Biomedical subjects

T Iga

Publications and source records attributed to T Iga.

At least 37 records · Page 2Linked to original sources

PubMed2000

Comparative pharmacodynamic analysis of Q-T interval prolongation induced by the macrolides clarithromycin, roxithromycin, and azithromycin in rats.

In order to evaluate the arrhythmogenic potency of macrolide antibiotics in a quantitative manner, we analyzed the influence of clarithromycin (CAM), roxithromycin (RXM), and azithromycin (AZM) on Q-T intervals from pharmacokinetic and pharmacodynamic points of view and in comparison with the potency of erythromycin (EM) previously reported by us for rats. Male Sprague-Dawley rats were anesthetized, and CAM (6.6, 21.6, and 43.2 mg/kg of body weight/h), RXM (20 and 40 mg/kg/h), and AZM (40 and 100 mg/kg/h) were intravenously injected for 90 min to obtain the time courses of drug concentrations in plasma and the changes in the Q-T intervals during and after the drug injections. Distinct Q-T interval prolongation of up to 10 ms was observed with CAM at its clinical concentrations. RXM and AZM evoked Q-T interval prolongation at concentrations higher than their clinical ranges. The potencies for Q-T interval prolongation, assessed as the slope of the concentration-response relationship, were 6.09, 0.536, and 0.989 ms. ml/microg for CAM, RXM, and AZM, respectively. There was hysteresis between the change in the Q-T intervals and the time course of the plasma concentration of each drug. The rank order of clinical arrhythmogenicity was estimated to be EM > CAM > RXM > AZM, as assessed from the present results and our previous report for EM. In conclusion, RXM and AZM were estimated to be less potent at provoking arrhythmia than EM and CAM. These results should be useful for making a safer choice of an appropriate agent for patients with electrocardiographic risk factors.

Algorithms↗

PubMed2000

Influence of extracellular K+ concentrations on quinidine-induced K+ current inhibition in rat ventricular myocytes.

Hypokalaemia is one of the important risk factors for development of torsades de pointes. We recently reported that hypokalaemia increased the electrocardiographic QT interval in rats treated with quinidine, but did not alter the arrhythmogenic potency of quinidine. In this study, we have investigated the influence of extracellular potassium concentration ([K+]o) on the inhibition of several types of cardiac potassium currents by quinidine. Such types of currents include the delayed rectifier potassium current (I(K)), the transient outward current (Ito), and the inward rectifier potassium current (I(K1)), as measured in isolated rat ventricular cells using patch-clamp techniques. Concentration-dependent effects of quinidine on I(K), Ito, and I(K1) were evaluated under both normal ([K+]o = 5.4 mM) and hypokalaemic ([K+]o = 3.5 mM) conditions. In contrast to both I(K) and Ito, which were barely influenced by changes in [K+]o, I(K1) was significantly inhibited by hypokalaemia. Furthermore, while quinidine suppressed both I(K) and Ito in a concentration-dependent manner, the inhibitory potency of quinidine on these currents was not influenced by changes in [K+]o. The respective normal and hypokalaemic IC50 values for quinidine were 11.4 and 10.0 microM (I(K)), and 17.6 and 17.3 microM (Ito). Although higher concentrations of quinidine were required to inhibit I(K1), the inhibitory potency of quinidine was also found to be insensitive to changes in [K+]o. Thus, in rats, the inhibitory potency of quinidine for the K+ current-types I(K), Ito and I(K1) is barely influenced by changes in [K+]o. These findings are consistent with our previous report showing that the QT-prolonging potency of quinidine was not altered under hypokalaemic conditions. However, whilst hypokalaemia does not affect I(K) or Ito, it can inhibit I(K1) and can result in QT prolongation in-vivo.

Adrenergic alpha-Antagonists↗

PubMed2000

Inhibitory effect of azole antifungal agents on the glucuronidation of lorazepam using rabbit liver microsomes in vitro.

