B1 (OATP2B1) were incubated with 100 µM (R)- and (S)-fexofenadine in the presence or absence of 10 % apple juice. RESULTS: One-time ingestion of apple juice significantly decreased the area under the plasma concentration-time curve (AUC0-24) for (R)- and (S)-fexofenadine by 49 and 59 %, respectively, and prolonged the time to reach the maximum plasma concentration (t max) of both enantiomers (P < 0.001). Although apple juice greatly reduced the amount of (R)- and (S)-fexofenadine excretion into urine (Ae0-24) by 54 and 58 %, respectively, the renal clearances of both enantiomers were unchanged between the control and apple juice phases. For in vitro uptake studies, the uptake of both fexofenadine enantiomers into OATP2B1 complementary RNA (cRNA)-injected oocytes was significantly higher than that into water-injected oocytes, and this effect was greater for (R)-fexofenadine. In addition, apple juice significantly decreased the uptake of both enantiomers into OATP2B1 cRNA-injected oocytes. CONCLUSIONS: These results suggest that OATP2B1 plays an important role in the stereoselective pharmacokinetics of fexofenadine and that one-time apple juice ingestion probably inhibits intestinal OATP2B1-mediated transport of both enantiomers. In addition, this study demonstrates that the OATP2B1 inhibition effect does not require repeated ingestion or a large volume of apple juice.
Subject(s)
Beverages , Food-Drug Interactions , Fruit , Malus , Organic Anion Transporters/metabolism , Terfenadine/analogs & derivatives , Adult , Animals , Anti-Allergic Agents/blood , Anti-Allergic Agents/chemistry , Anti-Allergic Agents/pharmacokinetics , Anti-Allergic Agents/urine , Area Under Curve , Cross-Over Studies , Eating , Female , Histamine H1 Antagonists, Non-Sedating/blood , Histamine H1 Antagonists, Non-Sedating/chemistry , Histamine H1 Antagonists, Non-Sedating/pharmacokinetics , Histamine H1 Antagonists, Non-Sedating/urine , Humans , Intestinal Absorption , Male , Oocytes/metabolism , Organic Anion Transporters/genetics , RNA, Complementary/genetics , Stereoisomerism , Terfenadine/blood , Terfenadine/chemistry , Terfenadine/pharmacokinetics , Terfenadine/urine , Xenopus laevis , Young AdultABSTRACT
INTRODUCTION: Effectiveness and safety of warfarin therapy for non-valvular atrial fibrillation (NVAF) patients are strongly associated with its stability presented such as time in therapeutic range (TTR) of PT-INR. However, the factors that affect TTR have not been fully elucidated in Japan where majority of patients are controlled within the range of 1.6-2.6 of PT-INR irrespective of the age. METHODS: We retrospectively analyzed 163 NVAF patients taking warfarin to determine the factors that affect TTR including metabolic enzymes polymorphisms after TTR calculation with both the standard PT-INR range and the actual control range of 1.6-2.6. RESULTS: Overall TTR calculated using Japanese Guideline was 69.7 ± 25.1% (<70 and ≥ 70 years; 49.6 ± 24.8% and 77.8 ± 20.3%, respectively). After confirming that PT-INR values in patients < 70 years distributed in the same range as in those ≥ 70 years, as in a Japanese large cohort, we recalculated TTR of those < 70 years with 1.6-2.6 of PT-INR and found that it was 79.5 ± 20.1%. Poor control of this new TTR were significantly associated with the lower height, the higher serum creatinine, the lower creatinine clearance, female gender, and presence of congestive heart failure, (p<0.05 respectively). Multivariate analysis revealed female gender and presence of congestive heart failure as independent predictor of the lower TTR (p<0.05, p<0.01, respectively). Polymorphism of CYP2C9 and VKORC1 were related to the dosage of warfarin but not determinant of TTR. CONCLUSIONS: When evaluated using a range of PT-INR actually used in Japan, TTR is generally well controlled and female gender and presence of congestive heart failure significantly affected the poorer TTR control.
