Decreased cyclosporine absorption after treatment with GoLytely lavage solution in a kidney transplant patient.
Explore the source record for details and available documents.
Administration, Oral↗
Biomedical subjects
T Iga
Publications and source records attributed to T Iga.
Pharmacokinetic analysis of the disposition of valproate in pregnant rats.
Kinetic analysis of valproate (VPA) disposition in pregnant rats was performed. A dose-dependent saturable plasma elimination was observed in both the control and pregnant rats. Saturation was more remarkable in the pregnant rats and this was assumed to be due to the decreased hepatic extraction by metabolism. Pharmacokinetic parameters were calculated using a two-compartment open model with a Michaelis-Menten-type elimination process from the central compartment. In the pregnant rats, the calculated values of Km and Vmax decreased significantly, by one-half of those of the control rats, whereas no significant difference was observed in distribution rate constants (k12, k21) and volumes of distribution (V1, Vdss) between two groups of rats. Furthermore, the hepatic extraction of VPA in the control and pregnant rats was investigated in order to explain nonlinear pharmacokinetics of VPA. The values of the hepatic extraction ratio in the control and pregnant rats were 39.9 and 22.4% at the steady state concentration of approximately 20 micrograms/ml, respectively. The extraction ratios in the pregnant rats were lower than those of the control rats. This fact may be one of the reasons why the elimination of VPA in the pregnant rats is more susceptible to saturation.
Animals↗
Protein-mediated hepatic uptake of rose bengal in analbuminemic mutant rats (NAR). Albumin is not indispensable to the protein-mediated transport of rose bengal.
Recent kinetic studies using in situ perfused rat liver suggested that the hepatic uptake of extensively albumin-bound ligands is mediated primarily by direct interaction of the albumin-ligand complex with the hepatocyte surface rather than by the small unbound fraction of ligand, as has been generally believed [Ockner et al., Am. J. Physiol. 245, G13 (1983)]. In order to investigate this mechanism in vivo, rose bengal (RB) was injected iv to the normal and Nagase analbuminemic mutant rats (NAR) and both the pharmacokinetic parameters and the serum protein binding parameters for the two groups were compared. The serum disappearance curves of RB in normal rats and NAR were almost superimposed, and no significant difference in various pharmacokinetic parameters including the hepatic uptake clearance (k12V1) was observed between the two groups. Nevertheless, the unbound fractions of RB in serum were approximately 4-fold (equilibrium dialysis method) and 10-fold (spectrophotometric method) higher than those in normal rats. However, in both groups of rats RB is extensively bound to plasma proteins and more than 99.8% of RB in the plasma exists as the protein-bound form. The intrinsic ability of the two groups of rats to take up unbound RB was compared using isolated liver cells. No significant difference between the two groups was observed in the initial velocity of uptake. From these findings, we concluded that the hepatic uptake of RB is primarily driven by the serum protein-bound form and not by the unbound form and that the serum protein-mediated uptake mechanism of RB was not specific only for serum albumin but also for other serum proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Kinetics of receptor occupation and anticonvulsive effects of diazepam in rats.
Time courses of anticonvulsive effect nd benzodiazepine receptor occupation in the brain were determined after iv administration of diazepam (DZP) (1.2 mg/kg) to rats. Score for the anticonvulsive effect was assigned to each DZP-treated rat depending on the degree of protection against pentylenetetrazole-induced seizures. Measurement of in vivo receptor occupation was made by comparing the specific 3H-DZP binding in vitro to the crude synaptosomal fractions between vehicle-treated rats (control) and DZP-injected rats. The receptor occupation declined in parallel with the anticonvulsive effect with approximate half-life of 1 hr. A good linear correlation (r = 0.977) was observed between the receptor occupation and the anticonvulsive effect. The time course of anticonvulsive effect was further compared with that of DZP concentration in the brain which was previously reported [Igari et al., Drug Metab. Dispos. 10, 676 (1982)]. The anticonvulsive effect was nonlinearly related to the DZP concentration in the brain with the half-maximum concentration, Kd in vivo of 793 nM. The half-maximum concentration for the unbound DZP, Kd in vivo was also estimated to be 113 nM, which was still 50 times the values of Kd (2.3 nM) determined at 0 degree C from an in vitro binding study of 3H-DZP to the receptor in the crude synaptosomal fraction.
