Biomedical subjects

E Nakashima

Publications and source records attributed to E Nakashima.

At least 37 records · Page 2Linked to original sources

PubMed2001

Persistent subclinical inflammation among A-bomb survivors.

PURPOSE: To investigate the associations between inflammation tests and radiation dose in A-bomb survivors. SUBJECTS AND METHODS: Subjects were A-bomb survivors who underwent inflammation tests of leukocyte counts, neutrophil counts, erythrocyte sedimentation rate, corrected erythrocyte sedimentation rate, alpha-1 globulin, alpha-2 globulin and sialic acid between 1988 and 1992. Associations with radiation dose (DS86) were analyzed by regression analysis and heterogeneity among inflammatory diseases, anaemia at examination, or history of cancer was also tested. RESULTS: The associations with radiation dose were statistically significant for leukocyte counts (71.0mm(-3) Gy(-1), p=0.015), erythrocyte sedimentation rate (1.58 mm h(-1) Gy(-1) , p = 0.0001), corrected erythrocyte sedimentation rate (1.14mm h(-1) Gy(-1), p=0.0001), alpha-1 globulin (0.0057 g dl(-1) Gy(-1), p=0.0001), alpha-2 globulin (0.0128 g dl(-1) Gy(-1), p=0.0001), and sialic acid (1.2711 mg dl(-1) Gy(-1), p=0.0001) but not for neutrophil counts (29.9 mm(-3) Gy(-1), p=0.17). Heterogeneity was not statistically significant. Among inflammatory diseases, associations were the strongest for chronic thyroiditis and chronic liver diseases. CONCLUSIONS: This study suggests statistically significant association between inflammation in A-bomb survivors and radiation dose of during 1988-1992. The association might contribute, as an epigenetic and/or bystander effect, to development of several radiation-induced disorders.

Aged↗

PubMed2001

Application of the PKCYP-test in cases of altered CYP1A2 for multiple CYP systems in rat models of disease.

Previously, we established a method to assess drug metabolism capacity based on a pharmacokinetic estimation of the quantity of cytochrome P450 (CYP) in vivo (PKCYP-test) by introducing an apparent liver-to-blood free concentration gradient in vivo (qg). The qg values were determined as the ratio of in vivo-in vitro clearance. In this study, we examined the application of the PKCYP-test to the clearance of acetanilide and caffeine mediated by CYP1A2 using rat models in which the levels of CYP enzymes were reduced. Rats fed a choline-deficient diet (CD-fed) and aged rats were used as models for a low level of CYP in the liver. In both rat models, the contribution (fCYP) of CYP1A2 to the in vivo intrinsic clearance values (CLint) of acetanilide and caffeine metabolism was less than unity, suggesting that other metabolic pathways are involved in the CLint. The in vivo clearance for CYP1A2 was estimated by multiplying fCYP by CLint, then the value of qg was determined as the ratio of in vivo-in vitro clearance. We predicted the level of CYP1A2 in CD-fed and aged rats, based on the clearance of acetanilide mediated by CYP1A2, using the qg value of control rats. The clearance of caffeine mediated by CYP1A2 in CD-fed and aged rats, as estimated from the predicted level of CYP1A2, correlated with the observed values. In conclusion, we have demonstrated that the PKCYP-test can be applied to CYP1A2 for drugs metabolized by multiple CYP isozymes, and/or to models involving reduced CYP.

Acetanilides↗

PubMed2001

Synergistic effect of indomethacin with adriamycin and cisplatin on tumor growth.

