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The effects of Sho-saiko-to on the pharmacokinetics of tolbutamide were investigated in rats. After intravenous administration of tolbutamide (5 mg/kg), no significant change in the pharma-cokinetics of tolbutamide was observed in both groups of single and multiple (7 days) pre-administration of Sho-saiko-to (50 mg/kg). In the study of single oral administration of tolbutamide (50 mg/kg), co-administration of Sho-saiko-to tended to accelerate the initial absorption rate of tolbutamide. The area under the plasma concentration-time curve of tolbutamide after oral administration was significantly reduced by Sho-saiko-to. Subsequently, a significant decrease was observed in the oral bioavailability of this drug when Sho-saiko-to was given concomitantly. These findings suggest that Sho-saiko-to reduces the bioavailability of tolbutamide after oral dministration in rats, and that this change is not related to hepatic metabolism.

To clarify the effect of plasma albumin on the salivary excretion of mexiletine, we have investigated the kinetics of and correlation between plasma and saliva levels following bolus intravenous administration (5 mg/kg) in male Sprague-Dawley rats (analbuminemic and normal). Parotid and mandibular saliva was collected separately by stimulating salivation with constant rate infusion of pilocarpine (50 μg/kg/min). In both rats, the mexiletine levels in plasma, parotid and mandibular saliva declined biexponentially with time in almost parallel fashion. Although the mexiletine levels in both types of saliva were lower than that in plasma (p < 0.05 or 0.01), the drug level in parotid saliva was always higher than that in mandibular saliva in both groups (p < 0.05 or 0.01). Furthermore, in both rats, significant correlations were observed when all data relating mexiletine concentration in plasma and saliva were included (p < 0.001). The saliva to plasma drug concentration ratios (S/P ratios) for both saliva in analbuminemic rats (0.814±0.162 for parotid saliva, 0.367±0.074 for mandibular saliva) were higher than those in normal rats (0.727±0.110 for parotid saliva, 0.197±0.061 for mandibular saliva) (p < 0.01). These changes in the S/P ratios between both groups could not be explained by the pH for either parotid or mandibular saliva. In contrast, the slight increase in the unbound fraction of the drug in analbuminemic rats, though it was not significant from the unbound fraction in normal rats, tended to be consistent with the difference in the S/P ratios for both salivary glands. These aspects suggest the possibility that the extent of salivary excretion of mexiletine may be influenced by the albumin concentration and dependent on the unbound fraction in plasma.

To investigate the in vitro metabolism of [6]-gingerol, one of the major pharmacological constituents of ginger, in the intestine, [6]-gingerol was added to the jejunal mucosal and muscular tissue homogenates isolated from rats in high (50μg/ml) and low (10μg/ml) concentrations, and the residual [6]-gingerol concentration was periodically determined. In addition, the stability of [6]-gingerol at 20 μg/ml in rat whole blood was also examined in vitro to compare with the metabolic degradation in rat jejunal tissues. In the incubation mixture of rat mucosal layer with the high concentration, the residual [6]-gingerol was 96.5 ± 6.5% following 60 min of incubation. For the low that initial [6]-gingerol concentration, [6]-gingerol concentration was significantly decreased to 81.0 ± 6.1% after 60min (p < 0.001). On the other hand, cumulative amounts of [6]-gingerol decreased in jejunal mucosal homogenates with the high and low initial concentrations for 60min being 0.236 ± 0.449 and 0.231 ± 0.084μg/mg protein, respectively. The residual [6]-gingerol in the incubation mixture of muscular homogenate was about 95-98% at 60 min after the incubation in both the initial concentrations. Furthermore, no change was observed in the [6]-gingerol concentration in the incubation mixture of whole blood. These results suggest that [6]-gingerol may be subject to some metabolic degradation in the mucosal layer of rat jejunum. This first-pass metabolism in the jejunal region would be one of the reasons for the considerable amount which was not recovered as [6]-gingerol in the previous in situ absorption study.

In order to investigate the utility of therapeutic monitoring of mexiletine aided by the saliva drug levels, serum (total and unbound fraction) and saliva drug concentrations were measured in six inpatients with ventricular arrhythmia who were given an oral daily dose of 150 or 300 mg (t. i. d.) of mexiletine hydrochloride.Mexiletine levels in saliva were consistently much higher than the levels in serum of the patients. Saliva level to total and unbound serum drug concentration ratio (S/S ratio) varied markedly among patients from 4.5 to 32.0 and from 9.6 to 68.6, respectively, on the first day of medication. The predicted levels of mexiletine in the serum on day 7 and day 14 using the mean S/S ratio obtained on the first day of medication were almost identical to the observed levels in three of these patients, who showed a small ratio of saliva to total serum concentration, less than about 9 (or 21 for the ratio to unbound concentration). There was no correlation between the mexiletine level in saliva and the salivary flow rate.Four patients who received the drug at a daily dose of 300mg showed almost favorable trough drug levels in the serum total fraction ranging from 0.164 to 0.583 μg/ml, and ventricular premature contraction (VPC) in these patients was almost completely reduced (94.7-100.0%), except for one non-responder. Two patients who received 150 mg of the drug showed steady-state trough levels in the serum total fraction of less than 0.1μg/ml and the VPC of one of these two patients was hardly controlled. We, therefore, increased the daily dose to 300 mg in this patient, who was well controlled thereafter.From these findings, it is suggested that it may be possible to estimate the serum mexiletine levels from the saliva drug levels by using the initial S/S ratios inpatients with ratios of less than about 9.