Subject(s)
Anticoagulants/therapeutic use , Atrial Fibrillation/drug therapy , Warfarin/therapeutic use , Aged , Aged, 80 and over , Anticoagulants/administration & dosage , Aryl Hydrocarbon Hydroxylases/genetics , Asian People/genetics , Atrial Fibrillation/genetics , Cytochrome P-450 CYP2C9 , Drug Monitoring , Female , Humans , International Normalized Ratio , Japan , Male , Middle Aged , Polymorphism, Genetic , Retrospective Studies , Vitamin K Epoxide Reductases/genetics , Warfarin/administration & dosageABSTRACT
Fixed drug eruption is a common cutaneous adverse reaction in young patients with a characteristic clinical appearance. However, the diagnosis and identification of the substance may be difficult if food or food additives provoke the fixed eruption. A 26-year-old man had a history of two episodes of cutaneous erythema with residual pigmentation. Close examination of the history including his diet in addition to an oral challenge test and patch testing led to the diagnosis of fixed eruption secondary to quinine in tonic water. We examined for the presence of quinine in commercially available brands of tonic water using ultraviolet A and irradiation and high-performance liquid chromatography. Both Schweppes and CANADA DRY brands of tonic water emitted fluorescent light upon ultraviolet A irradiation, and contained quinine at concentrations of 67.9 and 61.3 mg/L, respectively. Quinine contained in some tonic waters may trigger fixed eruption.
Subject(s)
Carbonated Beverages/analysis , Drug Eruptions/etiology , Muscle Relaxants, Central/adverse effects , Quinine/adverse effects , Adult , Humans , Male , Muscle Relaxants, Central/analysis , Quinine/analysisABSTRACT
PURPOSE: Omeprazole has (R)- and (S)-enantiomers, which exhibit different pharmacokinetics (PK) among patients with cytochrome P450 (CYP) 2C19 genotype groups. The aim of this study was to investigate whether the 1-point, 4-h postdose (R)-omeprazole hydroxylation index (HI) of racemic omeprazole reflects the three CYP2C19 genotype groups in Japanese individuals. METHODS: Ninety healthy Japanese individuals were enrolled and classified into the three different CYP2C19 genotype groups: homozygous extensive metabolizers (hmEMs; n = 34), heterozygous EMs (htEMs; n = 44), and poor metabolizers (PMs; n = 12). Blood samples were drawn 4 h after the intake of an oral dose of omeprazole 40 mg, and plasma levels of omeprazole and its metabolites were analyzed by high-performance liquid chromatography (HPLC) using a chiral column. RESULTS: Mean plasma concentrations of (R)- and (S)-omeprazole in PMs were significantly higher than those in hmEMs and htEMs, and similar results were obtained in the case of omeprazole sulfone. Additionally, there was a significant difference in plasma concentrations of (R)-5-hydroxyomeprazole among CYP2C19 genotype groups, whereas no significant differences were observed in that of (S)-5-hydroxyomeprazole. Similarly, (R)-omeprazole HI in hmEMs, htEMs, and PMs were 5.6, 3.1, and 0.3, respectively, which were significantly different, but no significant difference was present in the (S)-omeprazole HI. CONCLUSION: Our findings demonstrate that (R)-omeprazole HI correlated better with CYP2C19 genotype groups than racemic-omeprazole HI, and these results may be useful for classification among patients in CYP2C19 genotype groups prior to omeprazole treatment.