In this study, we have examined the antitumor effect of combined administrations of indomethacin (IND) with chemotherapeutic drugs on tumor growth. Colon 26 clone 20 (C20) cells and monocyte chemotactant protein-1 (MCP-1) transfected C20 cells (C20betaA-2-1) were used and these cells were inoculated into the footpad of BALB/c mice. At day 1 after tumor inoculation, treatment with 0.001% IND via the drinking water was commenced. At days 4, 6, and 8, adriamycin or cisplatin was administered intravenously at a dose of 5 mg/kg or intraperitoneally at a dose of 2 mg/kg, respectively. Although IND, adriamycin and cisplatin only partially reduced the growth of the C20 tumors after treatment with each drug on its own, a marked synergistic effect was observed when they were given in combination. A synergistic effect between IND and cisplatin on C20betaA-2-1 was also observed. However, IND itself showed no suppression of C20betaA-2-1 tumor growth. These results suggest that combination of indomethacin with chemotherapeutic drugs could be an effective form of cancer chemotherapy. The observed effects may be dependent on the expression of MCP-1.

Adenocarcinoma↗

PubMed2001

Application of the PKCYP-test to predict the amount of in vivo CYP2C11 using tolbutamide as a probe.

Previous reports have shown that the determination of drug metabolism capacity can be made by the pharmacokinetic estimation of the quantity of cytochrome P450 (CYP) in vivo (PKCYP-test), in which an apparent liver-to-blood free concentration gradient in vivo (qg) is introduced, which is useful for evaluating fluctuations of CYPIA2 in rats. The aim of the present study was to examine the application of the PKCYP-test to evaluate the quantity of in vivo CYP2C11 by using tolbutamide as a probe, to confirm its validity using a physiologically-based pharmacokinetic rat model. Rats treated with carbon tetrachloride (CCl4-treated rats) were used as a model for low levels of CYP2C11 in the liver. In CCl4-treated rats, the total body clearance (CLtot) of tolbutamide and the amount of CYP2C11 fell to about a quarter and a third of that in control rats, respectively. The time-course of tolbutamide concentrations in serum in control rats could be simulated by a physiologically-based pharmacokinetic model. In CCl4-treated rats, take into consideration the qg value of control rats, the level of CYP2C11 was accurately predicted by the PKCYP-test, and the time-course of tolbutamide concentrations in serum could be predicted by the same physiologically-based pharmacokinetic model. In conclusion, we have shown that the PKCYP-test can be used to predict levels of CYP2C11. It was also demonstrated that the qg and amount of CYP are useful parameters in the PKCYP-test by constructing a physiologically-based pharmacokinetic model which was applied to the PKCYP-test.

Animals↗

PubMed2001

Correlation between fatty liver and coronary risk factors: a population study of elderly men and women in Nagasaki, Japan.

The relation between fatty liver, detected by ultrasonography as a marker of visceral fat accumulation, and coronary risk factors was studied in 810 elderly men and 1,273 elderly women in Nagasaki, Japan from 1990 to 1992. The prevalence of fatty liver was 3.3% in the male and 3.8% in the female non-obese participants (BMI, body mass index < 26.0 kg/m2) and 21.6% in the male and 18.8% in the female obese participants (26.0 kg/m2 < or = BMI). Fatty liver was significantly (p < 0.01) related to hypercholesterolemia and hypertriglyceridemia in the men and to hypertension, hypercholesterolemia, low-HDL cholesterol, hypertriglyceridemia and diabetes mellitus or impaired glucose tolerance (DM+IGT) in the women independent of age, obesity, smoking and drinking. Non-obesity with fatty liver, rather than obesity with or without fatty liver, had the highest odds ratio for hypertension and low-HDL cholesterol in the men and for hypercholesterolemia, low-HDL cholesterol, hypertriglyceridemia and DM+IGT in the women. The prevalence of fatty liver is the same in elderly men and women, and fatty liver is an independent correlate of coronary risk factors in the elderly.

Aged↗

PubMed2001

Placental transport of bile acids: analysis of bile acids in maternal serum and urine, umbilical cord blood, and amniotic fluid.