Objectives This study was designed to investigate the effects of Sho-saiko-to (Xiao Chai Hu Tang), a Chinese traditional medicine, on the membrane permeability of tolbutamide in the intestinal tract. We carried out an in-situ loop study with rat jejunum and a transport study with Caco-2 cell monolayers. Methods In the in-situ loop study, absorption clearance of tolbutamide was estimated from the drug concentrations in the loop and plasma. The apical-to-basolateral and basolateral-to-apical transport of tolbutamide and d-mannitol, a paracellular transport marker, was assessed using Caco-2 cell monolayers cultured on a polycarbonate membrane. Key findings The absorption clearance of tolbutamide was enhanced by a concomitant dose of Sho-saiko-to over 10 min in the rat in-situ loop. Sho-saiko-to increased the apical-to-basolateral transport of tolbutamide, whereas the basolateral-to-apical transport of this drug was reduced by Sho-saiko-to. On the other hand, in both directions the Papp of d-mannitol was reduced by the presence of Sho-saiko-to. Furthermore, the apical-to-basolateral transport of tolbutamide in ATP-depleted Caco-2 cells was diminished by Sho-saiko-to. These findings suggest that Sho-saiko-to can facilitate the epithelial membrane permeability of tolbutamide across the rat jejunum in-situ and Caco-2 cell monolayers. Since Sho-saiko-to suppressed the passive transport of tolbutamide from the apical-to-basolateral side, enhanced permeability may be related to effects of Sho-saiko-to on the energy-dependent transport of tolbutamide in the intestine. Conclusions Our findings suggest that Sho-saiko-to might facilitate the energy-dependent transport of tolbutamide across the rat jejunum in-situ and Caco-2 cell monolayers.

To investigate the kinetics and correlation between serum and saliva levels of mexiletine, serum (total and unbound) and saliva drug concentration-time courses have been analysed in five normal healthy volunteers after administration of a single oral dose (200 mg) of the drug. Mexiletine levels in saliva were always higher than those in serum. The drug concentration-time curve in each sample was analysed according to the non-linear least squares regression program MULTI, for a two-compartment model with first-order absorption. The saliva drug concentration in the post-absorption phase was found to be well correlated with either corresponding serum total or serum unbound drug level in four of the subjects. Although there was a large inter-individual variation in the ratio of saliva to serum drug concentrations as well as in the pharmacokinetic parameters, an almost consistent ratio was obtained in each individual.

Although Sho-saiko-to (Xiao Chai Hu Tang), a major Chinese traditional medicine, is frequently prescribed with other synthetic or biotechnological drugs for the treatment of various chronic diseases, there is a dearth of information about interactions between sho-saiko-to and co-administered drugs. This paper reports the effects of Sho-saiko-to on the pharmacokinetics and glucose responses of a sulphonylurea hypoglycaemic agent, tolbutamide, after their oral administration in rats. After oral administration of tolbutamide (50 mg kg−1) with or without Sho-saiko-to extract powder (300 mg kg−1) to male Sprague-Dawley rats cannulated in the jugular vein, plasma tolbutamide and glucose levels were periodically measured. Co-administration of Sho-saiko-to tended to elevate the plasma tolbutamide concentration in the absorption phase. A two-compartment lag-time model was found to describe the plasma tolbutamide concentration-time data. The maximum concentration of tolbutamide was significantly increased and time to reach the maximum concentration was reduced to about 70% by co-administration with Sho-saiko-to. There was no significant change in area under the curve or in the elimination half-life of tolbutamide. The extent of the lowering effect of tolbutamide on plasma glucose levels was increased up to 0.75 h and decreased after 5 h after co-administration of Sho-saiko-to. In conclusion, these studies suggest that sho-saiko-to slightly hastens the gastrointestinal absorption of tolbutamide. Furthermore, it is considered that elevation of the gastrointestinal absorption rate by Sho-saiko-to might potentiate the hypoglycaemic effect of this sulphonylurea in the early period after oral administration.

In order to obtain in vitro evidence for a specific transport system of valproic acid (VPA) at the blood-cerebrospinal fluid (CSF) interface, the uptake of VPA by isolated rat choroid plexus was investigated. The uptake clearance of [3H]VPA decreased with the increase of the unlabeled VPA concentration in the incubation medium. Kinetic analysis yielded an apparent Km of 10.0 mM, Vmax of 0.0871 mumol s-1 g-1 and Kns, a permeability coefficient of the nonsaturable component, of 6.85 microL s-1 g-1, indicating that both saturable and nonsaturable systems may contribute to VPA uptake by choroid plexus. Organic anions, penicillin G, p-aminohippurate, salicylate, and probenecid significantly inhibited VPA uptake by choroid plexus. We suggest that VPA translocation through choroidal membrane is partly operated by the organic anion transport system. A significant decrease of VPA uptake induced by 2,4-dinitrophenol, stilbenedisulfonate, and hypothermia (10 degrees C) indicates the involvement of an energy-dependent, carrier-mediated transport system. These results demonstrate that VPA is actively transported through the rat choroidal epithelium via a saturable system probably shared by organic anions.

The effect of steady-state plasma concentrations on the salivary excretion of mexiletine was investigated following simultaneous bolus intravenous injection of the loading dose (2·7 or 16·1 mg kg−1) and constant-rate intravenous infusion of the maintenance dose (15 or 102 μg min−1 kg−1) in male Wistar rats. Parotid and mandibular saliva was collected separately by stimulating salivation with a constant-rate infusion of pilocarpine (50 μg kg−1 min−1) in each rat. The low and high steady-state levels of mexiletine in blood plasma were attained at 0·259 + 0·123 and 1·616 ± 0·475 μg mL−1, respectively, within the first 1–2 h after drug administration. Similarly, the two different steady-states in both parotid and mandibular saliva were attained. Although the mexiletine levels in both types of saliva were lower than that in plasma, the drug level in parotid saliva was always higher than that in mandibular saliva at any steady-state (P < 0·001 or 0·01). In parotid saliva, the high steady-state produced greater saliva to plasma drug concentration ratios (S/P ratio, 0·475 + 0·160) than that (0·386±0·131) at the low steady-state (P < 0·05). The S/P ratio for mandibular saliva at the high (0·204 ± 0·060) steady-state was also greater than that at the low (0·158 ± 0·050) steady-state (P < 0·01). These changes in the S/P ratio could not be explained by the pH for either parotid or mandibular saliva, but partially by the change in the unbound fraction of the drug which tended to be consistent with that in the ratio for both salivary glands. These findings suggest that the salivary excretion of mexiletine may be dependent on the plasma unbound concentration in rats.

