研究者詳細 - 谷川原　祐介

論文 - 谷川原　祐介

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薬理動態からみた肝局所化学療法における経動脈性および経門脈性抗癌剤投与の比較

塩谷　雅文，具　英成，楠　信也，北川　哲司，前田　一郎，富永　正寛，谷川原　祐介，黒田　嘉和，斎藤　洋一

癌と化学療法 22 （ 11 ） 1560 - 1562 1995年09月

ISSN 0385-0684

We investigated the adriamycin (ADR) pharmacokinetics following intraarterial and intraportal infusion under hepatic venous isolation and charcoal hemoperfusion (HVI·CHP), HVI·CHP was used to measure the first pass amount of adriamycin through the liver and to reduce hepatic re entry of the drug. Beagles underwent a 10-min ADR infusion (1 mg/kg) either through the hepatic artery (group 1, n = 5) or the portal vein (group II, n = 5) under a 20 min HVI·CHP. During HVI·CHP, the hepatic venous flow rate and plasma ADR levels in prefilter (hepatic venous level), postfilter and peripheral blood were serially measured. Based on these measurements, the hepatic extraction ratio (HER) of ADR was calculated. Areas under the time concentration curves of prefilter levels in groups I and II were 6.1 ± 1.6 and 16.9 ± 5.0 μg · min/ml, respectively, showing a significant difference between two groups (p<0.01). On the contrary, HER of group I (81.2%) was significantly higher than that of group II (47.2%, p<0.01). These results indicate that intraarterial infusion of ADR is superior to intraportal infusion in terms of local drug delivery to the liver and systemic drug toxicities.

Premarketing population pharmacokinetic study of levofloxacin in normal subjects and patients with infectious diseases

Tanigawara Y., Nomura H., Kagimoto N., Okumura K., Hori R.

Biological and Pharmaceutical Bulletin 18 （ 2 ） 315 - 320 1995年

ISSN 0918-6158

The population pharmacokinetics of levofloxacin (LVFX), the l-enantiomer of ofloxacin, were studied in 522 subjects, including normal subjects and patients with infectious diseases. Altogether, 1572 LVFX serum concentrations were obtained following a single oral administration during clinical trials. The influences of renal function, age, meals and concurrent drug administration on the pharmacokinetic parameters of LVEX were examined by the likelihood ratio test using a nonlinear mixed-effect model (NONMEM). In patients with renal insufficiency, the total body clearance (CL) of LVFX was related to creatinine clearance (Ccr) and body weight (WT), as expressed by CL=0.0836 Ccr+0.013 WT. The CL with normal renal function was 0.178 (l/h/kg). The apparent volume of distribution (Vd) was calculated to be 1.46 (l/kg). The elderly subjects, aged 65 years old or over, exhibited, on average, a 32% reduction in CL and 6% greater Vd. LVFX was rapidly absorbed in the gastrointestinal tract, but the concurrent administration of antacids (magnesium, aluminum, etc.) decreased the bioavailability of LVEX by 15-52%. The recommended dose of LVFX was decided on the basis of current pharmacokinetic information and the minimum inhibitory concentrations. Population pharmacokinetic parameters are also useful for the individualization of a dosage regimen by means of the Bayesian forecasting method.

Cepharanthin, a multidrug resistant modifier, is a substrate for P- glycoprotein

Hirai M., Tanaka K., Shimizu T., Tanigawara Y., Yasuhara M., Hori R., Kakehi Y., Yoshida O., Ueda K., Komano T., Inui K. I.