To investigate the role of placental transport of bile acids in fetal bile acid metabolism, such as with regard to synthesis of the unusual bile acids (1 beta- and 6 alpha-hydroxylated and unsaturated bile acids), we measured the concentrations of bile acids in umbilical cord blood, amniotic fluid, maternal serum and maternal urine at delivery by means of gas chromatography-mass spectrometry. Serum and urine from healthy nonpregnant women were used as controls. We detected large amounts of unusual bile acids, especially hyocholic acid and 3 beta-hydroxy-delta 5 bile acids, in amniotic fluid and umbilical cord blood. The concentration of total bile acids in maternal serum was less than that of control serum and umbilical cord blood, and the concentration of total bile acids in maternal urine was higher than that of control urine and amniotic fluid. In conclusion, the fetus synthesized large amounts of unusual bile acids, and these compounds were transported from fetus to mother by placental transfer. We suggest that pregnant women may excrete large amounts of bile acids into the urine to control serum concentration of bile acids in fetus.

Adult↗

PubMed2000

Physiologically-based pharmacokinetic analysis of grepafloxacin.

Grepafloxacin (GPFX) is a synthetic new quinolone antimicrobial agent that possesses an extensive tissue distribution and exhibits a strong antibacterial activity in vivo. In this study, the tissue distribution characteristics of GPFX were examined using tissue concentration-time profiles following intravenous administration to rats. Subsequently, the pharmacokinetics of GPFX were analyzed based on the physiological pharmacokinetic model. The tissue-to-plasma partition coefficients (Kp) of GPFX in rats were high in all tissues except brain. A pharmacokinetic model for rabbits, monkeys and dogs was constructed using the tissue-to-plasma free concentration ratio (Kp,f) of GPFX in rats to simulate the GPFX concentration-time profile in plasma following intravenous administration of GPFX to each animal. The calculation-derived concentrations correlated well with the experimentally-derived data, suggesting that there are no interspecies differences in the high tissue distribution characteristics of GPFX. The clearance rates of GPFX in humans were predicted from the pharmacokinetic parameters of rats, rabbits, monkeys and dogs by an animal scale-up method and a pharmacokinetic model for humans was constructed. The GPFX concentration-time profiles in plasma, following oral administration of GPFX to humans, were predicted within 0.5-1.0 h of mean absorption time and the calculation-derived results were in good agreement with the experimental data. Thus, it is suggested that the concentration-time profile in plasma and all human organs can be predicted from the pharmacokinetic data of animals.

Administration, Oral↗

PubMed2000

Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis.

CONTEXT: Cirrhosis is widely regarded as being irreversible. Recent studies have demonstrated that fibrosis may decrease with time in humans and experimental animals if the disease activity becomes quiescent. The histologic appearance of regressing cirrhosis in the human has not been described in detail. OBJECTIVES: To define histologic parameters that indicate regression of cirrhosis and to provide an interpretation of how regression occurs from a histologic point of view. DESIGN: A patient who underwent a series of biopsies that showed apparent regression of hepatitis B cirrhosis is presented. In addition, 52 livers removed at transplantation having cirrhosis or incomplete septal cirrhosis were graded for histologic parameters that suggest progression or regression of fibrosis. Progression parameters were steatohepatitis, inflammation, bridging necrosis, and piecemeal necrosis. The regression parameters (collectively called the hepatic repair complex) were delicate perforated septa, isolated thick collagen fibers, delicate periportal fibrous spikes, portal tract remnants, hepatic vein remnants with prolapsed hepatocytes, hepatocytes within portal tracts or splitting septa, minute regenerative nodules, and aberrant parenchymal veins. RESULTS AND CONCLUSIONS: Regression parameters were found in all livers and were prominent in the majority. Livers with micronodular cirrhosis, macronodular cirrhosis, and incomplete septal cirrhosis demonstrate a histologic continuum. A continuum of regressive changes was also seen within individual livers. These appearances allow one to understand visually how fibrous regions of hepatic parenchyma can be returned toward a normal appearance. Many examples of incomplete septal cirrhosis could be the product of regressed cirrhosis.