The pharmacokinetics of [6]-gingerol were investigated in rats with acute renal failure induced by bilateral nephrectomy, or those with acute hepatic failure induced by a single oral administration of carbon tetrachloride (CCl4), to clarify the contribution of the kidney and liver to the elimination process of [6]-gingerol. After bolus intravenous administration, a plasma concentration-time curve of [6]-gingerol was illustrated by a two-compartment open model. There was no significant difference in either the plasma concentration-time curve or any pharmacokinetic parameters between the control and nephrectomized rats. It is suggested, therefore, that renal excretion does not contribute at all to the disappearance of [6]-gingerol from plasma in rats. In contrast, hepatic intoxication with CCl4 elevated the plasma concentration of [6]-gingerol at the terminal phase. Its elimination half-life increased significantly, from 8.5 to 11.0 min, in CCl4-intoxicated rats. The extent of [6]-gingerol bound to serum protein was more than 90% and was affected very slightly by the CCl4-intoxication. These aspects indicate that [6]-gingerol is eliminated partly by the liver.

Salivary excretion of mexiletine was investigated following bolus intravenous administration (10 mg kg−1) in rats. Parotid and mandibular saliva was collected separately by stimulating salivation with constant rate infusion of pilocarpine (3 mg kg−1 h−1). The mexiletine levels in blood plasma and parotid and mandibular saliva declined biexponentially with time in almost parallel fashion. Although the mexiletine levels in both types of saliva were lower than that in plasma, the drug level in parotid saliva was always higher than that in mandibular saliva. Significant correlations were observed when all data relating mexiletine concentration in plasma and saliva were included (P < 0·001). The saliva/plasma drug concentration ratios (S/P ratios) did not vary to a large extent (0·56 ± 0·10 for parotid saliva, 0·21 ± 0·06 for mandibular saliva), but there was a consistent tendency for the higher plasma drug levels in the distribution phase to produce relatively high S/P ratios for both parotid and mandibular saliva. Moreover, the plasma mexiletine levels calculated by the equation of Matin et al (1974) employing the observed values for the saliva drug level, saliva pH and free fraction of mexiletine in plasma were significantly higher than the observed drug levels. Therefore, it is suggested that the salivary excretion of mexiletine could not be explained quantitatively by simple, passive secretion based on pH-partition theory.

To evaluate the distribution, metabolism and excretion of urea in normal rats, plasma concentration profiles, whole-body autoradiograms and urinary, fecal and expiratory excretions following intravenous administration of 14C-urea were investigated. High (1000 mg/kg) and low (0.0675 or 0.117 mg/kg) doses of urea were employed to examine dose-induced differences in the plasma levels and in the whole-body autoradiograms. Plasma radioactivity-time curves were analyzed according to a two-compartment open model. There were no significant differences in almost all of the pharmacokinetic parameters for these two doses. Even in the case of parameters with significant differences (α, β and k10), the dose dependency was considered to be rather small. When these parameters are compared with those for creatinine, k12 and k21 (which are both transfer rate constants for urea between plasma and tissue compartments) were significantly larger than those for creatinine, while (Vd')extrap for urea was about one-third of that for creatinine. There was also no significant dose dependency in the whole-body autoradiograms. The distribution pattern of urea radioactivity was almost uniform except in the kidney and urinary bladder even at an early stage (at 5 and 20 min). Following the intravenous doses, urea was regarded as being eliminated predominantly via the renal route, since more than 80% of the dose was excreted into the urine in 24 h. However, expiratory excretion of the radioactivity was about 12% in 24 h following i.v. administration of 14C-urea, while that after p.o. administration was approximately 37%.

The difference in saliva/plasma concentration ratio (S/P ratio) of urea between mandibular and parotid glands in dogs was investigated in detail by a technique of retrograde ductal injection of HgCl2. In every dog, four kinds of saliva [untreated (control) mandibular and parotid saliva, HgCl2-treated mandibular and parotid saliva] were collected under pilocarpine stimulation of salivation. The following results were obtained.(1) It was verified in this study that S/P ratios of urea and Na+ were significantly increased in HgCl2-treated mandibular saliva.(2) S/P ratios of urea and Na+ in HgCl2-treated parotid saliva were also significantly higher than those in untreated saliva. These results suggested that parotid salivary urea is also reabsorbed in the striated duct of dogs.(3) In untreated glands, the mean Cpr/CM ratio of urea (the ratio of urea concentration in parotid saliva to that in mandibular saliva) was about 1.65. This ratio tended to decrease toward unity in the HgCl2-treated gland. Therefore, it was suggested that the striated duct might play an important role in the gland-specific difference of S/P ratios of urea between the salivary glands of dog.

A retrospective bibliographical review was carried out to evaluate objectively the antipepticulcer activity of various agents in experimental animal models. In the present study, we selected benexate, cetraxate, clebopride, plaunotol, sofalcone, teprenone, and troxipide, which have been approved in Japan from 1979 to 1988, as enhancers of mucosal defense.Relationship between ulcer inhibition rate (UIR) and pharmacological effective oral dosewas examined in rats, as regards eight experimental peptic ulcer models. Most of theagents inhibited stress-, indomethacin-, and acetic acid-induced ulcer. It was found thatthe dose exhibiting the, pharmacological effect was remarkably different .among agents ineach model or among models in each agent. Therefore, the dose for UIR 50%, UIR50% (or UIR30% in acetic acid ulcer), which was calculated by the least-squares linear regressionanalysis of UIR versus logarithm of dose, was used as an index for the evaluation of eachinhibitory activity against ulceration. It was found that cetraxate was relatively. effectivein ethanol ulcer, plaunotol in stress and aspirin ulcer, and teprenone in indomethacin andethanol ulcer. Clebopride and plaunotol showed smaller UIR50% againststress ulcer, andteprenone and troxipide showed smaller UIR50% against indomethacin ulcer. Smaller UIR50% for ethanol ulcer was found with sofalcone and teprenone, and smaller .UIR30%for acetic acid ulcer was found with sofalcone. It is suggested that UIR50% (or UIR30%) may be a useful index for evaluating the preclinical anti-ulcer property and its rank orderamong various agents even in the absence of well-designed comparative studies.