Subject(s)
Anti-Ulcer Agents/pharmacokinetics , Aryl Hydrocarbon Hydroxylases/genetics , Drug Monitoring/methods , Omeprazole/pharmacokinetics , Polymorphism, Genetic , Proton Pump Inhibitors/pharmacokinetics , Alleles , Anti-Ulcer Agents/blood , Anti-Ulcer Agents/chemistry , Aryl Hydrocarbon Hydroxylases/metabolism , Chromatography, High Pressure Liquid , Cytochrome P-450 CYP2C19 , Exons , Genetic Association Studies , Humans , Hydroxylation , Japan , Metabolic Detoxication, Phase I , Omeprazole/analogs & derivatives , Omeprazole/blood , Omeprazole/chemistry , Pilot Projects , Proton Pump Inhibitors/blood , Proton Pump Inhibitors/chemistry , StereoisomerismABSTRACT
The effect of rifampicin on the pharmacokinetics of fexofenadine enantiomers was examined in healthy subjects who received fexofenadine alone or with single or multiple doses of rifampicin (600 mg). A single coadministered dose of rifampicin significantly decreased the oral clearance (CL(tot)/F) and renal clearance (CL(r)) of S- and R-fexofenadine by 76 and 62%, and 73 and 62%, respectively. Even after multiple doses, rifampicin significantly decreased these parameters, although the effect on the CL(tot)/F was slightly blunted. Multiple doses of rifampicin abolished the difference in the CL(tot)/F of fexofenadine enantiomers, whereas the stereoselectivity in the CL(r) persisted. Rifampicin inhibited the uptake of fexofenadine enantiomers by human hepatocytes via organic anion transporter (OAT) OATP1B3 and its basal-to-apical transport in Caco-2 cells, but not OAT3-mediated or multidrug and toxic compound extrusion 1 (MATE1)-mediated transport. The plasma-unbound fraction of S-fexofenadine was 1.8 times higher than that of R-fexofenadine. The rifampicin-sensitive uptake by hepatocytes was 1.6 times higher for R-fexofenadine, whereas the transport activities by OATP1B3, OAT3, MATE1, or P-glycoprotein were identical for both enantiomers. S-fexofenadine is a more potent human histamine H1 receptor antagonist than R-fexofenadine. In conclusion, rifampicin has multiple interaction sites with fexofenadine, all of which contribute to increasing the area under the curve of fexofenadine when they are given simultaneously, to surpass the effect of the induction of P-glycoprotein elicited by multiple doses.
Subject(s)
Histamine H1 Antagonists, Non-Sedating/pharmacokinetics , Rifampin/pharmacology , Terfenadine/analogs & derivatives , Adult , Aged , Female , Humans , Male , Middle Aged , Organic Anion Transporters, Sodium-Independent/metabolism , Organic Cation Transport Proteins/metabolism , Reference Values , Rifampin/administration & dosage , Terfenadine/pharmacokinetics , Young AdultSubject(s)
Antiviral Agents/therapeutic use , Epidemics/prevention & control , Influenza, Human/prevention & control , Zanamivir/analogs & derivatives , Administration, Inhalation , Antiviral Agents/administration & dosage , Guanidines , Humans , Influenza A Virus, H1N1 Subtype/drug effects , Influenza, Human/epidemiology , Japan/epidemiology , Neuraminidase/antagonists & inhibitors , Pyrans , Sialic Acids , Zanamivir/administration & dosage , Zanamivir/therapeutic useABSTRACT
Am80, a synthetic retinoid, has been used in differentiation therapy for acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA) as one of natural retinoid has been also used to treat APL. ATRA treatment causes neuronal differentiation by inducing tropomyosin-related kinase B (TrkB) expression and increasing the sensitivity to brain-derived neurotrophic factor (BDNF), a TrkB ligand. In the present study, we investigated the effects of Am80 on neuronal differentiation, BDNF sensitivity and TrkB expression in human neuroblastoma SH-SY5Y cells. Treatment with Am80 induced morphological differentiation of neurite outgrowth and increased the expression of GAP43 mRNA, a neuronal differentiation marker. Additionally, TrkB protein was also increased, and exogenous BDNF stimulation after treatment with Am80 induced greater neurite outgrowth than without BDNF treatment. These results suggest that Am80 induced neuronal differentiation by increasing TrkB expression and BDNF sensitivity.
