Yukinao Kohda

Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy

AIM To assess whether or not co-administration of proton pump inhibitors (PPIs) is a risk factor for delayed elimination of plasma methotrexate (MTX) in high-dose MTX (HDMTX) therapy for malignant diseases. METHODS To assess the effects of PPI co-administration on elimination of plasma MTX, we examined plasma MTX concentration data on 171 cycles of HDMTX therapy performed in 74 patients. We performed multiple logistic regression analysis to evaluate PPI co-administration as a risk factor. Inhibitory potencies of omeprazole, lansoprazole, rabeprazole and pantoprazole on MTX transport via breast cancer resistance protein (BCRP, ABCG2) were also investigated in an in vitro study using membrane vesicles expressing human BCRP. RESULTS We identified co-administration of PPIs as a risk factor for delayed elimination (odds ratio 2.65, 95% confidence interval 1.03, 6.82) as well as renal and liver dysfunction. All four PPIs inhibited BCRP-mediated transport of MTX, with half-maximal inhibitory concentrations of 5.5-17.6 microM--considerably higher than the unbound plasma concentrations of the PPIs. CONCLUSIONS Our results support previous findings suggesting that PPI co-administration is associated with delayed elimination of plasma MTX in patients with HDMTX therapy. This drug interaction, however, cannot be explained solely by the inhibitory effects of PPIs on BCRP-mediated MTX transport.

Controlled release of lidocaine hydrochloride from buccal mucosa-adhesive films with solid dispersion

Solid dispersion films were prepared with a highly water-soluble medicine, lidocaine hydrochloride (LDC), water-insoluble ethylcellulose (EC) and water-soluble hydroxypropylcellulose (HPC). The release profiles of LDC from the solid dispersion films of different composition, and the suppression mechanism of the release in the LDC-EC-HPC system were studied. The release rate of LDC from the solid dispersion film as drug-reservoir was well controlled at EC/HPC composition ratio of 5/5. The mechanism of controlled release was speculated that there was a little release of HPC together with LDC, and the retained HPC was swelled in the film by the permeating fluid. Then, the release of LDC occurred via diffusion into the swelled HPC phase, causing a marked decrease in the release rate. The film for clinical use, which had the 30% LDC solid dispersion film, adhered almost completely to the buccal mucosa. These observations will provide useful information on clinical application of the LDC-EC-HPC solid dispersion film.

The awakening concentration of sevoflurane in children.

UNLABELLED Sevoflurane is frequently used as a rapidly acting drug for the induction of anesthesia. We investigated the awakening concentration (MAC-awake) of sevoflurane in ASA physical status I children (age range 2-10 yr). We also investigated the effects of two different doses of clonidine (2 and 4 microg/kg) on the MAC-awake of sevoflurane. Subjects were randomly divided into three groups and received placebo (n = 24), clonidine 2 microg/kg (n = 17), or clonidine 4 microg/kg (n = 22) orally, 100 min before the induction of anesthesia. Sedation scores were estimated, by using a five-point scale, after entry into the operating room, and anesthesia was induced and maintained with sevoflurane in oxygen and balanced nitrogen, without an additional anesthetic. After surgery, end-tidal sevoflurane was decreased stepwise by 0.2% at 15-min intervals, a standardized verbal command was played to the patients, and the MAC-awake was determined. The MAC-awake of sevoflurane alone was 0. 78% +/- 0.24% (mean +/- SD), which decreased to 0.36% +/- 0.09% and 0.36% +/- 0.16% (both P <0.0001, compared with the control group) after premedication with the small and large doses of clonidine, respectively. The lack of any dose-response relationship might be explained by a plateau effect. IMPLICATIONS The awakening concentration of sevoflurane in unpremedicated children was 0.78%. Oral clonidine premedication at a dose of 2 microg/kg reduced the awakening concentration to 0.36%. However, an additional decrease in this value was not observed after the administration of the larger dose of clonidine premedication (4 microg/kg).

