Hisakazu Ohtani

Bottom-up modeling and simulation of tacrolimus clearance: prospective investigation of blood cell distribution, sex and CYP3A5 expression as covariates and assessment of study power

The objectives were to investigate the ability of population‐based in vitro–in vivo extrapolation (IVIVE) to reproduce the influence of haematocrit on the clearance of tacrolimus, observed previously, and to assess the power of clinical studies to detect the effects of covariates on the clearance of tacrolimus.

Characterization of transplacental transfer of paroxetine in perfused human placenta: development of a pharmacokinetic model to evaluate tapered dosing.

The aim of this study was to determine whether a tapered dosage regimen of paroxetine in pregnant women might be useful to avoid withdrawal syndromes in neonates after delivery. We characterized the transplacental transfer of paroxetine in perfused human placenta, fitting a pharmacokinetic model to the results and applying the model and parameters to evaluate a tapered dosage regimen. Paroxetine was perfused from the maternal or fetal side of an isolated human placental preparation with various perfusion protocols, and paroxetine concentrations in the effluent and placental tissue were determined. The transplacental pharmacokinetic parameters of paroxetine were estimated by simultaneous fitting of a five-compartment transplacental pharmacokinetic model to the set of paroxetine concentration profiles. The developed model and parameters were used to simulate the maternal and fetal concentrations of paroxetine, and the results were compared with reported data. Paroxetine showed a larger distribution volume in placental tissue and a smaller transplacental transfer as compared with antipyrine, a passive diffusion marker. A five-compartment model could well describe the transplacental transfer of paroxetine and could well simulate the maternal and umbilical venous concentrations of paroxetine at delivery. Transplacental transfer kinetic parameters of paroxetine were estimated by fitting a pharmacokinetic model to perfusion study data. The model and parameters appeared to be suitable for simulation of paroxetine kinetics in fetus. The model was also applicable to design a dosage regimen to avoid an abrupt decrease of paroxetine concentration in fetal plasma.

Prediction of the extent and variation of grapefruit juice-drug interactions from the pharmacokinetic profile in the absence of grapefruit juice

The aim of this study was to develop a method for predicting the extent of grapefruit juice (GFJ)–drug interactions and their interindividual variations from the pharmacokinetic profile in the absence of GFJ. The pharmacokinetic profiles of 13 drugs after intravenous and oral administration were used to develop and validate the method. For each drug, the proportion absorbed into the intestine and the intestinal availability (Fg) were calculated from clinical data taken from the literature. Then, the AUC ratio (the ratio of the AUC with GFJ to that without GFJ) was predicted by assuming that Fg was 1.0 when GFJ was concomitantly ingested. According to the developed method, the AUC ratio of felodipine was 2.50 and its coefficient of variation (CV) was 45%, which agreed well with the observed AUC ratio of 2.48 and CV of 51%. Although the developed method overestimated the AUC ratios of some drugs such as nisoldipine, no underestimation occurred. The predicted CV values were consistent with those observed. The developed method might be useful to predict the AUC ratio, along with its interindividual variation, from the pharmacokinetic profile in the absence of grapefruit juice. Copyright

Food intake attenuates the drug interaction between new quinolones and aluminum

BackgroundIntestinal absorption of new quinolones is decreased by oral administration of polyvalent metal cations. Some clinical studies have demonstrated this drug - drug interaction is more prominent under fasted condition. However, the effect of food intake on the extent of drug - drug interaction between new quinolones and metal cations remains to be investigated quantitatively and systematically. The aim of this study was to develop an animal model that enables to evaluate the effect of food intake on the extent of drug - drug interaction in the gastrointestinal tract by chelation and to apply the model to evaluate quantitatively the effect of food intake on the drug - drug interaction between two new quinolones, ofloxacin or ciprofloxacin and sucralfate.MethodsThe rats were orally administered new quinolones (5.3xa0mg/kg of ofloxacin or 10xa0mg/kg of ciprofloxacin) with or without 13.3xa0mg/kg of sucralfate under fasted or fed condition and plasma concentration profiles of new quinolones were monitored. To the fed group, standard breakfast used in human studies was pasted and administered at a dose of 8.8xa0g/kg.ResultsThe area under the plasma concentration - time curves (AUC0–6) of ofloxacin and ciprofloxacin under the fasted condition were significantly decreased to 28.8 and 17.1% by co-administration of sucralfate, respectively. On the contrary, sucralfate moderately decreased the AUC0–6 of ofloxacin and ciprofloxacin to 54.9 and 33.2%, respectively, under fed condition. The effects of sucralfate and food intake on the kinetics of ofloxacin in this study were well consistent with the results of previous clinical trial.ConclusionsThe developed animal model quantitatively reproduced the effect of food intake on the drug - drug interaction between ofloxacin and sucralfate. The similar influences were observed for the drug - drug interaction between ciprofloxacin and sucralfate, suggesting that the extent of drug - drug interaction caused by chelation is generally attenuated by food intake.