Animals↗
Effect of surgery on serum alpha 1-acid glycoprotein concentration and serum protein binding of DL-propranolol in phenobarbital-treated and untreated rats.
Explore the source record for details and available documents.
Animals↗
Physiologically based pharmacokinetics of radioiodinated human beta-endorphin in rats. An application of the capillary membrane-limited model.
In order to simulate the distribution and elimination of radioiodinated human beta-endorphin (125I-beta-EP) after iv bolus injection in rats, we proposed a physiologically based pharmacokinetic model incorporating diffusional transport of 125I-beta-EP across the capillary membrane. This model assumes that the distribution of 125I-beta-EP is restricted only within the blood and the tissue interstitial fluid, and that a diffusional barrier across the capillary membrane exists in each tissue except the liver. The tissue-to-blood partition coefficients were estimated from the ratios of the concentration in tissues to that in arterial plasma at the terminal (pseudoequilibrium) phase. The total body plasma clearance (9.0 ml/min/kg) was appropriately assigned to the liver and kidney. The transcapillary diffusion clearances of 125I-beta-EP were also estimated and shown to correlate linearly with that of inulin in several tissues. Numerically solving the mass-balance differential equations as to plasma and each tissue simultaneously, simulated concentration curves of 125I-beta-EP corresponded well with the observed data. It was suggested by the simulation that the initial rapid disappearance of 125I-beta-EP from plasma after iv injection could be attributed in part to the transcapillary diffusion of the peptide.
Animals↗
Effect of serum from renal failure and cirrhotic patients on the blood-brain barrier permeability to DL-propranolol in rats.
Our previous studies using an in vivo tissue-sampling single-carotid injection method have shown that the transport of DL-propranolol into rat brain is inhibited by the serum from rats with uranyl nitrate-induced acute renal failure. The present studies were designed to examine the effect of serum from patients with renal or liver disease on the transport of DL-propranolol into the rat brain. While the binding of DL-propranolol to serum from cirrhotic patients was significantly decreased compared to normal serum, there was no change for the serum from patients with renal failure. In the carotid injection studies, the brain transport parameters such as the brain uptake index (BUI), the unidirectional extraction ratio (ET), the blood-brain barrier permeability surface area product (PSapp), and PSapp corrected for the unbound fraction (PSuapp) in rats injected with serum from patients with renal failure were significantly reduced to approximately 40-53% of those in controls. No change in BUI, ET, and PSapp was found in rats injected with serum from cirrhotic patients. However, the cirrhotic patients adopted in the present study had relatively mild liver disease (judging from the biochemical blood test), and we cannot refer to the more severe cirrhotic patients only from this study. Moreover, significant correlations were observed between the biochemical parameters (blood urea nitrogen, serum creatinine concentration) representing the degree of renal failure and the transport parameters (ET, PSapp, or PSuapp) of DL-propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Efflux of cimetidine from the rat cerebrospinal fluid.
Explore the source record for details and available documents.
Animals↗
Nonlinear tissue distribution of ouabain in rabbits.
Nonlinear and slow tissue distribution of ouabain was found in rabbits, and the contribution of the ouabain binding to Na+,K+-ATPase was also examined in the heart. The tissue-to-plasma concentration ratio (Kp) of ouabain in each tissue increased with time until 120 min. In addition, the Kp also depended on the plasma concentration (Cp). In the heart, Kp decreased from 12.6 +/- 1.2 to 1.9 +/- 0.2 with the increase of the Cp from 67.3 +/- 5.0 to 497 +/- d 85.2 nM. These data indicate that ouabain distributes slowly into each tissue by a saturable process. The specific binding of ouabain to cardiac Na+,K+-ATPase was measured using crude homogenates. The dissociation constant and the binding capacity were 86 nM and 2.3 nmol/ml of 0.5% homogenate, respectively. The tissue-to-plasma concentration ratio (Kp,vitro) was constructed based on these binding parameters and this explained almost 40% of the Kp obtained in vivo. These results suggest that the ouabain binding to Na+,K+-ATPase might play one of the major roles in the slow and nonlinear tissue distribution of ouabain in rabbits.
Animals↗
Tissue distribution of 14C-diazepam and its metabolites in rats.