Azole antifungal agents (azoles) have inhibitory effects on the cytochrome P450. However, the effect of azoles on conjugative metabolism has not been given much attention. Lorazepam (LZP), a benzodiazepine sedative agent, is known to be metabolized by uridine 5'-diphosphate (UDP)-glucuronyltransferase. Herein we report investigation of the effect of azoles on the enzyme-kinetics of glucuronidation of lorazepam using rabbit liver microsomes in vitro. The Km and Vmax for LZP glucuronidation were determined to be 0.26+/-0.08 mM and 1.25+/-0.21 nmol/min/mg protein, respectively, when evaluated in the presence of a detergent 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CHAPS) (0.8 mg/mg protein). Azoles fluconazole, miconazole, and ketoconazole competitively inhibited the glucuronidation of LZP, with Ki values of 7.17+/-4.78 mM, 0.17+/-0.08 mM, and 0.092+/-0.026 mM, respectively. These results are comparable to the previously reported Ki values of azoles with zidovudine (AZT) glucuronidation (1.4, 0.18, and 0.08 mM for fluconazole, miconazole, and ketoconazole, respectively) [Sampol et al., Br. J. Clin. Pharmacol., 40, 83-86, 1995]. Therefore, in order to avoid possible side effects of LZP, the concomitant administration of LZP and azoles should be carefully evaluated.

Animals↗

PubMed2000

[Development and evaluation of an individuals-oriented information-provision system for outpatients--utility of "drug Usage sheets" and "Drug Information Cards" for patient consultation].

We have implemented an information-provision system for outpatients at the department of pharmacy, University of Tokyo Hospital, in order to comply with the revised Pharmacists' Law by which pharmacists have been obliged to provide patients with information necessary for rational usage of medicine at the time they receive dispensed drugs. This system is linked on-line with the order entry system to print "Drug Usage Sheets" containing important drug information such as therapeutic effects and adverse reactions, as well as photographic color views of drugs. We prepared the sheets by extracting and classifying the original information, and by converting medical terms into lay expressions. Moreover, we developed "Drug Information Cards" to inform each patient of severe side effects and drug interactions, which should affect drug compliance, and implemented an individuals-oriented information system using both the "Drug Usage Sheets" and "Drug Information Cards." In this study, we evaluated the usefulness of this system from the viewpoint of patients' recognition and understanding on necessary drug information. It was indicated from questionnaires to patients that the "Drug Usage Sheets" help most patients understand the names, usage, effects, and general cautions including slight adverse reactions (i.e. grade 1), and that the use of colored letters for important parts and pictograms is a useful method to attract more attention from patients as compared with a conventional method using only letters. Most patients answered that the "Drug Usage Sheets" can be utilized in many ways and valuable in taking drugs with assurance. We formulated the "Drug Information Cards" by information processing: separation of early symptoms of adverse effects into subjective and objective ones and their classification into related organs. Moreover, the brand names of drugs which may cause drug interactions have been listed on the cards so that worsening of adverse reactions and drug interactions can be avoided. Although 14% of the patients answered that they became unsecured when informed on side effects, the percentage of such patients was significantly higher with those who received caution-required drugs for the first time or who have experienced drug side effects before, suggesting the need for combining oral explanation based on each patient's background and understanding on drug adverse effects. In conclusion, an efficient provision of drug information became possible through our integration of necessary drug information in this study, and the individuals-oriented system of drug information was established, which was demonstrated to contribute to the rational usage of medicine.

Drug Information Services↗

PubMed2000

Quantitative prediction of metabolic inhibition of midazolam by erythromycin, diltiazem, and verapamil in rats: implication of concentrative uptake of inhibitors into liver.