The extent of drug-drug interaction between amlodipine and activated charcoal is attenuated by food intake in rats

Activated charcoal decreases gastrointestinal absorption of concomitantly administered drugs. The absorption of amlodipine (AML) was reported as almost completely attenuated by 25xa0g of activated charcoal under a fasted condition, but not affected by 2xa0g of activated charcoal under a fed condition. However, it is not clear whether this difference resulted from the food intake or the dose of activated charcoal. The aim of this study was to quantitatively evaluate the effect of food intake on drug interactions caused by adsorption to activated charcoal in the gastrointestinal tract in rats. The rats were orally administered 0.08xa0mg/kg of AML, with or without 33xa0mg/kg of activated charcoal, under the fasted or fed condition and the plasma concentration profiles of AML were monitored. For the fed group, the standard breakfast used in clinical studies was smashed and administered at a dose of 11xa0g/kg. The AUC value of AML under the fasted condition was significantly decreased to 24.8% by coadministration of activated charcoal. On the other hand, activated charcoal moderately decreased the AUC value of AML to 74.8% under the fed condition. These results suggest that the extent of drug interactions caused by activated charcoal is attenuated by food intake.

Development and evaluation of an overseas clinical rotation program for undergraduate pharmacy students in Japan

BACKGROUND AND PURPOSEnInternationalization of pharmacists, as well as pharmacy students, in terms of both the knowledge to care for international patients and to have medical information literacy, is a current concern in Japan.nnnEDUCATIONAL ACTIVITY AND SETTINGnKeio University Faculty of Pharmacy has developed an elective course for pharmacy students, based on written agreements with the United States and Thailand that establish a student clinical rotation exchange program. The exchange program lasts for four to six weeks and involves clinical rotations in hospitals abroad during the students sixth year. Rotations follow a four-week didactic preparatory course. The course objectives are to acquire the knowledge, skills, and attitude needed to function as leading pharmacists with an international perspective.nnnMETHODSnWe asked students to complete a feedback survey inquiring about the usefulness of preparatory courses, self-evaluation pre- and post-rotation satisfaction with the program, and overall self-assessment.nnnFINDINGSnTwenty-fourxa0out ofxa041, i.e., 58.5% of the students replied with feedback. All respondents replied that the preparatory course was useful. They also replied that, based on their self-evaluation, they were satisfied with their level of English language skill improvement after the rotation. Pharmaceutical knowledge satisfaction, however, was slightly decreased. All respondents replied that this program was of a satisfactory nature, with 71%, 63%, and 92% of the respondents replying that they could acquire the knowledge, skills, and attitude program objectives respectively.nnnSUMMARYnIt is possible to successfully develop an overseas clinical rotation program. Students were quite satisfied upon completion and achieved the expected objectives.

Inactivation kinetics and residual activity of CYP3A4 after treatment with erythromycin

This study aimed to characterize the inactivation kinetics of cytochrome P450 3A4 (CYP3A4) by erythromycin, which involves mechanism‐based inhibition (MBI), in detail. In addition to an MBI assay based on the conventional method in which erythromycin and recombinant CYP3A4 were pre‐incubated for 15 min, the study also evaluated the long‐term MBI kinetics of this reaction by pre‐incubation for 120 min. Mechanism‐based inhibition profiles were obtained using three typical substrates, testosterone, midazolam and nifedipine. In the long‐term assay, erythromycin evoked a time‐dependent biphasic reduction in enzyme activity, but some residual activity (α) was detected in the terminal phase. The inactivation rate constant obtained in the presence of 30 μm erythromycin using nifedipine as a substrate was 1.44‐fold higher than that acquired using testosterone, while there was no difference among the α values obtained with the three substrates. In the short‐term assay, time‐dependent monophasic inactivation was observed. To extrapolate these data to in vivo, the extent of the increase in the area under the curve (AUC ratio) induced by erythromycin was estimated from the results of the conventional short‐term experiment and the long‐term experiment examining residual activity. The AUC ratio estimated from the long‐term kinetics (2.92) was closer to the clinically reported values (3.3–4.42). In conclusion, the relatively long‐term evaluation of the kinetics of CYP3A4 inactivation revealed that the enzyme was not fully inactivated by erythromycin. To improve the estimation of the extent of the drug–drug interactions induced by MBI from in vitro data, longer‐term investigations of the target enzymes inactivation profile might be necessary.