Journal of Pharmacology and Experimental Therapeutics 275 （ 1 ） 73 - 78 1995年

ISSN 0022-3565

P-glycoprotein modulators are respected to be multidrug resistance reversing agents in cancer chemotherapy. Some calcium channel blockers, calmodulin inhibitors or immunosuppressive agents have been used in clinical studies, although the dose of these drugs required to test in vitro experimental data might cause potent pharmacological effects which are not desirable in patients. By using LLC-GA5-COL150 cells that express P- glycoprotein specifically on the apical membranes, we examined the transport of anticancer drugs mediated by P-glycoprotein. Cepharanthin, a biscoclaurine alkaloid, potently inhibits the transport of vinblastine and daunorubicin, both commonly used anticancer agents. The 50% inhibitory concentration of cepharanthin on daunorubicin transport was 2.06 μM. Combined inhibitory effects on daunorubicin transport were observed when cepharanthin was used together with cyclosporin A, a potent immunosuppressive agent and P- glycoprotein modulator. Cepharanthin itself was transported by P- glycoprotein. Transcellular transport of cepharanthin across LLC-GA5-COL150 cell monolayers was saturable when its concentration was under 5 μM, and the transport was inhibited by P-glycoprotein modulators. These results indicate that cepharanthin can reverse multidrug resistance, and proper combination with other P-glycoprotein modulators could potentiate its inhibitory effect on expelling the anticancer drugs out of the cell via P-glycoprotein.

Population pharmacokinetics of theophylline. III. Premarketing study for a once-daily administered preparation

Tanigawara Y., Komada F., Shimizu T., Iwakawa S., Iwai T., Maekawa H., Hori R., Okumura K.

Biological and Pharmaceutical Bulletin 18 （ 11 ） 1590 - 1598 1995年

ISSN 0918-6158

The population pharmacokinetic parameters for a once-daily administered preparation, Uniphyl were estimated from data collected in the premarketing clinical trial. Altogether, 2772 serum theophylline concentrations were obtained from 131 normal subjects and 306 patients suffering from chronic asthma or chronic obstructive pulmonary disease who participated in the phase I, II, and III clinical trials in Japan. The serum concentration profile was described by a linear one-compartment model with first-order absorption. The factors affecting the pharmacokinetics of this drug were examined by the likelihood ratio test using a nonlinear mixed effect model (NONMEM). The first-order absorption rate constant (Ka) for a 200-mg tablet in a fasting condition was obtained as 0.0773 (1/h), which was smaller than the elimination rate constant (0.168 1/h), indicating the flip-flop characteristic of this preparation. Food ingestion increased the Ka by 17% and the absorption lag time by 5-fold but did not affect the extent of absorption. The 400-mg tablet showed a Ka value 19%, smaller than the 200-mg tablet. Children not older than 15 years showed 58% longer absorption lag time. The inter-individual variability in Ka was 19%, suggesting small variability in the in vivo release process. The total body clearance was related to hepatic function, smoking habits, and age. Furthermore, clearance decreased in association with the severity of illness. The findings obtained here are useful not only for the initial dosage adjustment for patients with a variety of backgrounds but also for dose individualization based on serum concentration monitoring with or without the Bayesian feedback method.

Predictive performance of the Bayesian analysis

Tanigawara Yusuke, Yano Ikuko, Kawakatsu Kazuo, Nishimura Koichi, Yasuhara Masato, Hori Ryohei

Journal of Pharmacokinetics and Biopharmaceutics 22 （ 1 ） 59 - 71 1994年02月

ISSN 0090-466X

The present paper reports theoretical equations for the predictive performance of the Bayesian forecasting method. The precision of parameter estimates and predicted concentrations for an individual was described by general equations with the aid of a variance-covariance matrix of parameter estimates that involved the Bayes theorem. The equations were applied to assess the predictive performance of the one-point Bayesian method in association with blood sampling time, the population parameters, and the pharmacostatistical model. The simulation study showed that the prediction error in parameter estimates essentially depended upon the sampling time but the magnitude of dependency was affected by the size of inter-and intraindividual variances. With a smaller value of interindividual variance, the dependency on sampling time was less apparent. Effects of sampling time were further examined using clinical data obtained from 20 patients taking theophylline, and the results were in good agreement with the theoretical consideration. The present general equations are useful to investigate the sampling strategy as well as structural and variance modeling on the predictive performance of the Bayesian method. © 1994 Plenum Publishing Corporation.

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日本人における薬物動態母集団パラメータの推定（１）：ジゴキシン

堀　了平，宮崎　勝巳，水柿　道直，緒方　宏泰，後藤　光良，市村　藤雄，安原　眞人，谷川原　祐介，橋本　征也，小上　淑子，三牧　孝至，田中　一彦，奥村　勝彦，五味田　裕，樋口　駿

TDM研究 11 （ 1 ） 7 - 17 1994年

Renal handling of tobramycin in the isolated perfused rat kidney

Aiba T., Itoga Y., Shimizu H., Tanigawara Y., Hori R.