To evaluate the degree of drug-drug interaction concerning metabolic inhibition in the liver quantitatively, we tried to predict the plasma concentration increasing ratio (R) of midazolam (MDZ) by erythromycin (EM), diltiazem (DLZ), or verapamil (VER) in rats. MDZ was administered through the portal vein at the steady state of plasma concentration of these inhibitors. The R values in the area under the plasma concentration curve of MDZ in the presence of EM, DLZ, and VER were 2.02, 1.64, and 1.30, respectively. The liver to plasma unbound concentration ratios of EM, DLZ, and VER at the steady state after infusion were 20.8, 1.02, and 3.01, respectively, suggesting concentrative uptake of EM and VER into the liver. The predicted R value in the presence of EM calculated by use of plasma unbound concentration was 1.03, whereas the value calculated with liver unbound concentration was 1.61, which was very close to the observed value. These findings indicated the need to consider the concentrative uptake of inhibitors into the liver for the quantitative prediction of metabolic inhibition. However, the predicted values in the presence of DLZ or VER calculated by use of liver unbound concentration were still underestimated. This result may be due to the metabolic inhibition by the metabolites of both inhibitors. Therefore, when predicting the degree of metabolic inhibition quantitatively, the inhibitory effect by coadministered drugs and the disposition of these metabolites in the liver must also be considered.

Animals↗

PubMed1999

Imaging of thermal activation of actomyosin motors.

We have developed temperature-pulse microscopy in which the temperature of a microscopic sample is raised reversibly in a square-wave fashion with rise and fall times of several ms, and locally in a region of approximately 10 micrometers in diameter with a temperature gradient up to 2 degrees C/micrometers. Temperature distribution was imaged pixel by pixel by image processing of the fluorescence intensity of rhodamine phalloidin attached to (single) actin filaments. With short pulses, actomyosin motors could be activated above physiological temperatures (higher than 60 degrees C at the peak) before thermally induced protein damage began to occur. When a sliding actin filament was heated to 40-45 degrees C, the sliding velocity reached 30 micrometers/s at 25 mM KCl and 50 micrometers/s at 50 mM KCl, the highest velocities reported for skeletal myosin in usual in vitro assay systems. Both the sliding velocity and force increased by an order of magnitude when heated from 18 degrees C to 40-45 degrees C. Temperature-pulse microscopy is expected to be useful for studies of biomolecules and cells requiring temporal and/or spatial thermal modulation.

Actomyosin↗

PubMed1999

Pharmacokinetic-pharmacodynamic analysis of the arrhythmogenic potency of a novel antiallergic agent, ebastine, in rats.

Ebastine (EBS), a novel nonsedative antiallergic agent, is similar to terfenadine in its chemical structure. However, clinical arrhythmogenicity of EBS remains controversial. In this study, we evaluated the possible arrhythmogenic potency of EBS as assessed by QT prolongation from a pharmacokinetic-pharmacodynamic viewpoint in comparison with that of terfenadine. EBS was intravenously infused into anesthetized rats at a rate of 3.0 or 10 mg/kg/h for 60 min, and electrocardiographic effects were continuously monitored from lead II. The plasma concentrations of EBS and its major metabolite, carebastine, were also measured under the same conditions. When intravenously administered, EBS exhibited QT prolongation in an infusion rate-dependent manner, with a lag time. Pharmacokinetic-pharmacodynamic analysis of EBS based on the effect-compartment model revealed values of EC50, Emax and EC(10 ms), (where 10 ms of QT prolongation was evoked) of 0.73 microg/mL, 12.5 ms and 2.90 microg/mL, respectively. The EC(10 ms) value of EBS was five times higher than that of terfenadine reported previously (Ohtani et al., J. Pharm. Pharmacol., 49, 458-462 (1997)). In conclusion, EBS was suggested to be less arrhythmogenic than terfenadine.

Animals↗

PubMed1999

Mechanism of the uricosuric action of the anti-inflammatory drug E3040 used to treat inflammatory bowel disease I: study using a rat model of hyperuricemia.