Effects of CYP2D6 genotypes on age‐related change of flecainide metabolism: involvement of CYP1A2‐mediated metabolism

AIMS The aim of this study was to clarify the effects of CYP2D6 genotype on age-related change in flecainide metabolism in patients with supraventricular tachyarrhythmias. An in vitro study using microsomes was performed to identify other CYPs responsible for age-related change in flecainide metabolism. METHODS The study population comprised 111 genotyped patients: CYP2D6-homozygous extensive metabolizers (hom-EMs, n= 34), heterozygous EMs (het-EMs, n= 56), and intermediate and poor metabolizers (IMs/PMs, n= 21). Serum concentrations of flecainide and its metabolites [m-O-dealkylated flecainide (MODF) and m-O-dealkylated lactam of flecainide] were determined by use of a high-performance liquid chromatography. Metabolic ratio (MR) was expressed as serum concentrations of flecainide to its metabolites. In vitro formation of MODF was examined in human liver microsomes and cDNA-expressed CYP isoforms. RESULTS MR was higher in elderly patients (> or =70 years) than in middle-aged patients (<70 years). The increase of MR in elderly patients differed among CYP2D6 genotypes: 1.6-fold in het-EMs [4.3, 95% confidence interval (CI) 2.8, 5.7 vs. 2.7, 95% CI 2.3, 3.1, P < 0.05], 1.5-fold in IMs/PMs (6.0, 95% CI 4.5, 7.6 vs. 4.1, 95% CI 2.9, 5.4, P < 0.05), and no change in hom-EMs. The in vitro study using microsomes revealed that both CYP2D6 and CYP1A2 were involved in the formation of MODF. MODF formation in CYP2D6 PM microsomes increased as CYP1A2 activity increased. CONCLUSIONS The results suggest that patients with poor CYP2D6-mediated metabolism (het-EMs and IMs/PMs) showed age-related reduction in flecainide metabolism because metabolism was taken over by CYP1A2, whose activity decreases with age.

Free lidocaine concentrations during continuous epidural anesthesia in geriatric patients.

Background and Objectives To evaluate the effects of aging on lidocaine pharmacokinetics, the plasma concentrations of total and free lidocaine and its metabolites were measured during continuous thoracic epidural anesthesia in middle-aged (age 41 ± 9 years, n = 7) and elderly (age 72 ± 2 years, n = 7) male patients. Methods After establishment of general anesthesia, 7 mL 1.5% lidocaine with epinephrine 1:200,000 was injected into the epidural space and subsequently infused at a rate of 5 mL/h for 5 hours. Plasma concentrations of total and free lidocaine, monoethylglycinexylidide (MEGX), and glycinexylidide (GX) were measured at 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, and 300 minutes after initial lidocaine injection using high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Results The elderly group showed a stronger upward trend in the corrected free lidocaine concentrations and lower corrected total MEGX concentrations than the middle-aged group. Conclusions Lidocaine metabolite activity in the elderly male patients was lower than that in the middle-aged male patients. Free lidocaine concentration is prone to increase in elderly patients. Caution must be exercised during continuous thoracic epidural anesthesia combined with general anesthesia in geriatric patients.

The reduction in minimum alveolar concentration for tracheal extubation after clonidine premedication in children

The effects of clonidine on minimum alveolar concentration for tracheal extubation (MAC-ex) have not been elucidated. Clonidine may lead to prolonged emergence from anesthesia. We investigated the effects of oral clonidine premedication on MAC-ex and examined the emergence properties of sevoflurane in children. Sixty ASA physical status I pediatric patients, aged from 2 to 9 yr, were randomly divided into one of three groups and received placebo, clonidine 2 &mgr;g/kg, or clonidine 4 &mgr;g/kg (n = 20 each) orally, 100 min before the induction of anesthesia. The induction of anesthesia, tracheal intubation, and maintenance of anesthesia were performed with sevoflurane in air and oxygen. MAC-ex was defined according to the modification of Dixon’s up-and-down method, with 0.25% as a step size. In addition, in the Control and 4 &mgr;g/kg groups, the time from tracheal extubation to spontaneous eye opening (eye-opening time) and the time from tracheal extubation to leaving the operating room (awakening time) were recorded. MAC-ex for sevoflurane (mean ± sd) was 1.63% ± 0.13%, 1.04% ± 0.26%, and 0.66% ± 0.09% respectively in the Control group, 2 &mgr;g/kg group, and 4 &mgr;g/kg group. Significant differences were observed among the three groups. The eye-opening times were 5.7 ± 3.5 min in the Control group and 5.1 ± 1.0 min in the 4 &mgr;g/kg group. The awakening times were 9.7 ± 3.7 min in the Control group and 9.2 ± 3.8 min in the 4 &mgr;g/kg group. No significant differences were observed among the groups.

The plasma concentration of lidocaine's principal metabolite increases during continuous epidural anesthesia in infants and children

C ontinuous epidural anesthesia is frequently used for anesthesia and analgesia during and after surgery in infants and children. Nevertheless, there are no data on the pharmacokinetics of repeatedly administered epidural lidocaine in children. We measured the concentrations of lidocaine and its principal active metabolite, monoethylglycinexylidide (MEGX), in plasma samples obtained in a group of infants and children during continuous epidural anesthesia with lidocaine.