Journal of Pharmaceutical Sciences 83 （ 5 ） 723 - 726 1994年

ISSN 0022-3549

The renal handling of tobramycin (TOB), an aminoglycoside antibiotic (AG), was studied using a single-pass isolated perfused rat kidney with moment analysis. In the bolus administration study at tracer concentration (7.4 μM), 32% of the glomerular-filtrated TOB remained in the lumen, but no TOB was found in the vein. This ratio of the luminal uptake was reduced in a dose-dependent manner. Other aminoglycosides such as gentamicin inhibited this uptake, but tetraethylammonium and glucosamine had no effect. In addition, under the alkalinuria condition, TOB uptake was decreased to 67% of the control value. This indicated that TOB has mainly been taken into the renal epithelial cells from their luminal site and that this uptake process was saturable and specific for AGs which have more than one cationic group. The present findings should be helpful in developing a method to reduce the nephrotoxicity of AGs and to identify their toxicity mechanisms.

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バミカミドのPopulation Pharmacodynamics

寺川　雅人，伊与田　奈美，谷川原　祐介，

臨床薬理 25 （ 4 ） 603 - 613 1994年

ISSN 0388-1601

The population pharmacodynamics of vamicamide, a new anticholinergic drug, were analyzed by nonlinear mixed effect modeling (NONMEM) in 16 healthy male subjects. The subjects were given orally 18, 36 or 48 mg of vamicamide in a single- or multiple-dose regimen. Serum concentrations of vamicamide were measured frequently; the average urine flow rates (AFRs) estimated simply by dividing the urine volume by the time during voiding, were measured on each occasion of urination. Serum concentrations corresponding to the time of urination were predicted by curve-fitting the individual data (a total of 293 serum data) to a one-compartment model with first-order absorption. The serum concentration-AFR data (381 data pairs) thus obtained were used for NONMEM analysis. The Emax model with baseline controls was used for serum cncentration-AFR response data. The voided volume significantly affected not only the baseline AFR but also maximum response (Emax). However, the concentration which causes half of Emax (EC₅₀) was independent of voided volume and was estimated to be 167 ng/ml. At the serum concentration of 140 ng/ml, which is the maximum serum concentration at therapeutic standard dosage regimen, the percent reduction of AFR from the baseline value was estimated to be 32 and 38% when the voided volume is assumed to be 400 ml, respectively. Despite the wide range of variability in AFR, the NONMEM analysis provided clinically significant concentration-response curves. This population approach appears recommendable for further clinical applications.

Population analysis of the dose-dependent pharmacokinetics of zonisamide in epileptic patients

Hashimoto Y., Odani A., Tanigawara Y., Yasuhara M., Okuno T., Hori R.

Biological and Pharmaceutical Bulletin 17 （ 2 ） 323 - 326 1994年

ISSN 0918-6158

The pharmacokinetics of zonisamide was studied using routine therapeutic drug monitoring data from 68 epileptic patients. The 266 serum concentration data at steady-state after repetitive oral administration were analyzed using the nonlinear mixed effects model (NONMEM) program designed for estimation of population pharmacokinetic parameters. A one-compartment model with dose- dependent clearance was used for the pharmacokinetic analysis of zonisamide. The volume of distribution (V) was estimated to be 1.27 l/kg in a typical 33- kg patient, assuming that the bioavailability of orally administered zonisamide is 100%. The maximal daily dose to be cleared (V(max)) and the concentration giving half maximal clearance (a Michaelis-Menten constant) was 27.6 mg/d/kg and 45.9 μg/ml, respectively. The parameter of a power function of weight to adjust V and V(max) was estimated to be 0.741. In addition, V(max) for zonisamide appears to be 13% increased in patients receiving carbamazepine concurrently. The population pharmacokinetic parameters of zonisamide will be useful for designing dosage regimens in epileptic patients.