E3040, a new class of anti-inflammatory drug, was found to reduce the plasma uric acid level in the first phase of clinical studies. In the present study, the mechanism of the uricosuric action of E3040 was investigated using the hyperuricemia model rat. The fractional excretion of uric acid (FEurate), an indicator of the excretion of uric acid in the renal tubules, at 30, 60 and 90 min after administration of E3040 (50 mg kg(-1)) was significantly elevated as compared with that in the control. This elevation of the FEurate by E3040 was dose-dependent. Although the FEurate was elevated spontaneously 30 min after administration of E3040-sulfate (E-Sul) and glucuronide (E-Glu) (100 mg kg(-1), respectively), the value was not significantly different from the control. Based on these results, it was suggested that E3040 has a uricosuric action, probably in the proximal tubules, and the uricosuric action after administration of E3040 may be mainly due to the parent drug. Concerning the tissue distribution, the kidney concentration of E-Sul after i.v. administration of the E3040 (50 mg kg(-1)) was higher than that of the parent drug (kidney/plasma ratio approximately 2).

Animals↗

PubMed1999

Effect of itraconazole on the pharmacokinetics of digoxin in guinea pigs.

The effect of itraconazole (ITZ) on the pharmacokinetics of digoxin (DGX) was investigated in guinea pigs. The plasma concentrations of DGX in guinea pigs following treatment with ITZ (20 mg/kg intraperitoneally (i.p.)) after intravenous (i.v.) administration of DGX (0.125 mg/kg) were significantly higher than in the controls. The percentage cumulative excretion (6.9%) of DGX in bile of the ITZ-treated group up to 6 h after administration of DGX was significantly reduced (p < 0.05) compared with 10.5% in the control. The percentage cumulative excretion (3.1%) of DGX in urine of the ITZ-treated group up to 6 h after administration was also one third that in the controls. The total, biliary, renal and metabolic clearances for DGX in the ITZ-treated group were significantly reduced, while the V(dss) was unaffected. The plasma unbound fraction of DGX (ranged 47-58%) in the ITZ-treated group was generally similar to that in the controls (50-57%). The blood-to-plasma concentration ratio of DGX (range 1.28-1.42) in the absence of ITZ did not change in the presence of ITZ. Based on these results, the pharmacokinetic interaction between DGX and ITZ may be due not only to a reduction in the renal clearance but also to a reduction in the metabolic clearance of DGX by ITZ.

Animals↗

PubMed1999

Mechanism of the uricosuric action of E3040, a drug used to treat inflammatory bowel disease II: study using DBA/2N mice.

In the initial phase of clinical studies, it was shown that E3040, a new type of anti-inflammatory drug, reduced plasma uric acid levels. The present study describes a comparison of the excretion of uric acid in the proximal tubules of the kidney after administration of E3040 and its conjugates, sulphate and glucuronide, with that of other general uricosuric agents in DBA/2N mice. The aim of this investigation was to elucidate the mechanism for the uricosuric action of E3040. It was found that E3040 increased the excretion rate of uric acid in a dose-dependent manner, and the excretion rates following 10 and 50 mg/kg doses were significantly greater than that of the control group. The paradoxical effect observed with probenecid was not seen in the E3040 dose-response curve for the uric acid excretion rate. Neither E3040-sulphate nor E3040-glucuronide increased the excretion rate of uric acid significantly, even at a high dose, such as 200 mg/kg. In the pyrazinoic acid suppression test, the uric acid excretion rate after concomitant administration of E3040 and pyrazinoic acid was significantly higher than that after administration of pyrazinoic acid alone, and the rate after concomitant administration was 30% of the level after administration of E3040 alone. The change in the excretion rate of uric acid after concomitant administration of E3040 and pyrazinoic acid was similar to that of AA193, a selective inhibitor of the presecretory reabsorption of uric acid. From these results, it appears that E3040 may exert its uricosuric action by reducing the presecretory reabsorption of uric acid rather than increasing its secretion.