Adult↗

PubMed1999

An aldose reductase inhibitor prevents the glucose-induced increase in PDGF-beta receptor in cultured rat aortic smooth muscle cells.

To examine the role of platelet-derived growth factor (PDGF) and the polyol pathway in the growth activity of smooth muscle cells (SMCs), [(3)H]-thymidine incorporation, [(125)I]-PDGF-BB binding and expression of PDGF-beta receptor protein were measured in rat aortic SMCs cultured with 5.5 or 20 mM glucose with or without anti-PDGF antibody or an aldose reductase inhibitor, epalrestat. SMCs cultured with 20 mM glucose demonstrated an accelerated thymidine incorporation compared with SMCs cultured with 5.5 mM glucose, which was prevented by anti-PDGF antibody. This acceleration of growth activity by 20 mM glucose was accompanied by an increase in PDGF-BB binding, which was due to the increased number of PDGF-beta receptors and the overexpression of PDGF-beta receptor protein. Epalrestat prevented all these abnormalities. These observations suggest that polyol pathway hyperactivity plays an important role in the proliferation of SMCs which may be mediated through the accelerated expression of PDGF-beta receptor protein.

Aldehyde Reductase↗

PubMed1999

An aldose redutase inhibitor prevents the intimal thickening in coronary arteries of galactose-fed beagle dogs.

AIMS/HYPOTHESIS: Although increased polyol pathway activity has been implicated in the pathogenesis of diabetic microangiopathy, the relation with diabetic macroangiopathy remains unclear. Galactose feeding is known to stimulate the polyol pathway and to develop abnormalities similar to those in diabetic microangiopathy. Our study was conducted to investigate whether an activation of polyol pathway by long-term treatment with galactose produced morphological changes in coronary arteries of dogs and the effect of an aldose reductase inhibitor, epalrestat, was also studied. METHODS: Dogs received either normal chow or chow containing 30% galactose with or without epalrestat given orally (20 or 50 mg x kg(-1)). After 44 months, morphometric analyses of coronary arteries were carried out and the galactitol contents in aortas were measured. RESULTS: The ratio of areas of the intimal layer to those of the medial layer, an indicator of intimal thickening, was statistically significantly increased in galactose-fed dogs compared with control dogs. Galactose-fed dogs had a remarkable accumulation of galactitol in their aortas. These morphological and biochemical deficits were reduced by treatment with epalrestat. CONCLUSION/INTERPRETATION: This report morphologically shows diabetes-like macrovascular abnormalities in galactosaemic animals, suggesting that polyol pathway hyperactivity is closely related to the development of diabetic macroangiopathy, which could be prevented by aldose reductase inhibition.

Aldehyde Reductase↗

PubMed1999

Effect of vitamin E and allylamine on the proliferation of cultured aortic smooth muscle cells from streptozotocin-induced diabetic rats.

To investigate the effect of vitamin E on the proliferation activity of vascular smooth muscle cells (SMCs) in diabetes mellitus, [3H]-thymidine incorporation was measured in cultured SMCs isolated from normal and streptozotocin-induced diabetic rats treated with or without vitamin E and/or allylamine. Untreated diabetic rats demonstrated significantly elevated concentrations of serum total cholesterol, triglycerides and malondialdehyde (MDA). Allylamine caused a further increase in serum MDA. Treatment with vitamin E decreased the serum concentrations of triglycerides and MDA in both allylamine-treated and -untreated diabetic rats. [3H]-Thymidine incorporation in cultured SMCs from diabetic rats was significantly increased compared with that from normal rats. SMCs from allylamine-treated diabetic rats showed an enhanced increase in thymidine incorporation compared with that from untreated diabetic rats. The increase in thymidine incorporation in SMCs from untreated and allylamine-treated diabetic rats was significantly reduced by the treatment with vitamin E. These observations suggest that vitamin E has a preventive effect on the proliferation of vascular SMCs in diabetes, and that this effect may be mediated through an enhancement of free radical scavenging.