Analysis of the Mechanism of Prolonged Persistence of Drug Interaction between Terbinafine and Amitriptyline or Nortriptyline

The purpose of the study was to quantitatively estimate and predict drug interactions between terbinafine and tricyclic antidepressants (TCAs), amitriptyline or nortriptyline, based on in vitro studies. Inhibition of TCA-metabolizing activity by terbinafine was investigated using human liver microsomes. Based on the unbound Ki values obtained in vitro and reported pharmacokinetic parameters, a pharmacokinetic model of drug interaction was fitted to the reported plasma concentration profiles of TCAs administered concomitantly with terbinafine to obtain the drug-drug interaction parameters. Then, the model was used to predict nortriptyline plasma concentration with concomitant administration of terbinafine and changes of area under the curve (AUC) of nortriptyline after cessation of terbinafine. The CYP2D6 inhibitory potency of terbinafine was unaffected by preincubation, so the inhibition seems to be reversible. Terbinafine competitively inhibited amitriptyline or nortriptyline E-10-hydroxylation, with unbound Ki values of 13.7 and 12.4u2009nM, respectively. Observed plasma concentrations of TCAs administered concomitantly with terbinafine were successfully simulated with the drug interaction model using the in vitro parameters. Model-predicted nortriptyline plasma concentration after concomitant nortriptylene/terbinafine administration for two weeks exceeded the toxic level, and drug interaction was predicted to be prolonged; the AUC of nortriptyline was predicted to be increased by 2.5- or 2.0- and 1.5-fold at 0, 3 and 6 months after cessation of terbinafine, respectively. The developed model enables us to quantitatively predict the prolonged drug interaction between terbinafine and TCAs. The model should be helpful for clinical management of terbinafine-CYP2D6 substrate drug interactions, which are difficult to predict due to their time-dependency.

Current status of illegal trade in pharmaceutical products on Internet auction sites in Japan and responses of site administrators to such transactions

In Japan, it is illegal to sell pharmaceuticals on Internet auction sites, although a considerable number of pharmaceuticals are listed on such sites. We investigated the current situation regarding the illegal trade in pharmaceuticals on Japanese Internet auction sites and the responses of site administrators to such transactions. We searched for pharmaceuticals and gray items that were suspected of being pharmaceuticals on Yahoo-oku! (Yahoo! Auctions, Japan) over a 37-day period and then submitted violation reports indicating that selling pharmaceuticals is illegal or that the description of an item was insufficient. The reports were directed to the site administrators and forwarded to the sellers. One hundred and six pharmaceutical products and 34 gray items were identified during the study period. After the submission of the violation reports, only 28 of the pharmaceutical products and one of the gray items were deleted by the administrator, while 18 of the pharmaceutical products and 7 of the gray items were withdrawn by their sellers. However, 41 pharmaceuticals and 20 gray items were sold. Most of the gray items were listed using characteristic terms or abbreviations without photographic images. More than 70% of the identified pharmaceuticals had a contraindication(s) other than hypersensitivity. In conclusion, the illegal trade in pharmaceuticals on Internet auction sites remains a serious problem in Japan, and the responses of site administrators to such transactions are inadequate. The government and pharmaceutical industry may have to take measures such as providing public and administrative guidance to stop the illegal trade in pharmaceuticals on the Internet.

Variation in the inhibitory potency of terbinafine among genetic variants of CYP2D6

Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic enzyme that is involved in the metabolism of many drugs. Terbinafine (TER) is a CYP2D6 inhibitor and causes persistent drug interactions in the clinical setting; however, its inhibitory mechanism and the differences in its inhibitory potency among genetic variants of CYP2D6 remain to be investigated. This study aimed to investigate the inhibitory mechanism of TER and the differences in its inhibitory potency among three CYP2D6 variants, CYP2D6.1, CYP2D6.2, and CYP2D6.10. In a competitive inhibition study, the metabolic activity of the CYP2D6 was assessed based on their demethylation of dextromethorphan in the presence or absence of TER, and the time-dependency of the inhibitory effects were examined by preincubating the enzymes with TER. TER had weaker inhibitory effects on CYP2D6.2 and CYP2D6.10 than on CYP2D6.1; i.e., TER exhibited Ki values (the concentration of inhibitor that results in half-maximal inhibition) of 0.0525, 0.355, and 1.85xa0μM for CYP2D6.1, CYP2D6.2, and CYP2D6.10, respectively. The inhibitory effects of TER were not time-dependent. Since TERs Ki value for CYP2D6.10 was 35.2-fold higher than its Ki value for CYP2D6.1, the CYP2D6 genotype of subjects should be taken into account when estimating the severity of drug interactions involving TER.