マイクロパーティクルEIA法によるタクロリムスの血中濃度モニタリング

橋田　亨，池西　政幸，虎口　美典，谷川原　祐介，木邑　道夫，安原　眞人，堀　了平，上本　伸二，田中　紘一，小澤　和恵

TDM研究 11 （ 1 ） 18 - 22 1994年

P-glycoprotein-mediated transcellular transport of MDR-reversing agents

Saeki Tohru, Ueda Kazumitsu, Tanigawara Yusuke, Hori Ryohei, Komano Tohru　

FEBS Letters 324 （ 1 ） 99 - 102 1993年06月

ISSN 0014-5793

Understanding of the interactions between P-glycoprotein and multidrug resistance (MDR) reversing agents is important in designing more effective MDR modulators. We examined transcellular transport of several MDR modulators by using a drug-sensitive epithelial cell line, LLC-PK₁ and its transformant cell line, LLC-GA5-COL300, which expresses human P-glycoprotein on the apical surface. Basal-to-apical transports of azidopine and diltiazem across the LLC-GA5-COL300 monolayer were increased and apical-to-basal transports were decreased compared to those across the LLC-PK₁ monolayer, indicating that P-glycoprotein transports azidopine and diltiazem. Movements of nitrendipine and staurosporine across the epithelial monolayer were not affected by P-glycoprotein. These results suggests that some MDR modulators exert their inhibitory effect not only by blocking the initial binding of anticancer drugs but throughout the course of the transport process. © 1993.

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Human P-glycoprotein transports cyclosporin A and FK506

Saeki Tohru, Ueda Kazumitsu, Tanigawara Yusuke, Hori Ryohei, Komano Tohru

Journal of Biological Chemistry 268 （ 9 ） 6077 - 6080 1993年03月

ISSN 0021-9258

Cyclosporin A, a cyclic undecapeptide, and FK506 are efficient immunosuppressive agents. They also attract attention as effective P-glycoprotein modulators that inhibit P-glycoprotein from binding to anticancer drugs and overcome multidrug resistance. Cyclosporin A itself interacts with a common binding site of P-glycoprotein to which Vinca alkaloids and verapamil bind. We were interested to determine whether cyclosporin A and FK506 are substrates for P-glycoprotein to transport, and we studied their transcellular transport. In LLC-PK₁ cells, derived from porcine kidney proximal tubule and forming a highly polarized epithelium, cyclosporin A was transported in a saturable manner. LLC-GA5-COL300, a transformant cell line derived by transfecting LLC-PK₁ with human MDR1 cDNA isolated from normal adrenal gland, expresses P-glycoprotein specifically on the apical surface and shows a typical multidrug-resistant phenotype. LLC-GA5-COL300 cells showed increased transport of cyclosporin A from the basal to the apical side. Kinetic analysis showed that this transport was a typical saturable transport with the calculated apparent Michaelis constant (K_m^app) and the maximum flux (V_max) as 8.4 μM and 2.4 nmol/mg protein/h, respectively. LLC-GA5-COL300 also snowed increased transport of FK506 from the basal to the apical side. These results indicate that P-glycoprotein transports the immunosuppressive agents cyclosporin A and FK506.

Population pharmacokinetics of theophylline. II

Yano I., Tanigawara Y., Yasuhara M., Okumura K., Kawakatsu K., Nishimura K., Hori R.

Biological and Pharmaceutical Bulletin 16 （ 5 ） 501 - 505 1993年

ISSN 0918-6158

The population pharmacokinetics of theophylline were studied in 55 patients with stable chronic airway obstruction. Two hundred and seventy six theophylline serum concentrations after intravenous short infusion were analyzed using a nonlinear mixed-effect model. The influence of hepatic dysfunction, smoking habit, age and the measurement of arterial blood gases (oxygen tension: PaO₂, carbon dioxide tension: PaCO₂, blood pH) and clinical laboratory tests (serum albumin concentration, haematocrit) on the pharmacokinetic parameters of theophylline was examined by the likelihood ratio test. Assessment of each factor was made by a forward selection method. In the final regression model, the total body clearance (CL, l/h/kg) was related to the value of PaCO₂ as well as to the presence of hepatic dysfunction, and the volume of distribution (V(d), l/kg) was related with the PaCO₂ value as expressed in the following equations: CL=exp(- 3.78 - 0.525. HF+ 0.0233. PaCO₂) and V(d)=exp(- l.12 + 0.00934. PaCO₂), where HF is a categorical variable with a value of unity if a patient has hepatic dysfunction otherwise zero. The interactions among blood gas measurements were observed and the CL and V(d) of theophylline would be inversely correlated with PaO₂ or pH, if we selected PaO₂ or blood pH to be a more important factor than PaCO₂. The inter-individual variabilities in CL and V(d) were 38.5% and 12.5%, respectively, and the residual variability in theophylline serum concentrations was 10.6% as a coefficient of variation. This final model and the population parameters of theophylline will be useful for individualization of a drug dosage regimen by means of the Bayesian method. Significant correlation between arterial blood gas measurements and pharmacokinetic parameters observed in this study indicates that the pharmacokinetics of theophylline can vary in association with the severity of respiratory diseases.

Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney

Hori R., Okamura N., Aiba T., Tanigawara Y.

Journal of Pharmacology and Experimental Therapeutics 266 （ 3 ） 1620 - 1625 1993年

ISSN 0022-3565

The mechanism for renal tubular secretion of digoxin as well as its interaction with quinidine or verapamil were investigated using the isolated perfused rat kidney. [³H]Digoxin was instantaneously administered into the renal artery together with [¹⁴C]inulin and Evans blue-albumin, and renal venous and urinary outflow curves were measured. The ratio of fractional excretion to filtration fraction for digoxin was 2.40 ± 0.40, indicating involvement of tubular secretion. Quinidine and verapamil decreased the ratio of fractional excretion to filtration fraction in a concentration-dependent manner, and this inhibition was indicated to occur at transport from cells to lumen across luminal membranes. Neither tetraethylammonium nor p- aminohippurate affected the renal handling of digoxin. Because ouabain and digitoxose showed no influence on the value of fractional excretion to filtration fractions, Na⁺,K⁺-ATPase is not involved in the tubular secretion of digoxin. A metabolic inhibitor, 2,4-dinitrophenol, markedly inhibited digoxin secretion. Agents that bind to P-glycoprotein, such as vinblastine, daunorubicin and reserpine, markedly inhibited the secretion of digoxin. Recently, we have found that digoxin is a substrate transported by P-glycoprotein. The findings obtained here support the hypothesis that digoxin is secreted by P-glycoprotein located on the luminal membrane of renal tubular epithelial cells, and that clinically important interactions with quinidine and verapamil are caused by the inhibition of P-glycoprotein.

Digoxin-cyclosporin A interaction

Okamura N., Hirai M., Tanigawara Y., Tanaka K., Yasuhara M., Ueda K., Komano T., Hori R.

Journal of Pharmacology and Experimental Therapeutics 266 （ 3 ） 1614 - 1619 1993年

ISSN 0022-3565

The mechanism of a renal tubular digoxin-cyclosporin A interaction was elucidated using a kidney epithelial cell line and the isolated perfused rat kidney. The cells expressed an excess amount of human P-glycoprotein on the apical membranes by transfection with MDR1 cDNA. Cyclosporin A inhibited the trans-epithelial transport of digoxin mediated by human P-glycoprotein; net basal-to-apical transport across the cell monolayer was 22.8, 21.2, 6.61 and 0.91 pmol/mg of protein/3 hr in the presence of 0, 1, 5 and 10 μM cyclosporin A, respectively. Cyclosporin A also reduced the renal tubular secretion of digoxin by the kidney. The ratio of fractional excretion/filtration fraction for digoxin was 2.88 ± 0.71 (mean ± S.D.) in the control, and this was decreased to 1.21 ± 0.09 and 1.05 ± 0.13 in the presence of 1 and 5 μM cyclosporin A, respectively. Because no signs of acute nephrotoxicity were observed, a direct effect of cyclosporin A accounted for the reduced secretion. On the other hand, digoxin did not affect cyclosporin A transport by P-glycoprotein. These findings indicate that serum concentrations of digoxin in patients should be carefully monitored when administered concurrently with cyclosporin A. The present transepithelial transport system using the transfectant cells is a simple and useful screening system for predicting drug interactions that can occur in a clinical situation.