Subject(s)
Benzoates/pharmacology , Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Neoplasm Proteins/metabolism , Neuroblastoma/enzymology , Receptor, trkB/biosynthesis , Tetrahydronaphthalenes/pharmacology , Brain-Derived Neurotrophic Factor/metabolism , Cell Differentiation/drug effects , Cell Line, Tumor , GAP-43 Protein/biosynthesis , Humans , Neurites/enzymology , Neuroblastoma/pathologyABSTRACT
Multidrug resistance P-glycoprotein (P-gp; also known as MDR1 and ABCB1) is expressed in the luminal membrane of the small intestine and blood-brain barrier, and the apical membranes of excretory cells such as hepatocytes and kidney proximal tubule epithelia. P-gp regulates the absorption and elimination of a wide range of compounds, such as digoxin, paclitaxel, HIV protease inhibitors and psychotropic drugs. Its substrate specificity is as broad as that of cytochrome P450 (CYP) 3A4, which encompasses up to 50 % of the currently marketed drugs. There has been considerable interest in variations in the ABCB1 gene as predictors of the pharmacokinetics and/or treatment outcomes of several drug classes, including antidepressants and antipsychotics. Moreover, P-gp-mediated transport activity is saturable, and is subject to modulation by inhibition and induction, which can affect the pharmacokinetics, efficacy or safety of P-gp substrates. In addition, many of the P-gp substrates overlap with CYP3A4 substrates, and several psychotropic drugs that are P-gp substrates are also CYP3A4 substrates. Therefore, psychotropic drugs that are P-gp substrates may cause a drug interaction when P-gp inhibitors and inducers are coadministered, or when psychotropic drugs or other medicines that are P-gp substrates are added to a prescription. Hence, it is clinically important to accumulate data about drug interactions through studies on P-gp, in addition to CYP3A4, to assist in the selection of appropriate psychotropic medications and in avoiding inappropriate combinations of therapeutic agents. There is currently insufficient information available on the psychotropic drug interactions related to P-gp, and therefore we summarize the recent clinical data in this review.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Cytochrome P-450 CYP3A/metabolism , Psychotropic Drugs/adverse effects , Psychotropic Drugs/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Animals , Biological Transport , Cytochrome P-450 CYP3A Inhibitors , Drug Interactions , Humans , Psychotropic Drugs/administration & dosage , Substrate SpecificityABSTRACT
Climatic conditions may have affected the incidence of influenza during the pandemic of 2009 as well as at other times. This study evaluated the effects of climatic conditions on influenza incidence in Okinawa, a subtropical region in Japan, during the 2009 pandemic using surveillance data from rapid antigen test (RAT) results. Weekly RAT results performed in four acute care hospitals in the Naha region of the Okinawa Islands from January 2007 to July 2011 were anonymously collected for surveillance of regional influenza prevalence. Intense epidemic peaks were noted in August 2009 and December 2009-January 2010 during the influenza pandemic of 2009. RAT positivity rates were lower during the pandemic period than during the pre- and post-pandemic periods. Lower ambient temperature was associated with higher influenza incidence during pre- and post-pandemic periods but not during the pandemic of 2009. Lower relative humidity was associated with higher influenza incidence during the pandemic as well as during the other two periods. The association of climatic conditions and influenza incidence was less prominent during the pandemic of 2009 than during pre- and post-pandemic periods.
Subject(s)
Climate , Epidemics , Influenza, Human/epidemiology , Population Surveillance , Antigens, Viral/immunology , Humans , Incidence , Influenza A Virus, H1N1 Subtype/immunology , Influenza B virus/immunology , Influenza, Human/diagnosis , Japan/epidemiologyABSTRACT
Diabetes mellitus (DM) is a risk factor of tuberculosis (TB). We studied the clinical presentation of pulmonary TB among patients with DM in comparison with patients without DM who were admitted into the hospital of the University of the Ryukyus from 2006 to 2010. The clinical data were collected from medical records retrospectively. Ten cases (25%) of hospitalized patients with pulmonary TB had DM. The DM group showed lower Body Mass Index and higher incidence of chronic heart failure and chronic renal failure. The DM group also were more likely to have cavitary lesion, had longer period of hospitalization, and higher mortality. Their causes of deaths were mainly the co-morbidities and associated complications. Further studies are warranted in order to fully elucidate the relationships between pulmonary TB and DM.