We have kinetically investigated the tissue distribution of 14C-diazepam and described the appearance and disappearance of its metabolites (3-hydroxydiazepam, desmethyldiazepam, and oxazepam) following a single iv injection of 14C-diazepam into rats. Significant amounts of oxazepam were detected in plasma and various tissues in the rat, contrary to previous reports. Concentration-time profiles of diazepam in the main disposing organs (liver, kidney, and lung) and the other organs (brain, heart, and small intestine) indicated that diazepam was distributed rapidly to these organs. Concentration-time profiles of diazepam in the main tissues for drug distribution (skin and adipose) indicated that diazepam was slowly distributed to these tissues, whereas that in muscle, which is also responsible for drug distribution, indicated that diazepam was less rapidly distributed to this tissue. Metabolites appeared in plasma and various tissues or organs immediately after iv injection of diazepam. Metabolites levels in plasma and various tissues or organs were significantly lower than that of diazepam except for liver and small intestine, where metabolites levels were higher compared to that of diazepam and metabolites exhibited a considerable persistence.
Adipose Tissue↗
Kinetic analysis of tolbutamide-sulfonamide interaction in rabbits based on clearance concept. Prediction of species difference from in vitro plasma protein binding and metabolism.
The interaction between tolbutamide (TB) and sulfonamide (SA) in rabbits was quantitatively investigated by both in vivo and in vitro experiments, and the mechanisms of species difference between rabbits and rats were analyzed by comparing the two total body clearances (CLtot) obtained from in vivo and in vitro studies. The sulfonamides used were sulfaphenazole (SP) and sulfadimethoxine (SDM). In vivo CLtot of TB was changed little by SA in rabbits, which was contrary to the phenomenon seen in rats, i.e. CLtot was markedly decreased by SA in rats (Sugita et al., Biochem. Pharmacol., 30, 3347, 1981). The total body clearance defined as CL in vitro tot.pred was predicted for TB in the presence and absence of SA by the equation: CL in vitro tot.pred congruent to fB CL in vitro int, where fB is the blood-free fraction and CL in vitro int is the hepatic intrinsic clearance of unbound drug obtained from in vitro experiments using liver microsomal fraction. A comparatively good agreement was observed between the two CLtot obtained from in vivo and in vitro data. The analysis in rabbits based on these in vitro experiments showed that the small gross changes of in vivo CLtot induced by SA were due to the compensative changes of two factors, i.e. fB and CL in vitro int which in the presence of SA were approximately 200 and 50% of the control, respectively. However, in rats, the marked decrease of in vivo CLtot induced by SA was explained by the greater degree of the decrease in CL in vitro int than that of the increase in fB.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effect of pregnancy on tissue distribution of salicylate in rats.
The effect of pregnancy on tissue distribution of salicylate was studied by comparing both pharmacokinetic and protein-binding parameters between 20-day-pregnant rats and nonpregnant (control) rats. In the pregnant rats, the volume of distribution increased significantly (p less than 0.05) from 164 ml/kg of the control to 225 ml/kg, and the total body clearance also increased significantly (p less than 0.05) from 12.1 ml/hr/kg of the control to 19.8 ml/hr/kg. But these changes did not affect the plasma disappearance half-life of salicylate in the pregnant rats. The serum unbound fraction (fs) of the pregnant rats at 8 hr after iv administration of salicylate increased remarkably from 0.14 of the control to 0.67. The fs in the fetal serum (0.41) was lower than that in the maternal serum in spite of the lower albumin concentration in the fetal serum. A nonlinear serum protein binding was observed both in the control and in the fetal rats, but not observed in the pregnant rats. In the pregnant rats, the tissue-to-serum concentration ratios (Kp) of all tissues studied were larger than those in the control rats, and the values of Kp in the fetal were larger than those in the maternal. To elucidate these difference in Kp values between the pregnant and control rats, a mathematical model was proposed, where salicylate was distributed in the interstitial fluid, bound to the interstitial albumin, and translocated into the intracellular fluid according to the pH partition theory. The Kp values of most tissues in the control and pregnant rats were predicted successfully by using this model.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Pharmacokinetic analysis of enterohepatic circulation of buprenorphine and its active metabolite, norbuprenorphine, in rats.