Parotid saliva (Pr) and mandibular-sublingual saliva (MS) were collected separately by means of permanent fistulae in order to investigate the excretion of indomethacin in saliva of dogs receiving a single intravenous dose of 20 mg/kg. Drops of citric acid solution were placed on the tongue to stimulate salivary secretion. The concentrations of indomethacin both in saliva and plasma declined biexponentially with time. There was a good linear relationship between the drug concentration in each saliva and plasma. The Pr and MS levels were 7.4% and 4.4% of the plasma levels, respectively. Indomethacin concentrations in Pr were significantly higher than in MS (p less than 0.05). The roles of salivary pH and salivary protein binding were discussed in respect to the mechanism of salivary excretion of the drug.

The extent of levodopa decarboxylation in a jejunal preparation permitting continuous in situ collection of the mesenteric blood was compared in rats 5 to 104 weeks old. The fraction of the absorbed amount that was metabolized (decarboxylated) in the jejunal segment was relatively high (approximately 0.7 to 0.8) in 9- to 15-week-old rats, whereas the fraction in relatively aged (52- and 104-week-old) and young (5- and 7-week-old) rats was considerably less (approximately 0.4 or less). These fractions were found to correlate better with the extent of relative contribution of the intestine in producing the overall first-pass effect of this drug after oral administration. In addition, kinetic studies on the jejunal metabolism of levodopa in vitro showed that a capacity-limited (i.e. saturable) decarboxylation rate was highest in 11-week-old rats. Therefore, the capacity-limited decarboxylation rate in the small intestine may be a determining factor in the age-dependent systemic availability of this drug when administered orally.

Salivary excretion profiles of 5-fluorouracil (5-FU) were investigated following bolus intravenous administration at three dose levels (12.5, 25, and 50 mg/kg) in rats. Mandibular (M) and parotid (Pr) saliva samples were periodically collected separately via cannulas inserted into the ducts by stimulating salivation with pilocarpine infused intravenously. Simultaneously, salivary pH, flow rate, and protein concentration were determined.(1) Plasma and saliva 5-FU concentration decreased bi-exponentially with time. A relatively scattered relationship but a statistically significant correlation was found between each of the saliva concentrations and plasma 5-FU concentration (p

Apparent blood flow rate in jejunum, kidney, liver or skeletal muscle was directly measured by the hydrogen gas clearance method in 7-week-old rats anesthetized with urethane at four dose levels (0.5, 0.8, 1.0 and 1.5 g/kg, i.p.). The apparent blood flow in each organ or tissue was reduced with the urethane dose. Jejunal blood flow was most sensitive to the dose-related decrease. Assuming that the organ (or tissue) to blood partition coefficient of hydrogen gas is unity and extrapolating the flow data to zero urethane dose for each organ, the flow rate values were almost comparable with the literature data in conscious rats. The applicability of the hydrogen gas clearance method to examine the effect of age on organ or tissue blood flow in rats was also discussed. Organs with relatively high sensitivity to aging were the stomach, jejunum and kidney.

Presystemic elimination of levodopa (20 mg kg−1) has been studied in 5- to 104-week-old male Wistar rats. The gastrointestinal and hepatic contribution to the overall first-pass effect was estimated separately after the drug had been administered intravenously, orally and intraportally. The contribution of the gut to the overall first-pass effect of this drug was greater than that of the liver in any age-group of the rats. Both the overall and intestinal first-pass effects of levodopa were greatest in 11-week-old rats and relatively small in both young (between weeks 5 and 7) and aged (between weeks 52 and 104) rats. In contrast, the hepatic first-pass effect did not show any significant age-dependent change. Age-related change in the jejunal blood flow could not explain the unique age-dependence in the intestinal first-pass metabolism of levodopa. However, the present age-dependence in the oral systemic availability of this drug between adult (11 weeks) and aged (52 to 104 weeks) rats was found to be similar to the tendency that has been reported between normal adult subjects and aged patients with Parkinson's disease.

The saliva to venous-effluent concentration ratio (S/E ratio) for procainamide (PA) was determined and compared with the ratio calculated by using the intracellular pH value of glandular cells. Exposed mandibular gland was perfused in situ with Krebs-Ringer bicarbonate buffer containing PA (10–100 μg/ml) and acetylcholine (ACh, 0.1 to 10μM) or pilocarpine (10μM). These perfusion conditions maintained almost normal physiological function of the mandibular gland throughout the perfusion period of 60 min, since the salivary Na + and K + concentrations were kept at almost constant levels, comparable with those reported in vivo , and the salivary flow, pH and protein level were also stabilized. Under fixed stimulation conditions with 1 μM ACh or 10 μM pilocarpine, the perfusate PA concentration ranging from 20 to 100 μg/ml did not affect the S/E ratio (approximately 0.3). There was a negative correlation between the S/E ratio and salivary pH when stimulated with 0.1 to 10 μM ACh. However, Matin's equation [S.B. Matin et al., Clin. Pharmac. Ther. 16 , 1052 (1974)] employing venous effluent and salivary pH values did not explain fully these observed ratios. In contrast, Borzelleca's model [J.F. Borzelleca and J.W. Putney, J. Pharmac. exp. Ther. 174 , 527 (1970)] for salivary drug transport using intracellular pH of the mandibular gland cells predicted S/E ratios relatively close to the observed values when the gland was perfused at pH 7.4 or 8.0.