Subject(s)
Diabetes Complications , Tuberculosis, Pulmonary/complications , Adult , Aged , Female , Hospitalization , Hospitals, University , Humans , Inpatients , Male , Middle Aged , Retrospective StudiesABSTRACT
PURPOSE: To elucidate the stereoselective pharmacokinetics of omeprazole enantiomers and their metabolites after racemic IV dosing because there is little information about the stereoselective metabolism of omeprazole in in vivo study. METHODS: Seventeen subjects were classified into three CYP2C19 groups based on their genotypes: homozygous extensive metabolizers (hmEMs; n = 5), heterozygous EMs (htEMs; n = 7) and poor metabolizers (PMs; n = 5). RESULTS: After single IV administration of racemic omeprazole (20 mg), the mean area under the plasma concentration-time curve (AUC(0-∞)) of R(+)-omeprazole in PMs was significantly higher than that in hmEMs and htEMs, while that of S(-)-omeprazole was no significance among three genotypes because of a wide inter-individual variability. In addition, although the AUC(0-∞) of R(+)-5-hydroxyomeprazole were determined among three genotypes, the that of S(-)-5-hydroxyomeprazole was undetectable in the hmEMs and barely detectable in the htEMs. Conversly, the AUC(0-∞) of S(-)-5-hydroxyomeprazole was greater than that of R(+)-5-hydroxyomeprazole in the PMs. CONCLUSIONS: These data therefore suggest that, for EMs, the CYP2C19-mediated formation from R(+)-enantiomer is a 5-hydroxy-metabolite, while that from S(-)-enantiomer may be a minor metabolite. Thus, the in vivo disposition of S(-)- and R(+)-omeprazole after racemic dosing may be different among the CYP2C19 genotypes.
Subject(s)
Anti-Ulcer Agents/blood , Anti-Ulcer Agents/metabolism , Aryl Hydrocarbon Hydroxylases/genetics , Omeprazole/blood , Omeprazole/metabolism , Adult , Anti-Ulcer Agents/chemistry , Cytochrome P-450 CYP2C19 , Female , Genotype , Humans , Hydroxylation , Male , Omeprazole/chemistry , Stereoisomerism , Young AdultABSTRACT
Although the interaction between selective serotonin reuptake inhibitors (SSRIs) and other drugs is important in the treatment of depression, there have been few studies of SSRIs concerning transporter-mediated interactions in humans. The objective of this study was to evaluate the in vivo effects of commonly used SSRIs on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate.Twelve healthy volunteers (3 females and 9 males) were enrolled in this study. Each subject received a 60-mg dose of fexofenadine orally at baseline. Afterward, they were randomly assigned to receive 3 treatments with a 60-mg dose of fexofenadine after a 7-day treatment with fluvoxamine (50 mg/d), paroxetine (20 mg/d), or sertraline (50 mg/d), with 2-week intervals between the agents.Fluvoxamine pretreatment significantly increased the maximum plasma concentration, the area under the concentration time curves, and the 24-hour urinary fexofenadine excretion by 66% (P = 0.004), 78% (P = 0.029), and 78% (P < 0.001), respectively, without prolonging its elimination half-life. Paroxetine extended the elimination half-life of fexofenadine by 45% (P = 0.042), and it increased the 24-hour urinary fexofenadine excretion by 55% (P = 0.002). Sertraline did not alter any of the pharmacokinetic parameters of fexofenadine.This is the first report of the different effects of 3 commonly used SSRIs on fexofenadine pharmacokinetics in humans. Our 7-day, repeated-dose clinical study in healthy volunteers indicates that fluvoxamine and paroxetine, but not sertraline, may impact the patient exposure to fexofenadine, which is likely the result of P-glycoprotein inhibition in the small intestine and/or the liver.
