Hiroaki Kubo

Population Pharmacokinetics of Arbekacin, Vancomycin, and Panipenem in Neonates

ABSTRACT Immature renal function in neonates requires antibiotic dosage adjustment. Population pharmacokinetic studies were performed to determine the optimal dosage regimens for three types of antibiotics: an aminoglycoside, arbekacin; a glycopeptide, vancomycin; and a carbapenem, panipenem. Eighty-three neonates received arbekacin (n = 41), vancomycin (n = 19), or panipenem (n = 23). The postconceptional ages (PCAs) were 24.1 to 48.4 weeks, and the body weights (BWs) ranged from 458 to 5,200 g. A one-compartment open model with first-order elimination was applied and evaluated with a nonlinear mixed-effect model for population pharmacokinetic analysis. In the fitting process, the fixed effects significantly related to clearance (CL) were PCA, postnatal age, gestational age, BW, and serum creatinine level; and the fixed effect significantly related to the volume of distribution (V) was BW. The final formulas for the population pharmacokinetic parameters are as follows: CLarbekacin = 0.0238 × BW/serum creatinine level for PCAs of <33 weeks and CLarbekacin = 0.0367 × BW/serum creatinine level for PCAs of ≥33 weeks, Varbekacin = 0.54 liters/kg, CLvancomycin = 0.0250 × BW/serum creatinine level for PCAs of <34 weeks and CLvancomycin = 0.0323 × BW/serum creatinine level for PCAs of ≥34 weeks, Vvancomycin = 0.66 liters/kg, CLpanipenem = 0.0832 for PCAs of <33 weeks and CLpanipenem = 0.179 × BW for PCAs of ≥33 weeks, and Vpanipenem = 0.53 liters/kg. When the CL of each drug was evaluated by the nonlinear mixed-effect model, we found that the mean CL for subjects with PCAs of <33 to 34 weeks was significantly smaller than those with PCAs of ≥33 to 34 weeks, and CL showed an exponential increase with PCA. Many antibiotics are excreted by glomerular filtration, and maturation of glomerular filtration is the most important factor for estimation of antibiotic clearance. Clinicians should consider PCA, serum creatinine level, BW, and chemical features when determining the initial antibiotic dosing regimen for neonates.

Evaluation of colonic absorbability of drugs in dogs using a novel colon-targeted delivery capsule (CTDC).

A series of dog studies were performed to examine the in vitro/in vivo relationship of drug release behavior of the newly developed colon-targeted delivery capsule (CTDC). The four kinds of CTDCs containing theophylline, each of which has a different in vitro dissolution lag time, were orally administered to four beagle dogs under fasted condition, and the onset times of drug absorption were compared. The CTDC with longer in vitro lag time had a later onset of drug absorption. It was also found that the time difference between the gastric emptying and the onset of drug absorption was almost equal to the in vitro dissolution lag time of the capsule, suggesting a similar performance of CTDC in the gastrointestinal tract. From the comparison to the absorption behavior of the colon arrival marker, i.e. sulfasalazine, it was proved that the CTDC with the lag time of 3 h can deliver the drug directly to the colon. This result implied that the CTDC can be used as a non-invasive means for assessing the regional absorbability of drugs in the gastrointestinal tract. To evaluate the absorbability of drugs in the colon, three model drugs, theophylline (THEO), acetaminophen (ACET), and phenylpropanolamine hydrochloride (PPA) were directly delivered to the colons of beagle dogs using the CTDC with the lag time of about 3 h. The obtained relative bioavailabilities to the solution form were as high as 94.2%, 71.0%, and 91.5% for THEO, ACET and PPA, respectively, suggesting that the colonic absorbability of those drugs is essentially good.

Rapid method for determination of kanamycin and dibekacin in serum by use of high-pressure liquid chromatography.

A rapid, simple, and accurate method for the determination of kanamycin and dibekacin in serum by use of high-pressure liquid chromatography is described. The serum proteins were precipitated with 3.5% perchloric acid containing sodium octanesulfonate. After centrifugation, a sample of the supernatant was directly injected into the chromatograph. The determination of kanamycin and dibekacin was performed by a combination of reverse-phase, ion-pair chromatography, postcolumn derivatization with o-phthalaldehyde, and fluorescence detection. The correlation coefficients with fluorescence polarization immunoassay were 0.996 for kanamycin and 0.957 for dibekacin.