Animals↗

PubMed1999

Increase in the incidence of cervical and trochanteric fractures of the proximal femur in Niigata Prefecture, Japan.

This study aimed to determine the incidence of cervical and trochanteric fractures of the proximal femur in 1994 in Niigata Prefecture, Japan, and to compare this incidence with those previously reported in Niigata in 1985, 1987, and 1989. We visited all hospitals within Niigata Prefecture having an orthopedic department and reviewed the medical records and radiographs of all patients who sustained such fractures in 1994. The population of Niigata Prefecture was determined in 1994 to be 2,483,879 (1,205,151 males and 1,278,728 females). The population over 65 years of age was 428,795 (172,788 males and 256,007 females), representing 17.3% of the total population. In 1994, there were 1,468 cervical or trochanteric fractures in 378 males and 1,090 females, with a male-to-female ratio of 1:2.9. The incidence of these fractures in persons over 65 years of age was 304 fractures per 100,000 population per year. Of 528 cervical and 940 trochanteric fractures, the latter accounted for 64% of the total number. The age-specific incidence of the fractures in Niigata exhibited an exponential increase with age, similar to those reported in Sweden and the United States. However, the incidence was lower than in those countries. When comparing the number of cervical and trochanteric fractures in 1994 with the numbers reported in 1985, 1987, and 1989, it is evident that the overall number and incidence of these fractures has been increasing over this period. Even if the difference of the age-specific population among these years is adjusted, the fractures have been increasing.

Adolescent↗

PubMed1999

Sustained QT prolongation induced by tacrolimus in guinea pigs.

Recently, clinical cases have been reported of QT prolongation and torsades de pointes associated with the use of tacrolimus (FK506). We examined the relationship between QTc prolongation and the pharmacokinetics of FK506 in guinea pigs in order to evaluate the arrhythmogenicity of FK506 in comparison with quinidine (QND). FK506 (0.1 or 0.01 mg/hr/kg) or QND (30 mg/hr/kg) was intravenously infused to guinea pigs and time profiles of drug concentration in blood and QTc interval were examined during and after infusion. Both FK506 and QND evoked a significant QTc prolongation, and the dose-response relationship showed an anti-clockwise hysteresis, FK506-induced QTc prolongation persisted throughout the duration of the experiment despite a decline in the plasma FK506 concentration, whilst QND-induced QTc prolongation disappeared as plasma concentrations decreased. FK506 induced a sustained QTc prolongation in guinea pigs at drug concentrations in blood that correspond to its therapeutic range in human, suggesting that it might be of clinical significance to monitor the electrocardiogram, especially when patients have congenital or acquired QT-prolonging risk factors.

Animals↗

PubMed1999

Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats.

Disopyramide (DP) is known to induce QT prolongation and Torsades de Pointes (TdP) when administered concomitantly with erythromycin (EM). To define and evaluate quantitatively the arrhythmogenic risk of the concomitant administration of DP and EM, we investigated the influence of EM on the pharmacokinetics and pharmacodynamics of DP in rats. The time profiles of change in QT interval and plasma concentration of each drug were evaluated during and after constant intravenous infusion of DP (6.0 or 15.0 mg/kg/h), EM (4.0 or 8.0 mg/kg/h), and coadministration of DP and EM (DP 6.0 mg/kg/h plus EM 4.0 mg/kg/h). Each agent induced QT prolongation at plasma concentrations within the therapeutic range in humans. DP-induced QT prolongation was proportional to its plasma concentration. In the case of EM, the Emax model with an "effect compartment" could explain the relationship between plasma EM concentrations and changes in QT interval. Although coadministration of EM with DP gave enhanced QT prolongation compared to dosing with DP alone, EM did not affect the pharmacokinetics of DP. In conclusion, it was shown that a pharmacodynamic interaction contributes to the electrocardiographic adverse reaction (i.e., QT prolongation) induced by coadministration of DP and EM in rats.