Subject(s)
Fluvoxamine/pharmacology , Paroxetine/pharmacology , Sertraline/pharmacology , Terfenadine/analogs & derivatives , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Adolescent , Adult , Area Under Curve , Cross-Over Studies , Drug Interactions , Female , Half-Life , Humans , Intestine, Small/metabolism , Liver/metabolism , Male , Selective Serotonin Reuptake Inhibitors/pharmacology , Terfenadine/pharmacokinetics , Young AdultABSTRACT
AIM: This aim of this study was to characterize the impact of the P-glycoprotein (P-gp) inducer, carbamazepine, on fexofenadine enantiomer pharmacokinetics. METHODS: Twelve healthy volunteers initially received a 60mg dose of fexofenadine alone. Subsequently, a 100mg dose of carbamazepine was administered three times daily (300mg day(-1) ), and on day 7, fexofenadine was co-administered. RESULTS: Carbamazepine significantly decreased the area under the plasma concentration-time curve and the amount excreted into the urine of (S)- and (R)-fexofenadine. The P-gp inducer showed a greater effect on the pharmacokinetic parameters of (S)-fexofenadine. CONCLUSION: This study indicates that carbamazepine may alter the pharmacokinetics of fexofenadine enantiomers.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Anti-Allergic Agents/pharmacokinetics , Anticonvulsants/pharmacokinetics , Carbamazepine/pharmacokinetics , Terfenadine/analogs & derivatives , Adult , Area Under Curve , Asian People , Drug Interactions , Humans , Male , Stereoisomerism , Terfenadine/pharmacokinetics , Young AdultSubject(s)
Influenza A Virus, H1N1 Subtype/physiology , Influenza, Human/epidemiology , Pandemics , Adolescent , Adult , Age Distribution , Aged , Aged, 80 and over , Child , Child, Preschool , Critical Illness , Disease Outbreaks , Female , Humans , Infant , Influenza A Virus, H1N1 Subtype/isolation & purification , Influenza, Human/virology , Japan/epidemiology , Male , Middle Aged , Young AdultABSTRACT
Studies investigating the relationship between CYP2C19 genotype and the stereoselective metabolism of omeprazole have not been reported. In the present study, we developed a simple and sensitive analytical method based on column switching reversed phase high-performance liquid chromatography (HPLC) with UV detection to determine the concentrations of (R)- and (S)-omeprazole and of its principal metabolites, (R)- and (S)-5-hydroxyomeprazole, and the non-chiral, omeprazole sulfone, in human plasma. Sample preparation involved liquid-liquid extraction with diethyl ether:dichloromethane (60:40, v/v) followed by clean-up on a TSK BSA-ODS/S column (5 µm, 10 mm × 4.6mm i.d.) using phosphate buffer:acetonitrile (97:3, v/v, pH 6.4). After column switching, separation was performed on a Shiseido CD-ph chiral column (5 µm, 150 mm × 4.6mm i.d.) using phosphate buffer:methanol (45:55, v/v, pH 5.0) as mobile phase. The limit of quantitation (LOQ) was 5 ng/mL for all analytes with intra- and inter-day precisions (as coefficient of variation) of <9.5% and <9.6%, respectively for all analytes. The present method was successfully applied to a chiral pharmacokinetic study of omeprazole in human volunteers with different CYP2C19 genotypes. The results show that the formation of (R)-5-hydroxyomeprazole gives the best correlation with CYP2C19 genotype.