Prolongation of Epidural Anesthesia in the Rabbit with the Use of a Biodegradable Copolymer Paste Containing Lidocaine

Prolongation of the drug effect using a drug-delivery system has recently been introduced in local anesthesia. In this study, we investigated the prolonging effect of an epidurally injected biodegradable copolymer paste containing 10% lidocaine (Lid-CoPol). Twenty-nine rabbits were studied. A catheter was placed in the epidural space at the level of L6-7 in each animal. A solution of 10% lidocaine (Group I, n = 12), or a copolymer containing 10% lidocaine (Lid-CoPol), (Group II, n = 12) or copolymer paste only (Group III, n = 5) was injected epidurally at a dose of 0.15 mL/kg. The effect of each drug was assessed by evaluation of response to pain stimulation and of the degree of motor block produced. The plasma lidocaine concentration was also measured consecutively in five animals of both Groups I and II. The duration of sensory and motor block of Lid-CoPol was 800% and 975% longer, respectively, than that of plain lidocaine solution. Plasma lidocaine concentration reached a maximum 5 min after injection (5.5 +/- 0.5 micro gram/mL) in Group I. In Group II, the level reached a maximum 30 min aftter injection (3.7 +/- 1.5 micro gram/mL). The findings are attributed in part to the slow release of lidocaine from the biodegradable copolymer paste, which is suggested as a new drug-delivery system for local anesthetics. (Anesth Analg 1995;80:97-101)

Effects of voriconazole co-administration on oxycodone-induced adverse events: a case in the retrospective survey.

Letter to the editor Oxycodone, a semisynthetic μ-opioid receptor agonist, is widely used for acute and chronic pain [1]. Because oxycodone is a substrate of cytochrome P450 (CYP) 2D6 and 3A4 [2–4], pharmacokinetic drug interaction may occur under concomitant use of CYP inhibitors, such as azole antifungals. Hagelberg et al. recently reported a drug interaction between oxycodone and voriconazole, an antifungal agent with potent CYP3A4 inhibitory activity, in a pharmacokinetic study employing healthy individuals, where the area under the drug concentration-time curve for oxycodone increased by 2.7–5.6 fold under co-administration of voriconazole [5]. This finding suggests that voriconazole potentially enhances both the efficacy of and the occurrence of related adverse events when both drugs are used concomitantly. To assess the clinical impact of this drug interaction, we present a typical case and clinical survey of nine cancer patients who were treated simultaneously with oxycodone and voriconazole. The study was approved by the Ethical Committee of Tsukuba University Hospital (Tsukuba, Japan). A 41-year-old man (63.6 kg) with Burkitt’s lymphoma received oxycodone per os for his thigh pain. Dosage was maintained at 20 mg d after admission. As he was feverish due to possible Aspergillosis, with positive Aspergillus antigen, voriconazole iv was administered for 5 days (700 mg d; day 7, 400 mg d; day 8–11). The fever gradually declined, and serum Aspergillus antigen turned negative on day 13. The patient complained of nausea and vomited just after starting voriconazole (on days 8 and 9). A sudden reduction in heart rate was also observed on day 9. Although he had required additional oxycodone (rapid-release preparation) as the rescue dose (2.5–5.0 mg d) both before starting and after stopping voriconazole, he needed no rescue dose during voriconazole co-administration (Fig. 1). These observations suggested that voriconazole co-administration enhanced both the efficacy of and the adverse symptoms relating to oxycodone, resulting in no need for a rescue dose of oxycodone but inducing nausea and vomiting while both drugs were used concomitantly. The dosing schedule for other drugs (omeprazole, gabapentin, zolpidem, magnesia oxide) was unchanged before and after voriconazole administration. Liver and kidney function (aspartate aminotransferase, 52 IU L; alanine aminotransferase, 97 IU L; blood urea nitrogen, 6.5 mg dl; serum creatinine 0.49 mg dl), and other laboratory data were also unchanged throughout the study. M. Watanabe :M. Homma (*) :K. Momo :Y. Kohda Department of Pharmacy, Tsukuba University Hospital, 2-1-1 Amakubo, Tsukuba, Ibaraki 305-8576, Japan e-mail: masatoh@md.tsukuba.ac.jp

Impact of CYP3A5 genetic polymorphism on pharmacokinetics of tacrolimus in healthy Japanese subjects