Allylamine↗

PubMed1999

A protein kinase C-beta-selective inhibitor ameliorates neural dysfunction in streptozotocin-induced diabetic rats.

Increased protein kinase C (PKC) activity has been implicated in the pathogenesis of diabetic retinopathy and nephropathy. However, the role of PKC in diabetic neuropathy remains unclear. The present study was conducted to compare the effect of PKC inhibition by a PKC-beta-selective inhibitor, LY333531 (LY), on diabetic nerve dysfunction with that of an aldose reductase inhibitor, NZ-314 (NZ). Streptozotocin-induced diabetic rats were treated with or without LY and/or NZ for 4 weeks, and motor nerve conduction velocity (MNCV), coefficient of variation of R-R interval (CVR-R), sciatic nerve blood flow (SNBF), peak latencies of oscillatory potentials on electroretinogram, PKC activities in membranous and cytosolic fractions of sciatic nerves, and polyol contents in the tail nerves were measured. Untreated diabetic rats demonstrated delayed MNCV, decreased CVR-R, reduced SNBF, and prolonged peak latencies of oscillatory potentials. Treatment with LY as well as NZ prevented all these deficits in diabetic rats. There were no significant differences in PKC activities in membranous or cytosolic fractions of sciatic nerves between normal and diabetic rats. Treatment with neither LY nor NZ altered PKC activities. Nerve myo-inositol depletion in diabetic rats was ameliorated not only by NZ, but also by LY. These observations suggest that inhibition of PKC-beta by LY may have a beneficial effect in preventing the development of diabetic nerve dysfunction, and that this effect may be mediated through its action on the endoneurial micro-vasculature.

Aldehyde Reductase↗

PubMed1998

Urinary 7alpha-hydroxy-3-oxochol-4-en-24-oic and 3-oxochola-4,6-dien-24-oic acids in infants with cholestasis.

BACKGROUND/AIMS: Urinary 3-oxo-delta4 bile acids have been detected in infants who ultimately died of liver disease. We used qualitative and quantitative methods to compare urinary 3-oxo-delta4 bile acids in liver disease, determining their composition and evaluating the prognostic implication in patients of various ages with various liver diseases. METHODS: Gas chromatography-mass spectrometry was used to measure 3-oxo-delta4 bile acids in the urine of patients and healthy controls. RESULTS: Patients with a deficiency of 3-oxo-delta4-steroid 5beta-reductase and acute hepatic failure exhibited a significantly higher percentage of 3-oxo-delta4 bile acids in total bile acids in urine than the healthy controls or other patient groups, including those with neonatal cholestasis or biliary atresia (p<0.0001). The urinary 3-oxo-delta4 bile acids in patients with 3-oxo-delta4-steroid 5beta-reductase deficiency who had a poor prognosis were mainly 7alpha-hydroxy-3-oxochol-4-en-24-oic acid and 3-oxochola-4,6-dien-24-oic acid. CONCLUSIONS: Our results indicate that an increase in the 7alpha-hydroxy-3-oxochol-4-en-24-oic acid and 3-oxochola-4,6-dien-24-oic acid in the urine of patients with hepatobiliary disease indicates a poor prognosis.

Adolescent↗

PubMed1998

Synergistic antitumor interaction of human monocyte chemotactant protein-1 gene transfer and modulator for tumor-infiltrating macrophages.