The effect of age on the hepatic clearance of propranolol was studied by perfusing the liver isolated from 3- to 104-week-old rats. Propranolol levels in the recirculating perfusate declined biexponentially with time in all age groups. When the liver isolated from 7-week-old rats was perfused with propranolol (1 microgram/ml, 100 ml), hepatic clearance of this drug by the perfused liver (CLperf) increased from 0.589 to 1.14 ml X min-1 X (g liver)-1 with the increase of the perfusion flow rate from 1.0 to 2.0 ml X min-1 X (g liver)-1, confirming evidence of "perfusion-limited" hepatic clearance for this drug. Furthermore, there was no initial concentration(dose)-dependence in CLperf up to 2.5 micrograms/ml (i.e. 250 micrograms/organ). The effect of age on CLperf was then investigated by perfusing the isolated liver with 1.0 micrograms/ml propranolol at 2.0 ml X min-1 X (g liver)-1. Elimination of this drug from the perfusion medium was relatively rapid in 5- to 7-week-old rats, yielding the highest CLperf in these relatively young rats [approximately 1.0 to 1.1 ml X min-1 X (g liver)-1]. In contrast, CLperf values in both immature and older rats were 0.5 ml X min-1 X (g liver)-1 or less. The in vitro intrinsic hepatic clearance estimated in 5- and 7-week-old rats was about ten times as high as that in 104-week-old rats.

The salivary excretion of urea was investigated by collecting parotid saliva (Pr) and mandibular-sublingual saliva (MS) separately in beagle dogs. (1) After intravenous administration of urea (1.5 g/kg), urea concentrations in both Pr and MS were well correlated to but were lower than those in plasma. Urea concentrations in MS were significantly lower than those in Pr (p less than 0.05), indicating that there was glandular difference in salivary excretion of urea. (2) This glandular difference was not explained by Matin's equation, even if all variation factors in this equation were considered. (3) At relatively low salivary flow rates, the increase in saliva/plasma urea concentration ratio (S/P ratio) for both Pr and MS was found in the experiments for endogenous urea. (4) At relatively low salivary flow rates, glandular difference was observed in the S/P ratios of sodium ion. (5) Salivary clearance of urea was highly dependent on salivary flow rate under stimulated condition for salivation, and mean value of the salivary clearance of urea was about 20% of its total body clearance.

The effect of age on hepatic clearance of propranolol was investigated in male Wistar rats (3 to 104 weeks old). Pharmacokinetic analysis of the plasma propranolol data obtained after i.v. dosage (1.0 mg kg−1) indicated that both the elimination rate constant and the volume of distribution decreased with age between weeks 5 and 11, after when the distribution volume remained almost constant. The elimination rate constant was reduced consistently with age after 15 weeks. Total body clearance of the drug was reduced extensively with age between weeks 5 and 11 (94 to 43 ml min−1 kg−1) and decreased gradually thereafter. The plasma free fraction of propranolol also decreased with age, falling from more than 20% in 3 to 5 weeks-old rats to about 10% in rats of 52 to 104 weeks. In immature rats the renal clearance was approximately 5 to 12% of the total body clearance. Intrinsic hepatic clearance for unbound propranolol also decreased with age between weeks 7 and 24. As expected from the evidence that propranolol has a high extraction ratio, the extent of its hepatic clearance was significantly dependent on the liver blood flow. These data suggest that the age-dependent decrease in hepatic clearance of propranolol is largely due to a reduction of the elimination rate that might be accompanied by the age-dependent decrease in liver blood flow.

Plasma levels of propranolol after 2.5 mg kg−1 given i.v. and i.a. have been compared in 3- to 4-week-old rats to evaluate the effect of age on pulmonary first-pass elimination of the drug. In 5- to 52-week-old rats, the area under the plasma concentration-time curve (AUC) after an intra-arterial dose was always larger than that after the i.v. dose. The plasma elimination half-lives after both routes of administration were almost identical, but tended to increase with age between weeks 7 and 104. First-pass pulmonary clearance and extraction ratio tended to decrease with age between weeks 7 and 52.

Lung isolated from 7-week-old rats was perfused with pH 7.4 Krebs-Ringer bicarbonate buffer solution (35 mL) containing 1 to 100 μg mL−1 of propranolol and 3% BSA at the recirculation rate of 8 mL min−1. Almost parallel bi-exponential drug concentration-time curves were obtained at the initial load lower than 10 μg mL−1, whereas relatively slow, mono-exponential decline was found after perfusion at 100 μg mL−1. Pharmacokinetic analysis for the perfusate propranolol concentration-time curves when loaded at 1 to 10 μg mL−1 yielded almost comparable values for the pulmonary perfusion clearance (0.387 ± 0.092 to 0.486 ± 0.095 mL min−1 g−1). In contrast, this parameter was significantly reduced at 100 μg mL−1 (0.113 ± 0.042 mL min−1 g−1). The present findings suggest a trend towards saturation kinetics in the in-vitro pulmonary clearance of propranolol.

Indomethacin was measured in mandibular and parotid saliva, obtained from separate cannulas in the salivary ducts, after bolus intravenous administration (15 mg/kg) to male white rabbits that were stimulated for salivation with pilocarpine given subcutaneously. There was a significant correlation between each salivary drug concentration and plasma drug concentration. Saliva to plasma drug concentration ratio (S/P ratio) and pH were higher in mandibular saliva than in parotid saliva. These gland specific differences were in contrast with the previously reported differences in dogs. Matin's equation was found to predict approximately the mean observed S/P ratio of indomethacin for each saliva sample.