Subject(s)
Aryl Hydrocarbon Hydroxylases/genetics , Chromatography, High Pressure Liquid/methods , Omeprazole/blood , Omeprazole/metabolism , 2-Pyridinylmethylsulfinylbenzimidazoles/analysis , 2-Pyridinylmethylsulfinylbenzimidazoles/metabolism , Aryl Hydrocarbon Hydroxylases/metabolism , Cytochrome P-450 CYP2C19 , Genotype , Humans , Omeprazole/chemistry , Omeprazole/pharmacokinetics , Sensitivity and SpecificityABSTRACT
The prevalence of fluoroquinolone-resistant Streptococcus pneumoniae is increasing worldwide. In the present study, a comparison of drug sensitivity and genotypes of clinically isolated strains of levofloxacin (LVFX)-resistant S. pneumoniae obtained from Hong Kong, Okinawa Island and the Japanese main island (Honshu) was performed. MICs of quinolones (LVFX, tosufloxacin, ciprofloxacin, gatifloxacin and sitafloxacin (STFX)) and other antibiotics (penicillin G, cefcapene, cefditoren, clarithromycin and azithromycin) were determined by a microdilution broth method according to the Clinical and Laboratory Standards Institute Standards. The quinolone-resistance determining regions (QRDRs) of gyrA, gyrB, parC and parE of these strains were analyzed by PCR-based sequencing. All 40 strains tested had more than one amino-acid substitution in the QRDRs of gyrA, gyrB, parC or parE. Although there seemed to be some clonality in strains obtained from Hong Kong, there was no clonality in strains obtained from Okinawa and Japan. Strains obtained from Hong Kong, Okinawa Island and the Japanese main island were genetically different by pulsed-field gel electrophoresis analysis. The range of MIC values of STFX against isolates resistant to LVFX (MIC 4-32 mg l(-1)) was 0.12-0.5 mg l(-1), and MIC(80) values of STFX against LVFX-resistant isolates were 0.25 mg l(-1). This study suggests that LVFX-resistant S. pneumoniae is similar in all three locations and STFX is potent against LVFX-resistant S. pneumoniae with multiple mutations in QRDRs of gyrase A and topoisomerase IV.
Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial , Levofloxacin , Ofloxacin/pharmacology , Pneumococcal Infections/microbiology , Streptococcus pneumoniae/drug effects , Streptococcus pneumoniae/genetics , Bacterial Proteins/genetics , Cluster Analysis , DNA, Bacterial/chemistry , DNA, Bacterial/genetics , Electrophoresis, Gel, Pulsed-Field , Genes, Bacterial , Genotype , Hong Kong , Humans , Japan , Microbial Sensitivity Tests , Molecular Typing , Polymerase Chain Reaction , Sequence Analysis, DNA , Streptococcus pneumoniae/classification , Streptococcus pneumoniae/isolation & purificationABSTRACT
The CYP2D6*10(*10) allele that causes decreased CYP2D6 activity is present in Asians with a high frequency of approximately 50%. We studied the effects of the *10 allele on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole. The subjects were 63 Japanese patients with schizophrenia who had only the wild-type or *10 alleles. Twenty-seven patients were homozygous for the wild-type allele, 31 were heterozygous, and five were homozygous for the *10 allele. All patients had been receiving the fixed doses of aripiprazole for at least 2 weeks. The daily doses were 24 mg (n = 40) and 12 mg (n = 23). No other drugs except biperiden and flunitrazepam were coadministered. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection. The mean ± standard deviation values of concentration/dose ratios of aripiprazole in the patients with zero, one, and two *10 alleles were 9.0 ± 2.9, 12.7 ± 4.4, and 19.0 ± 6.8 ng/mL/mg, respectively, and those values for dehydroaripiprazole were 4.9 ± 1.6, 5.9 ± 1.7, and 5.9 ± 1.9 ng/mL/mg, respectively. The respective values for the sum of aripiprazole and dehydroaripiprazole were 13.9 ± 4.3, 18.6 ± 5.9, and 24.6 ± 8.5 ng/mL/mg. The mean concentration/dose ratios of aripiprazole were significantly (P < 0.01 or P < 0.001) different among the three genotype groups. The values for the sum of aripiprazole and dehydroaripiprazole were significantly higher in patients with one (P < 0.01) and two (P < 0.001) *10 alleles compared with those with zero *10 alleles. This study suggests that the *10 allele plays an important role in controlling the steady-state plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole in Asian subjects.