PURPOSE: In order to evaluate the possibility of synergistic antitumor gene therapy by the gene delivery of monocyte chemotactant protein-1 (MCP-1/MCAF/IE), the effect of a biological response modulater for macrophages on tumor progression of gene transfected tumor cells was studied. METHODS: Cachexia-inducing adenocarcinoma cells (cell line colon 26, clone 20) were transfected with either a control plasmid or MCP-1 cDNA. RESULTS: The production of MCP-1 reached 70-80 ng/ml in vitro when transfectant cells were cultured at a cell density of 1 x 10(5) cells/ml for 3 days. Transfection of MCP-1 cDNA did not affect the growth rate in vitro. Also, MCP-1-transfectants formed tumors after intra-footpad inoculation similar in size to the parental cells. The number of infiltrating macrophages in the primary tumor of the transfectant rapidly increased from the 3rd to 5th day after inoculation as revealed by immunohistochemical staining using an antibody against mouse macrophages. An earlier, greater, but no longer-lasting increase in tumor-infiltrating macrophages was induced in tumors by MCP-1 transfection was compared to that induced by the parent cells. On the 10th day after the inoculation, the tumor-infiltrating macrophages in mice inoculated MCP-1 transfectants were decreased to a level similar to that of the parent cells. Groups of mice were treated intraperitoneally with LPS at different times after the inoculation. Tumor cells producing high levels of MCP-1 were significantly lysed by macrophages treated with LPS, whereas parental or control transfected cells were not. Conclusions. Combination immunotherapy can provide a rationale for the application of MCP-1 treatment to increase immunological responses to cancer.

Adenocarcinoma↗

PubMed1998

Intestinal absorption of ursodeoxycholic acid in children and adolescents with inflammatory bowel disease.

BACKGROUND: Ursodeoxycholic acid absorption in the proximal intestine may be impaired in patients with inflammatory bowel disease. METHODS: We examined the intestinal absorption of ursodeoxycholic acid by the oral ursodeoxycholic acid tolerance test in 19 children and adolescents with inflammatory bowel disease at various stages, including 8 patients with unoperated Crohn's disease, 3 patients with ileal-resected Crohn's disease, 8 with ulcerative colitis, and 8 healthy control subjects. RESULTS: Ursodeoxycholic acid malabsorption was present in all patients with unoperated Crohn's disease in the first diagnosed active stage, in 3 of 5 patients in a relapsing active stage, and in 2 of 8 patients in remission. Ursodeoxycholic acid absorption was significantly lower in patients in the first diagnosed active stage than in the healthy controls (p < 0.01) or in patients in remission (p < 0.01). There was no significant difference between healthy controls and the patients in a relapsing active stage or in remission. Ursodeoxycholic acid absorption was abnormal during the first postoperative month in patients with ileal-resected Crohn's disease, but normalized over time. Malabsorption of ursodeoxycholic acid was not observed in any patients with ulcerative colitis. CONCLUSIONS: These findings suggest that absorption of ursodeoxycholic acid in the proximal intestine is impaired in patients with Crohn's disease and that the oral ursodeoxycholic acid tolerance test is a convenient and useful means of evaluating the absorption of bile acid in the proximal intestine in pediatric patients with ileal or ileocolic Crohn's disease.

Adolescent↗

PubMed1998

Human T-lymphotropic virus type-I infection, antibody titers and cause-specific mortality among atomic-bomb survivors.

There have been few longitudinal studies on the long-term health effects of human T-lymphotropic virus type-I (HTLV-I) infection. The authors performed a cohort study of HTLV-I infection and cause-specific mortality in 3,090 atomic-bomb survivors in Nagasaki, Japan, who were followed from 1985-1987 to 1995. The prevalence of HTLV-I seropositivity in men and women was 99/1,196 (8.3%) and 171/1,894 (9.0%), respectively. During a median follow-up of 8.9 years, 448 deaths occurred. There was one nonfatal case of adult T-cell leukemia/lymphoma (incidence rate = 0.46 cases/1,000 person-years; 95% confidence interval [CI] 0.01-2.6). After adjustment for sex, age and other potential confounders, significantly increased risk among HTLV-I carriers was observed for deaths from all causes (rate ratio [RR] = 1.41), all cancers (RR = 1.64), liver cancer (RR = 3.04), and heart diseases (RR = 2.22). The association of anti-HTLV-I seropositivity with mortality from all non-neoplastic diseases (RR = 1.40) and chronic liver diseases (RR = 5.03) was of borderline significance. Possible confounding by blood transfusions and hepatitis C/B (HCV/HBV) viral infections could not be precluded in this study. However, even after liver cancer and chronic liver diseases were excluded, mortality rate was still increased among HTLV-I carriers (RR = 1.32, 95% CI 0.99-1.78), especially among those with high antibody titers (RR = 1.56, 95% CI 0.99-2.46, P for trend = 0.04). These findings may support the idea that HTLV-I infection exerts adverse effects on mortality from causes other than adult T-cell leukemia/lymphoma. Further studies on confounding by HCV/HBV infections and the interaction between HCV/HBV and HTLV-I may be required to analyze the increased mortality from liver cancer and chronic liver diseases.