Fluorometric determination of isoniazid and its metabolites in urine by high-performance liquid chromatography using in-line derivatization

A rapid, simple, and accurate method has been developed for the determination of isoniazid and its metabolites (isonicotinic acid, isonicotinyl-glycine, and acetylisoniazid) in human urine by high-performance liquid chromatography. Isoniazid and its metabolites are separated by reversed-phase ion-exchange chromatography with a mobile phase containing hydrogen peroxide as a fluorogenic reagent and butanesulfonate as a hydrophobic ion exchanger, and are detected by fluorometry (excitation at 317 nm and emission at 415 nm) using in-line derivatization at high temperature (160°C). The detection limits are isonicotinic acid, 0.5 μmol/L; isonicotinylglycine, 1 μmol/L; acetylisoniazid, 1 μmol/L; and isoniazid, 1.5 μmol/L. This method can be applied for acetylator phenotyping.

Radioreceptor assay of clonazepam and diazepam in blood for therapeutic drug monitoring.

Rat cerebral cortex was used to prepare a suspension of benzodiazepine receptors. The suspension was mixed with an extract of specimen and [3H]flunitrazepam. The mixture was filtered through a membrane, and radioactivity on the membrane was measured. Clonazepam concentrations in patient plasma specimens determined by radioreceptor assay and gas-liquid chromatography agreed well. However, diazepam equivalent concentrations determined by radioreceptor assay were close to the sum of diazepam and desmethyldiazepam concentrations determined by high-performance liquid chromatography, as desmethyldiazepam had binding activity for the receptor. This receptor assay method is accurate, simple, requires less than 0.5 ml of plasma, and is therefore suitable for analyzing numerous samples in a short time.

Isoniazid Acetylation Phenotyping in the Japanese: The Molar Metabolic Ratio INH/AcINH.

The N-acetylation phenotyping of isoniazid (INH) was studied in 434 unrelated Japanese pulmonary tuberculosis patients. The frequency of slow acetylators was determined using three methods based on the urinary levels of INH and AcINH: percentage acetylisoniazid (%AcINH), the inactivation index or acetylation index (AcINH/INH), and the molar metabolic ratio (INH/AcINH) in urine. Frequency histograms and probit plots were constructed with the data obtained from each method. Using %AcINH with the conventional antimode of 70%, the number of slow acetylator was 12.7%. Using AcINH/INH, the number of slow acetylator was 52% according to the conventional antimode of 6.0. The molar metabolic ratio INH/AcINH showed explicitly the best bimodality and a clear-cut antimode among these three methods. From probit plots of INH/AcINH, an antimode of 0.45 can be suggested for the 434 Japanese patients; 377 patients (86.9%) as rapid acetylator and 57 patients (13.1%) as slow acetylator.

Ultraviolet detection of amino acids by reversed-phase liquid chromatography using an in-line reactor system.

高速液体クロマトグラフィー(HPLC)の流路系に銅の金属粉末を充てんした反応管を組み込み,アルカリ性の移動相を用いてアミノ酸を分離後,反応管から溶出した銅イオン(II)と錯体を形成させ,その紫外部吸収を検出するインライン反応系を用いた分析法を確立した.分離カラムはアルカリ性で安定なAsahipak ODP-50(5μm,250×6mm i.d.)を用い,インライン反応管(4×4mm i.d.)中の銅粉末(100～200メッシュ)の重量は150mgとし,HPLCの溶離液としてはイオン対試薬として10mMヘキサデシルトリメチルアンモニウムを含む25mMリン酸緩衝液(pH11)が分離に対し最適であり,検出は255nmで行った.20分以内で7種類のアミノ酸が良好な分離を示した.検出限界はプロリンで800pg(S/N=3)であった.

Determination of iodoform in rabbit plasma by HPLC.

血しょう中ヨードホルム濃度を簡便,迅速,再現性よく,HPLCを用いて測定する方法を確立した.逆相カラムを使用し,移動相には60%メタノール/pH3.8,5mMリン酸カリウム緩衝液,流量は1.0ml/min,検出波長は336nm,検出感度は0.005AUFSに設定した.前処理として,血しょうと等量のエーテルを用いて抽出及び除タンパクを行った.検量線は0.4～4.0μg/mlまで直線性を示し,内標準物質ジョードメタンとの比からY=0.729X+1.9×10-4(r=0.999)と良好な回帰方程式が得られた.この測定方法を,ヨードホルムガーゼを腹くう内に充てんしたウサギの血しょう中濃度測定に用いた.