Gastrointestinal first-pass elimination of propranolol and the effect of dose (1.0, 2.5, 5.0 and 10.0 mg kg−1) on its systemic availability were studied in male Wistar rats which received the drug intravenously, orally or intraportally. The plasma elimination half-life was not altered either by the route of administration or the dose. There was no gastrointestinal first-pass metabolism of propranolol, since the same systemic availability was obtained after oral and intraportal administration. Hepatic clearance was estimated to be constant at any dose. In contrast, the hepatic intrinsic clearance was found to be largely dependent on the portal dose.

Lungs isolated from 7-week-old rats were perfused with pH 7·4, oxygenated Krebs-Ringer bicarbonate buffer solution containing 2·5 μg mL−1 of propranolol and 3 to 5% BSA at the recirculation rate of 4 to 16 mL min−1, at 37°C for 60 min. The extent of propranolol metabolism after 60 min was less than 2·3% of the initial load under any in-vitro perfusion condition. Therefore, the amount disappearing from the perfusion medium was considered as being predominantly that taken up by tissue. Under all experimental conditions, perfusate drug level declined bi-exponentially with time. Apparent in-vitro pulmonary clearance of propranolol was not affected by the increase of BSA level from 3 to 5%. When the perfusate BSA level was fixed at 3%, the lowest recirculation rate (4 mL min−1) yielded the smallest clearance (about 0·15 mL min−1 g−1) but almost constant clearance value (about 0·40 mL min−1 g−1) was obtained at the rate ranging from 8 to 16 mL min−1. The tissue to medium concentration ratio of propranolol, after the perfusion with 3 to 5% BSA at the rate of 8 to 16 mL min−1, was approximately 35, whereas that with 3% BSA at 4 mL min−1 was reduced to about 20. The findings suggest evidence for flow-dependent in-vitro pulmonary clearance of propranolol.

Gastrointestinal tract of guinea pigs was recirculated in situ with ascorbic acid, and absorption rate was determined in order to discuss its feasible mechanism involved. The absorption rate of ascorbic acid from the small intestine was a little larger than that from the stomach especially in relatively lower dose, and a type of saturation kinetics was observed in both sites. Apparent Michaelis constants were 1.30 mM and 1.27 mM for stomach and small intestine respectively, indicating almost the same apparent affinity to both sites. Additional absorption experiments were carried out in the presence of three metabolic inhibitors (phlorizin, ouabain, and 2, 4-dinitrophenol), dehydroascorbic acid, and glucose. Phlorizin or glucose was considered to exert a competitively inhibiting effect on the small intestinal absorption of ascorbic acid, while the stomach absorption was affected neither remarkably nor competitively by almost all of the adjuvants. A difference in those inhibitoty effects as well as the properities of drug moiety is fully suggestive of that in absorption mechanism between the two sites. It may be simultaneously implied, from the blood level immediately after 1 hr tests of recirculation and its curve following i. v. administration of ascorbic acid, that the absorbed drug will be rapidly distributed in the animal tissue cells.

Salivary excretion of lithium was investigated following bolus intravenous administration at low or high dose (0.145 or 1.45 meq/kg) to beagle dogs. Salivation was stimulated with 10% citric acid. Parotid saliva (Pr) and mandibular-sublingual saliva (MS) were collected separately by means of permanent fistulae. (1) The concentrations of lithium in both saliva and plasma declined biexponentially with time at both dose levels. (2) The lithium concentrations in each saliva were higher than and well correlated to those in plasma at both dose levels. (3) The saliva/plasma lithium concentration ratios (S/P ratios; Pr 2.19, MS 1.59) at high dose were significantly higher than those (Pr 1.64, MS 1.35) at low dose in the Pr and MS (P

The absorption, distribution and elimination of creatinine and urea, which are considered to pass through the water-filled pores of biological membranes easily, were investigated in hyperthyroid mice to clarify the effects of enhanced blood circulation rate on drug behaviour in the body. The elimination rate constant in hyperthyroid mice was significantly and considerably larger than that in the control in both creatinine and urea (p less than 0.01). This result might be based on the increased urinary excretion rate of these two chemicals in hyperthyroid mice. The result of autoradiographic study indicated that creatinine was distributed more homogeneously in hyperthyroid mice than the control at 30 s and 2 min following intravenous administration. It was probably caused by the enhanced membrane permeability to creatinine due to some physiological changes (e.g. blood flow rate and pressure) or to a change of membrane itself. The gastrointestinal absorption of these two chemicals were also evaluated by the expiratory excretion of 14CO2 following oral administration. The results suggested that creatinine might be absorbed more slowly in hyperthyroid mice than in the control, and that in the case of urea such a difference in absorption might not exist.

To evaluate the distribution of creatinine in rats, urinary, fecal and expiratory excretion, plasma levels and whole-body autoradiography following intravenous or oral administration of [carbonyl-14C]creatinine was investigated. More than 90% of the exogeneous creatinine was excreted in the urine in 24 hr following intravenous administration, and both fecal and expiratory excretion were only about 1%. In case of oral administration, however, it was found that expiratory excretion could not be neglected, ranging from about 1 to 30%. Plasma creatinine concentration-time curves following the intravenous administration (70.4 micrograms/kg or 400 mg/kg as creatinine) were analyzed according to a two-compartment open model. There were significant but very small differences in the pharmacokinetic parameters for these two doses. When these parameters were compared with those of urea, k12 and k21, which are transfer rate constants between compartment 1 and 2, for creatinine were significantly smaller than those of urea. On the other hand, k10 was larger in creatinine. Furthermore, (V'd)extrap for creatinine was about three times that of urea. Whole-body autoradiograms at 5 minutes following intravenous administration showed that exogeneous creatinine distributes with higher concentrations in liver, lung and kidney than in muscle and fat. This results was remarkably different from that of urea which distributes almost uniformly throughout the body at the same time. This difference observed in the autoradiograms would be the consequence of the fact that urea has larger k12 and k21 than creatinine.