Tacrolimus (TAC), a calcineurin inhibitor, is an important immunosuppressive agent for treating autoimmune disease, including myasthenia gravis and rheumatoid arthritis, as well as for preventing allograft rejection in organ transplantation [1]. Since the therapeutic range of blood TAC is narrow, current interest focused on this drug is to maintain optimal blood concentrations in therapeutic drug monitoring (TDM) based on pharmacogenomic data, such as CYP3A5 and MDR1 gene polymorphisms [2]. Fukudo et al.[2] have reported that both CYP3A5 genotype and MDR1 mRNA expression were important factors affecting TAC pharmacokinetics in paediatric living related liver transplantation. Choi et al.[3] have revealed the impact of CYP3A5 genotype on TAC pharmacokinetics in healthy Koreans, where the area under the concentration–time curve (AUC) of TAC in subjects with CYP3A5*3/*3 was 2.5-fold higher compared with CYP3A5*1 carriers. We have examined the impact of CYP3A5 and MDR1 genetic polymorphism on TAC pharmacokinetics in healthy Japanese by using population pharmacokinetics (PPK) analysis. This study was approved by the Ethical Committee of University of Tsukuba (Tsukuba, Japan) and written informed consent was obtained in each case. Twenty healthy subjects received a single dose of oral TAC (2 mg; Prograf; capsule Astellas Pharma Inc., Tokyo, Japan). Venous blood samples for determining blood TAC were collected before and 1, 2, 4 and 8 h after the administration. Blood TAC was determined by microparticle enzyme immunoassay. Since the blood TAC concentration at 8 h after dose was as low as the detection limit for this method (1.5 ng ml−1), we did not measure the concentration after 8 h. PPK analysis was performed using WinNonMix (Version 2.0; Pharsight, Mountain View, CA, USA) with a one-compartment model to calculate apparent clearance (CL/F) and volume of distribution (V/F). The absorption rate constant (ka) was fixed to a reported value (4.5 h−1) [4]. Age, body weight, sex, and CYP3A5 and MDR1 genotypes were evaluated as the covariates by conducting a forward and backward stepwise regression analysis. Genome DNA was isolated from peripheral blood by using the QIAamp DNA Mini Kit (Qiagen GmbH, Hilden, Germany). The genotyping of CYP3A5 and MDR1 at the position of 1236C→T, 2677G→A/T and 3435C→T, was conducted by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method [5, 6]. MDR1−1517a T→C polymorphism, which was reported by Takane et al.[7] as the predictive factor of the expression level of MDR1 mRNA (NCBI dbSNP ID: rs28381796), was also genotyped by using a PCR-RFLP method developed in our laboratory. TAC pharmacokinetic parameters are summarized in Table 1. The AUC0−8h in subjects with CYP3A5*3/*3 were 1.8-fold higher than that in CYP3A5*1 carriers (P = 0.03), which agreed with the report of Choi et al.[3]. MDR1−1517a T/C genotype (n = 4) tended to have lower AUC0−8h compared with −1517a T/T genotype (n = 10) (20.8 ± 11.1 vs. 29.2 ± 8.2 ng h ml−1) in CYP3A5*1 carriers, although the difference was not statistically significant because of insufficient power. Table 1 Effect of CYP3A5 polymorphism on tacrolimus pharmacokinetics in healthy Japanese We conducted PPK analysis to estimate the contribution of CYP3A5 genotype on individual variations of TAC pharmacokinetics. Among the covariates, body weight affected the V/F and CL/F, and CYP3A5*1 allele only affected CL/F (Table 2). The estimated CL/F in subjects with CYP3A5*1 carriers was 1.5 times higher than that in subjects with CYP3A5*3/*3 (Table 2), which was comparable to measured values. The interindividual variability in CL/F with final model 4 was reduced from that with model 3 including no genetic covariates (22.4% to 9.7%, base model 1; 40.3%). These results suggest that approximately 32% of the interindividual variation of TAC CL/F can be explained by CYP3A5 polymorphism in healthy Japanese. This value is greater than the 9% and 23% reported, which were obtained in paediatric [2] and adult [8] liver transplantation situations, respectively. The liver transplantation is very complex in estimating the efficacy of CYP3A5 polymorphism on TAC pharmacokinetics, because of several issues such as the mismatch in genotype between recipients and donors and change in enzyme activities due to liver function, which may explain the discrepancy between the present and reported values. Because these factors associated with liver transplantation do not affect TAC pharmacokinetics in patients with myasthenia gravis and rheumatoid arthritis as well as healthy subjects, it is considered that the impact of CYP3A5 genotype on TAC TDM for autoimmune diseases is important. We therefore suggest that it would be useful to include CYP3A5 genotyping in TAC therapy for autoimmune diseases, especially in the Asian population, which frequently carry the CYP3A5*1 allele. Table 2 Summary of analysis models estimating for pharmacokinetic parameters of tacrolimus