Population pharmacokinetics of theophylline. I

Yano I., Tanigawara Y., Yasuhara M., Mikawa H., Hori R.

Biological and Pharmaceutical Bulletin 16 （ 1 ） 59 - 62 1993年

ISSN 0918-6158

The population pharmacokinetics of theophylline during constant-rate intravenous infusion has been studied in 66 children (8.7 ± 4.7 year of age; 26.0 ± 12.8 kg, mean ± S.D.) with an episode of acute asthma. One hundred and twelve theophylline serum concentrations (13.9 ± 4.8 μg/ml) collected retrospectively were analyzed using a nonlinear mixed-effect model. The influence of hepatic dysfunction, age, gender, days after admission, blood gas measurements (PaO₂, PaCO₂, blood pH) and clinical analyses data (total serum protein, albumin concentration, haemoglobin concentration, haematocrit) on theophylline clearance was examined by the likelihood ratio test. A final estimate of population mean clearance was 58.6 ml/kg/h, which was decreased by 36% in patients with hepatic dysfunction. Other factors tested displayed no statistically significant effect on theophylline clearance. The inter-individual variability in clearance was 26% while the intra-individual variability in theophylline concentrations was 2.6 μg/ml as a standard deviation, which was almost double that observed for stable patients. Taking into account that the therapeutic window of this drug is 10-20 μg/ml, this value indicates a relatively large intra-individual variability and suggests that frequent (daily) monitoring of serum concentrations is necessary for patients with an episode of acute asthma.

Human P-glycoprotein transports cortisol, aldosterone, and 　dexamethasone, but not progesterone

Ueda Kazumitsu, Okamura Noboru, Hirai Midori, Tanigawara Yusuke, Saeki Tohru, Kioka Noriyuki, Komano Tohru, Hori Ryohei

Journal of Biological Chemistry 267 （ 34 ） 24248 - 24252 1992年12月

ISSN 0021-9258

We expressed human MDR1 cDNA isolated from the human adrenal gland in porcine LLC-PK1 cells. A highly polarized epithelium formed by LLC-GA5-COL300 cells that expressed human P-glycoprotein specifically on the apical surface showed a multidrug-resistant phenotype and had 8.3-, 3.4-, and 6.5-fold higher net basal to apical transport of ³H-labeled cortisol, aldosterone, and dexamethasone, respectively, compared with host cells. But progesterone was not transported, although it inhibited azidopine photoaffinity labeling of human P-glycoprotein and increased the sensitivity of multidrug-resistant cells to vinblastine. An excess of progesterone inhibited the transepithelial transport of cortisol by P-glycoprotein. These results suggest that cortisol and aldosterone are physiological substrates for P-glycoprotein in the human adrenal cortex and that substances that efficiently bind to P-glycoprotein are not necessarily transported by P-glycoprotein.

Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK₁)

Tanigawara Y., Okamura N., Hirai M., Yasuhara M., Ueda K., Kioka N., Komano T., Hori R.

Journal of Pharmacology and Experimental Therapeutics 263 （ 2 ） 840 - 845 1992年

ISSN 0022-3565

This article represents the first evidence that the renal secretion of the commonly used drug, digoxin, is mediated by P-glycoprotein. In this study, it was demonstrated that digoxin is a substrate of P-glycoprotein, and the mechanism of a clinically important drug interaction, such as digoxin- quinidine, was elucidated. Human P-glycoprotein was expressed on the apical membrane of the porcine kidney epithelial cell line, LLC-PK₁ by transfecting with human MDR1 cDNA. The expression and function of P-glycoprotein were confirmed by Southern and Western blotting, RNase protection assay, immunostaining and transporting activity for vinblastine. The transepithelial transport of [³H]digoxin was measured across the cell monolayers grown on microporous polycarbonate membrane filters. The transfectant cells exhibited markedly greater basal-to-apical transport and less apical-to-basal transport than the host cells, and the former was 8-fold greater than the latter. The augmented transepithelial transport resulted from the increased efflux from cells to apical side. This oriented transport was inhibited by the presence of 20 μM vinblastine, quinidine or verapamil. The rate of efflux to the apical side was 2-fold greater than that to the basal side. Quinidine inhibited the efflux to the apical side but did not affect transport into the basal side. These findings demonstrate that digoxin is transported by human P-glycoprotein, which is a previously undiscovered drug transport system in the kidney other than organic cation and anion transport systems, and suggest a molecular mechanism for the renal tubular secretion of digoxin as well as clinically important digoxin-quinidine interaction via P-glycoprotein.