Animals↗

PubMed1999

Analysis of antiplatelet effect of ticlopidine in humans: modeling based on irreversible inhibition of platelet precursors in bone marrow.

The relationship between plasma concentration of ticlopidine and its inhibitory effect on platelet aggregation in human was analyzed using a pharmacokinetic/pharmacodynamic (PK/PD) model. The data of plasma concentration and inhibitory effect on platelet aggregation were taken from the literature. A two-compartment open model was fitted to plasma ticlopidine concentrations. Assuming that ticlopidine acts on platelet precursors in the bone marrow, the apparent reaction rate constant of ticlopidine and platelet precursors (K), apparent transformation rate constant of platelet precursors (kr) and apparent elimination rate constant of platelets (ke) were estimated. The estimated values +/- S.D. were 1.01 +/- 1.08 ml micrograms-1 hr-1 for K, 0.265 +/- 0.259 hr-1 for kr and 0.0747 +/- 0.0112 hr-1 for ke. The antiaggregation effects of ticlopidine on platelets after administration of 100, 200, and 300 mg (bid for 8 days) were simulated using the PD parameters of K, kr, and ke. While the antiaggregation effect reached steady state within 3-4 days without dose dependency of the interval, the maximum effect increased with dose. Furthermore, changing the elimination rate constant of ticlopidine from the central compartment in the model significantly changed the duration of inhibitory effect of ticlopidine on platelet aggregation. Therefore, the reported long duration of antiplatelet effect after discontinuation of ticlopidine, which is believed to be irreversible binding to the platelet, might have been partially caused by the delayed plasma elimination after a long therapy of ticlopidine. On the other hand, the mean life-span of platelets in the blood estimated by 1/ke after administration of ticlopidine was 14 hr, far below the life-span of platelets in the blood. For a more detailed analysis of the antiplatelet effect of ticlopidine, the possible contribution of reversible binding of the drug to glycoprotein IIb/IIIa should be considered in future PK/PD models.

Blood Platelets↗

PubMed1999

In vivo and in vitro toxicodynamic analyses of new quinolone-and nonsteroidal anti-inflammatory drug-induced effects on the central nervous system.

We investigated the correlation between an in vivo isobologram based on the concentrations of new quinolones (NQs) in brain tissue and the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) for the occurrence of convulsions in mice and an in vitro isobologram based on the concentrations of both drugs for changes in the gamma-aminobutyric acid (GABA)-induced current response in Xenopus oocytes injected with mRNA from mouse brains in the presence of NQs and/or NSAIDs. After the administration of enoxacin (ENX) in the presence or absence of felbinac (FLB), ketoprofen (KTP), or flurbiprofen (FRP), a synergistic effect was observed in the isobologram based on the threshold concentration in brain tissue between mice with convulsions and those without convulsions. The three NSAIDs did not affect the pharmacokinetic behavior of ENX in the brain. However, the ENX-induced inhibition of the GABA response in the GABAA receptor expressed in Xenopus oocytes was enhanced in the presence of the three NSAIDs. The inhibition ratio profiles of the GABA responses for both drugs were analyzed with a newly developed toxicodynamic model. The inhibitory profiles for ENX in the presence of NSAIDs followed the order KTP (1.2 microM) > FRP (0. 3 microM) > FLB (0.2 microM). These were 50- to 280-fold smaller than those observed in the absence of NSAIDs. The inhibition ratio (0.01 to 0.02) of the GABAA receptor in the presence of both drugs was well-fitted to the isobologram based on threshold concentrations of both drugs in brain tissue between mice with convulsions and those without convulsions, despite the presence of NSAIDs. In mice with convulsions, the inhibitory profiles of the threshold concentrations of both drugs in brain tissue of mice with convulsions and those without convulsions can be predicted quantitatively by using in vitro GABA response data and toxicodynamic model.

Animals↗

PubMed1999

Inhibitory effects of the antihistamines epinastine, terfenadine, and ebastine on potassium currents in rat ventricular myocytes.