Bilaterally nephrectomized rats were used to investigate the disposition of creatinine when renal function is acutely decreased. The percentage of radioactivity recovered in the expired air in 11 hours following intravenous administration of [carbonyl-14C] creatinine immediately and 24 hours after nephrectomy was 0.54 and 3.24% respectively, and these values were significantly different (p less than 0.05). As it was considered that expiratory excretion is one of the major elimination routes in nephrectomized rats, mechanism of expiratory excretion was investigated by incubating [carbonyl-14C] creatinine with the intestinal contents of the rats chronically loaded with creatinine [carbonyl-14C] Creatinine was completely metabolized in that intestinal contents, but 14CO2 was not produced. When the mixture of the metabolites was administered orally or intravenously to chronically creatinine loaded rats, however, about 50% of the total radioactivity was excreted into the expired air in 5 hours. Furthermore, biliary excretion of the radioactivity following intravenous administration of [carbonyl-14] creatinine in the nephrectomized rats was much greater than that in normal rats. These results indicate that expiratory excretion following intravenous administration [carbonyl-14C] creatinine to nephrectomized rats would arise following intestinal absorption of the creatinine metabolites, which seem to be produced by intestinal microflora after biliary excretion of creatinine. The change of disposition for urea by bilaterally nephrectomy was also studied to compare with that for creatinine.

The first-pass effect of aspirin was measured in male Wistar rats by comparing the plasma concentration after intravenous, oral or intraportal administration (10 mg kg−1) of the drug. Approximately 88 and 86% of the dose was excreted mostly as salicylic acid and its conjugated forms, glucuronide and sulphate, in urine within 48 h of i.v. or oral administration, respectively. This suggests that the gastrointestinal absorption of aspirin was essentially complete in rats. On the average, the area under the plasma concentration-time curve for unchanged aspirin following oral dosing (AUCo) was 0.35 of that obtained following i.v. administration (AUCi.v) and 0.53 of that following intraportal administration (AUCp). Therefore, orally administered aspirin is subject to first-pass metabolism both in the gut and in the liver of rats. The gastrointestinal first-pass effect is estimated to be relatively more important than the hepatic effect.

The effects of several metabolic inhibitors (50 μM) on the initial uptake rate of propranolol (0·5 to 500 #mUg mL−1) by the minced lungs (0·4g) isolated from 7-week-old rats has been investigated in oxygenated, pH 7·4 Krebs-Ringer bicarbonate buffer solution (20 mL) containing 3% BSA at 37°C for 5 min. The effect of the incubation temperature was also examined. Metabolism of propranolol was almost insignificant (i.e. less than 1·3% of the initial load). The overall initial uptake rate was considered to be a combination of apparent linear transport and saturable processes. For the control uptake rate, the linear transport rate constant was 1·26 ± 0·16 g−1 mL−1 min−1, while Vmax and Km' of the capacity limited uptake process were estimated as 0·727 ± 0·074 mg g−1 min−1 and 24·8 ± 2·71 μg mL−1, respectively. No metabolic inhibitor tested had an effect on the linear transport rate of propranolol but 2,4-dinitrophenol and potassium cyanide inhibited saturable uptake rate (i.e. Vmax) of propranolol significantly (P

Effect of ascorbic acid on in situ small intestinal absorption and hepato-biliary system of bile salts was investigated, by employing guinea pigs, for the purpose of explaining the physiological role of it to lower serum cholesterol. Firstly, the major bile acid and its salt were identified as chenodeoxycholic acid and its taurine conjugate, respectively. The critical micelle concentration (cmc) value of sodium chenodeoxycholate was estimated to beabout 0.9 mM, suggesting approximately the same order as reported on others with di-hydroxy groups. Added ascorbic acid did not exert any effect on the cmc value. Sodium taurochenodeoxycholate was favorably absorbed from the ileum portion of guinea pigs, and the absorption there appeared to obey such a type of saturation kinetics as has been demonstrated with other bile salts. Ascorbic acid was observed to inhibit the absorption significantly and especially in the lower concentration region of sodium taurochenodeoxycholatethan its cmc, where the percentage of inhibition was approximately 30 to 35. Double reciprocal treatment did not indicate any feasibility of competitive inhibition for the system of taurochenodeoxycholate and ascorbic acid. This effect of ascorbic acid should be explained neither by a change in physicochemical properties of the bile salt nor the direct action on intestinal mucosa, based on the results of cmc and additional pretreatment tests, but may be rather discussed by some participation in the hydrolysis and/or dehydroxylation of that salt occurring in the intestinal tissues other than mucosal membrane. Intraperitoneal administration of this vitamin and its dehydro form for 4 days enhanced the biliary amount of total chenodeoxycholate by about 60% of the control. Both in situ and in vitro experiments supported the in vivo results, so this metabolic aspect could be also recognized as one of the physiological functions of ascorbic acid which has been reported to lower serum cholesterol, in addition to suppressive effect on the ileal absorption of taurochenodeoxycholate.

The salivary excretion of phenobarbital was investigated by collecting parotid saliva (Pr) and mandibular-sublingual saliva (MS) separately after intravenous administration in beagle dogs. (1) The alterations in the proportions of saliva secreted by the different glands were produced by salivation stimulants such as citric acid, ascorbic acid, sodium chloride and sodium glutamate. (2) The phenobarbital concentrations in both Pr amd MS were lower than those in plasma. The drug concentrations in MS were significantly lower than in Pr with stimulus of 10% citric acid of 15% sodium chloride (p less than 0.05). There was a significant correlation between phenobarbital concentration in each saliva and plasma specimen ( p less than 0.05). (3) The stimulation with 10% citric acid produced higher saliva /plasma drug concentration ratios (S/P ratios: 0.923 +/- 0.175 for Pr, 0.633 +/- 0.073 for MS) than that with 15% sodium chloride (S/P ratios: 0.597 +/- 0.071 for Pr, 0.509 +/- 0.067 or MS). (4) The S/P ratios were hardly influenced by salivary flow rates, at least under the experimental conditions examined in this study. (5) The increased S/P ratios were observed with higher salivary pH and then the equation of Matin et al. 3) seemed to hold for the average values of salivary pH and S/P ratio. (6) The stimulation with 10% citric acid produced higher protein concentration in saliva and higher S/P ratio than that with 15% sodium chloride following alternate stimulations in the same dog.