The pharmacokinetic characteristics of buprenorphine (BN) and its active metabolite, norbuprenorphine (NBN), was investigated using rats. The elimination half-life (t1/2), total body clearance (CLtot), and steady-state volume of distribution (Vdss) of BN (0.6 mg/kg iv dose) in the intact rat were 2.8 hr, 23.3 ml/min/kg, and 4.2 liters/kg, respectively, and those of NBN (0.6 mg/kg iv dose) were 0.9 hr, 35.0 ml/min/kg, and 2.0 liters/kg. Within 24 hr after administration of BN (0.6 mg/kg dose) to the bile-fistula rat, 74.1% of dose was excreted in the bile as BN glucuronide (BN-Glu) and 18.5% as NBN glucuronide (NBN-Glu), and in urine < 3.2% as BN-Glu. After administration of NBN to the bile-fistula rat, 85.1% and 9.1% of the dose were excreted as NGN-Glu in bile and urine, respectively. The existence of the enterohepatic circulation (EHC) of BN and NBN was confirmed by using paired rats: the donor and recipient rats. Within 24 hr after administration of BN (0.6 mg/kg dose) to the donor rat, 58.8% of the dose was reexcreted as NBN-Glu in bile of the recipient and 25.1% as BN-Glu. Based on the results of in vitro metabolism, it was suggested that this increase in the proportion of NBN-Glu in bile observed after one enterohepatic cycling of BN may be due to the first-pass metabolism in the liver. BN was detected in the plasma of the recipient rat after administration of BN, to the donor rat.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Tissue distribution and metabolism of amitriptyline after repeated administration in rats.
Plasma concentration, tissue distribution, and metabolism of amitriptyline (AMI) in rats pretreated with AMI (20 mg/kg/day, ip dose, for 7 days; treated) were compared with control rats. Plasma concentrations of AMI after intravenous administration (2 and 10 mg/kg) to the treated rat were significantly higher than those to the control rat in both doses. The difference in the plasma concentration between both groups may be caused by a change of tissue distribution of AMI, because the blood cell-to-plasma concentration ratio and the tissue-to-blood concentration ratio values for various tissues in the treated rat were smaller than those in the control, respectively. The plasma unbound fraction of AMI in the treated rat was significantly smaller (p < 0.05). alpha 1-Acid glycoprotein concentration in plasma of the treated rat was approximately twice that in the control rat. These results suggest that the decrease of tissue distribution of AMI in the treated rat may be caused by the decrease in the plasma unbound fraction of AMI with the increase of alpha 1-acid glycoprotein in plasma. The area under the plasma concentration-time curve for AMI and its main metabolite, nortriptyline, in the treated rat after intraportal administration of AMI was 1/3 and 3-fold those in the control rats, respectively. On the other hand, the hepatic intrinsic clearance (CLH,Int) of the unbound drug in the treated rat was approximately twice that of the control, suggesting that the increase of the (CLH,Int) by repeated administration of AMI may result in the induction of oxidative metabolism.
Amitriptyline↗
Linear relationship between GABAA receptor occupancy of muscimol and glucose metabolic response in the conscious mouse brain. Clinical implication based on comparison with benzodiazepine receptor agonist.
The effect of muscimol, a GABAA receptor agonist, on the basic metabolic activity was investigated in the mouse brain and was correlated with its receptor occupancy. For the quantitative evaluation of the functional activity of the mouse brain, the cerebral glucose utilization was measured by the double tracer technique, using [14C] 2-deoxyglucose and [3H]3-O-methylglucose. The dose-dependent reduction in the cerebral glucose utilization was observed after intravenous administration of various doses of muscimol (0.3-1.5 mg/kg). On the other hand, the GABAA receptor occupancy of muscimol was determined by using the values of the unbound drug concentration in the brain tissue and the receptor dissociation constant based on the in vitro binding experiments using the dissociated brain cells. The tissue unbound concentration of muscimol was calculated by multiplying the total concentration in the brain after administration of muscimol and the tissue unbound fraction, which was measured by the equilibrium dialysis method using brain tissue homogenate. A linear relationship was observed between the GABAA receptor occupancy of muscimol and the decrease in the cerebral glucose utilization. This finding indicates that the simple receptor occupancy theory holds for this receptor-ligand system, and there is a large difference in the effect on glucose metabolic response between GABAA receptor-agonist interaction and benzodiazepine receptor-agonist interaction.
Animals↗