Adult↗

PubMed1998

Effect of sequence of administration on the pharmacokinetic interaction between the anticholinergic drug biperiden and [3H]quinuclidinyl benzylate or [3H]N-methylscopolamine in rats.

In rats the pharmacokinetic interactions between the anticholinergic drug biperiden and [3H]quinuclidinyl benzylate ([3H]QNB) or [3H]N-methylscopolamine ([3H]NMS) is affected by the sequence in which the drugs are administered. Drug concentrations in various tissues were determined after intravenous administration of [3H]QNB or [3H]NMS (325 ng kg(-1)). Biperiden (6.4 mg kg(-1)) was administered either 5 min before, concomitantly with or 20 min after injection of [3H]QNB or [3H]NMS. When biperiden was administered concomitantly with or before [3H]QNB, distribution of [3H]QNB among the regions of the brain and other tissues was reduced; at 4 h the ratio of the distribution of [3H]QNB for experimental animals to that for control animals ranged from 0.15 to 0.9. When biperiden was administered after [3H]QNB, the distribution of [3H]QNB in the brain and other tissues was significantly higher than for the other two treatments (P < 0.01). However, for [3H]NMS the sequence of administration had no effect on the distribution of the drug in the brain and other tissues except for the kidney. In-vitro, in crude synaptosomal membranes, the amount of [3H]QNB at 2 h relative to the control concentration at equilibrium was 87% when biperiden was added before [3H]QNB and 56% when biperiden was added after [3H]QNB. In both instances the concentration of [3H]NMS reached equilibrium within 30 min. These findings suggest that the difference between the rate constant of association and dissociation at the possible site of action gives rise to the effect of the sequence of administration on the pharmacokinetic interaction.

Animals↗

PubMed1998

Influence of ammonium chloride on the tissue distribution of anticholinergic drugs in rats.

Ammonium chloride (NH4Cl) increases lysosomal pH and thereby abolishes intralysosomal accumulation of drugs. Its effect on the tissue distribution of biperiden and trihexyphenidyl in rats has been investigated. The tissue-plasma concentration ratios (Kp) of these drugs in various tissues were determined by infusion studies at steady-state in the presence or absence of NH4Cl. Treatment with NH4Cl reduced the Kp values for both drugs, causing the largest reduction in Kp in the lung (52.1 to 11.8 for biperiden and 59.5 to 18.9 for trihexyphenidyl; ratios of decrease 0.77 and 0.68, respectively), followed by the heart and kidneys, with relatively small reductions in the brain, gut, muscle and fat. Subcellular fractionation studies in the lung indicated that the subcellular fraction-plasma concentration ratio of each drug at the steady state (K(p,sf)) was reduced by treatment with NH4Cl, with the largest decrease in the post-nuclear fraction (ratio of decrease 0.82 for biperiden and 0.74 for trihexyphenidyl), followed by the nucleus, microsomes and supernatant, in that order. A strong correlation was found between the ratio of decrease in K(p,sf) after NH4Cl treatment and the specific activity of acid phosphatases, a marker of lysosomes, in each fraction (biperiden, r = 0.948; trihexyphenidyl, r = 0.945). These results suggest that acidic organelles contribute significantly to the distribution kinetics of anticholinergic drugs.

Adipose Tissue↗