We examined and compared the inhibitory effects of three non-sedating antihistamines, terfenadine, ebastine, and epinastine, on delayed rectifier potassium current (IK) and transient outward potassium current (Ito) of rat isolated ventricular myocytes, using a patch clamp technique. Terfenadine, ebastine and epinastine were found to inhibit IK with IC50 values of 5.96, 15.3 and 145 microM, respectively. Ito was suppressed by epinastine with an IC50 value of 69.5 microM. The order of arrhythmogenicity, assessed by the inhibition of IK, was ranked as terfenadine > ebastine > epinastine, consistent with that of the potencies of each drug for QT prolongation reported in rats.

Animals↗

PubMed1999

Pharmacokinetic/pharmacodynamic analysis of tacrolimus-induced QT prolongation in guinea pigs.

Recently, several reports of clinical cases of QT prolongation and torsades de pointes, associated with the use of tacrolimus (FK506), have come to light. We have previously demonstrated FK506-induced QT prolongation in guinea pigs [Minematsu T., et al., Life Sci., 65, PL197-PL202 (1999)]. We now examined the relationship between QTc prolongation and the pharmacokinetics of FK506 in guinea pigs, in order to evaluate the arrhythmogenicity of FK506 when compared with that of quinidine sulfate (QND). Thus, dose-response relationships for FK506 (0.01 or 0.1 mg/h/kg) or QND (30 mg/h/kg) were investigated during and after intravenous infusion and also following intravenous bolus administration of FK506 (0.2 mg/kg). The dose-response relationship between plasma drug concentration and QTc prolongation for FK506 and QND were subsequently analyzed using an effect compartment model. The pharmacodynamic parameters thus obtained were as follows: kE0 2.72 x 10(-4) (min-1), Emax 27.1 (ms), EC50 0.376 (ng/ml) for FK506; and kE0 0.148 (min-1), K 8.41 (ms.ml/microgram) for QND. The anti-clockwise hysteresis observed for FK506-induced QT prolongation was successfully analyzed by the present pharmacokinetic/pharmacodynamic model, which may provide a rational basis for developing a clinical dosing regimen to avoid possible QT prolongation induced by FK506.

Animals↗

PubMed1999

[Pharmacokinetic analysis of antiplatelet effect of sarpogrelate hydrochloride and its application to drug dosage regimen--modeling based on reversible inhibition of 5-HT2 serotonergic receptor in the platelet membrane by sarpogrelate hydrochloride and its metabolite].

Sarpogrelate hydrochloride is an antiplatelet drug, and expected to be useful in the treatment of chronic arterial occlusive diseases. Sarpogrelate and its active metabolite (M-1) are potent inhibitors of human platelet aggregation, and selectively inhibit 5-HT2-serotonergic receptors on human platelets. However, the plasma concentrations of these inhibitors do not correlate to the inhibitory effect on platelet aggregation after administration. Sarpogrelate disappears from the plasma more rapidly in comparison to the duration of its pharmacological effect, and the plasma concentration of M-1 is very low (< 1/10 of sarpogrelate). In this paper, we describe a pharmacokinetic-pharmacodynamic model for ascertaining the antiplatelet effects of sarpogrelate and M-1, by considering both the competitive reversible inhibition and the association/dissociation process of these drugs at the 5-HT2 receptors on platelets (Most data used for analysis were obtained from the literatures, except for the serum protein binding rate of M-1). The developed model was well fitted to the actual data, and suggested that M-1 was more effective for the inhibition of platelet aggregation than sarpogrelate. On the basis of these findings, a new method was developed for predicting inhibitory effects on platelet aggregation after oral administration of sarpogrelate hydrochloride. This method is useful for planning a rational dosage regimen of sarpogrelate hydrochloride and predicting the duration of antiplatelet activity after the discontinuance of the drug.

Administration, Oral↗