Total body and hepatic clearance in rats of recombinant tissue-type plasminogen activator expressed in mouse C127 and Chinese hamster ovary cells

Hori R., He Y. L., Shima T., Inui K. I., Aoki S., Okumura K., Tanigawara Y.

Drug Metabolism and Disposition 20 （ 4 ） 541 - 546 1992年

ISSN 0090-9556

The total body and hepatic clearance of two recombinant human tissue-type plasminogen activators (t-PA) produced in mouse C127 cells [t-PA(C127)] and in Chinese hamster ovary cells [t-PA(CHO)] were determined in rats. Recombinant t-PA was administered as a constant iv or intraportal venous infusion for 60 min. The plasma t-PA level over 120 min was measured by an ELISA. Whole-body pharmacokinetics were characterized in terms of the total body clearance (CL(t)), total volume of distribution, and mean residence time in the body. Hepatic disposition was described by the hepatic clearance (CL(hep)) and the mean hepatoportal transit time. Whereas a marked hepatic extraction was observed with both-t-PAs, the estimated CL(hep) accounted for only one-half the CL(t). No elimination took place in the lung, because no difference was observed between iv and intraarterial administration. Extrahepatic elimination, such as that in circulating blood, appeared to play a significant role in the disposition of t-PA in vivo. t-PA(C127) is known to possess the Galα1-3Gal epitope in its complex-type carbohydrate chains, whereas this structure is not involved in t-PA(CHO). In the presence of Bandeiraea simplicifolia lectin I isolectin B₄, which is specific to the Galα1-3Gal, the CL(t) of t-PA(C127) was significantly decreased, whereas that of t-PA(CHO) was unchanged. These results imply that the formation of a high molecular weight complex by this carbohydrate epitope effectively reduces the rate of catabolism of t-PA in vivo.

Effect of leukotriene C₄ on theophylline disposition in guinea pigs

Tanigawara Y., Yano I., Yasuhara M., Hori R.

American Review of Respiratory Disease 146 （ 3 ） 616 - 620 1992年

ISSN 0003-0805

The pharmacokinetics of theophylline in acutely ill patients show wide intraindividual variability associated with the severity of clinical status. To investigate the mechanism of this variability, we studied the effects of leukotriene C₄ (LTC₄)-induced pathophysiologic changes on the disposition of theophylline. The plasma concentration-time profiles were measured after simultaneous intravenous bolus injection of theophylline and antipyrine in guinea pigs. The animals received 5 μg/kg of LTC₄ intravenously 60 min later. The plasma theophylline concentration 30 min after LTC₄ treatment was significantly lower (p < 0.05) than that of nontreated control animals, whereas the plasma antipyrine concentration at that time was not affected. In addition, the treated animals showed significantly slower declines in plasma concentrations of both drugs (0.0805 ± 0.0199 and 0.291 ± 0.020 h^-1 for theophylline and antipyrine, respectively, mean ± SEM) than did controls (0.197 ± 0.010 and 0.439 ± 0.028 h^-1). Leukotriene C₄ treatment also induced moderate bronchoconstriction and metabolic acidosis, increased blood hemoglobin concentration and hematocrit, and decreased concentration of serum proteins. In connection with these changes, the plasma unbound fraction of theophylline increased significantly (p < 0.001, 94.4 ± 3.3% in treatment versus 58.2 ± 4.4% in control), but that of antipyrine was unchanged (94.9 ± 3.0% in treatment versus 92.1 ± 0.9% in control). These findings indicated that an increase in the volume of distribution was responsible for the abrupt change in plasma theophylline concentration following LTC₄ treatment, and the apparent change in the volume of distribution was estimated as 26.1 ± 5.6%. Results showed that the LTC₄ response can influence the disposition kinetics of theophylline and suggested a possible mechanism for the intraindividual variability in acutely ill patients.

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