The role of mandibular striated duct in salivary excretion of endogenous urea was studied by a technique of retrograde ductal injection of HgCl2 and a stop flow analysis. (1) It was verified in this study that treatment with HgCl2 markedly inhibited Na+ reabsorption in the striated duct so that water reabsorption driven by the Na+ reabsorption would be inhibited substantially. (2) The saliva/plasma concentration ratios (S/P ratios) of urea in HgCl2-treated saliva (about 0.71) were significantly higher than those in untreated saliva (about 0.37). (3) The excretion rate of urea in HgCl2-treated saliva (about 0.02 mg/min/kg) was also significantly higher than those in untreated saliva (about 0.01 mg/min/kg) despite the same flow rate for both saliva samples. Furthermore, (4) The S/P ratios of urea in the second (0.25-0.50 ml) poststop-flow saliva (about 0.65) were significantly higher than those in prestop-flow saliva (about 0.35). These results suggest a possibility that salivary urea is reabsorbed in the dog mandibular striated duct and that the enhancement of the S/P ratio as well as the salivary level of urea by the pre-treatment with HgCl2 may be due to the inhibition of urea reabsorption.

To investigate the effect of age on the pulmonary uptake of propranolol, minced tissue (0·4 g) of lungs isolated from 3- to 104-week-old rats was incubated with the drug (1 to 500 ng μL−1) prepared in oxygenated, pH 7·4 Krebs-Ringer bicarbonate buffer solution (20 mL) containing 3% BS A for 60 min at 37°C. In any age-group the metabolism of propranolol was not significant (i.e. less than 0·6% of any initial load) under the present in-vitro conditions. The extent of uptake after the incubation with 2·5 μ mL−1 of the drug was largest in the 7 weeks (i.e. 82% of the initial load) and relatively small in the 3(64%), 24(61 %), 52(51%) and 104(48%) week old rats. Similar, specific age-dependence was observed in the tissue-to-medium concentration ratio of the drug. In any age-group, the initial uptake rate obtained in the first 5 min of the incubation was found to be a combination of apparently linear transport and saturable (capacity-limited) processes. There was a marked, specific age-dependence in the capacity-limited uptake rate. Although Km′ value was almost equivalent in any age-group (i.e. 24·4 to 25·4 μg mL1), Vmax exhibited a specific age-dependence by yielding the highest value in 7 weeks (0·726 ± 0·101 mg g−1 min−1) and relatively low values in 3 (0·501 ±0·082 mg g−1 min−1), 52 (0·410 ± 0·088 mg−1 g−1 min1) and 104 (0·397 ± 0·074 mg g−1 min−1) weeks.

Immediately after intraportal administration to rats, the ratio of liver to plasma concentrations for total aspirin was close to unity, whereas that for total salicylamide ranged from about 3 to 7. The hepatic accumulation of salicylamide appeared to be capacity-limited because of the ratio decreased with increases in the dose. In vitro experiments with isolated hepatocytes indicated that aspirin was slowly transported into the hepatocytes by an apparently linear process only, while salicylamide was taken up very rapidly by both saturable and apparently linear transport processes. The cell to medium concentration ratio estimated for the initially net transported component of the unchanged drug was significantly larger with salicylamide, which give ratios from 3.5 to 19, than with aspirin which gave an almost constant value lower than 2 despite wide variations in the initial concentration. For the capacity-limited uptake process of salicylamide; the kinetic parameters were estimated as V max = 0.325 nmole · (g cellular protein) −1 . sec −1 and K m = 201 μ M. Among various metabolic inhibitors, 2,4-dinitropherol (50μM) inhibited the uptake of salicylamide most extensively. The present comparison of the in vivo and in vitro data for aspirin with those for salicylamide confirmed the previously reported difference in the hepatic first-pass effect of these two drugs.

Flow rate, protein level and pH of mandibular and parotid saliva samples in rats were almost stabilized 2h after induction of salivation with pilocarpine (9ṁ0 mg h−1 kg−1). Salivary excretion profiles of procainamide, 50 mg kg−1 i.v., and its metabolite N-acetylprocainamide (NAPA) were then investigated. Plasma and salivary procainamide levels declined bi-exponentially with time almost in parallel. Salivary procainamide levels (Y) from both types of gland were correlated with the plasma level (X) over a wide concentration range [Y = 0ṁ108X + 1ṁ96 (r = 0ṁ795) for mandibular and Y = 0ṁ917X (r = 0ṁ974) for parotid glands]. The mean saliva to plasma concentration ratio (S/P ratio) was significantly higher in parotid (0ṁ974 ± 0ṁ243) than in mandibular (0ṁ284 05119) saliva samples. Similar correlations and S/P ratios were observed for NAPA. Procainamide and NAPA mean S/P ratios for saliva from both glands were fairly consistent with the calculated value according to the pH-partition hypothesis.

Salivary excretion of 5-fluorouracil (5-FU) was investigated during constant rate intravenous infusion (0.306 mg/kg/min) in three male beagle dogs. Parotid (Pr) and mandibular-sublingual (MS) saliva were collected separately by stimulating salivation with 10% citric acid. After the start of 5-FU infusion, plasma and salivary 5-FU concentration increased rapidly to approach their steady state levels. There was a significant correlation between each saliva and plasma 5-FU concentration (p less than 0.01). The saliva/plasma drug concentration ratio (S/P ratio) and salivary pH were significantly higher in Pr than in MS saliva (p less than 0.001), similar to the results following bolus intravenous administration of 5-FU in beagle dogs. Both S/P ratio and salivary clearance increased with time before steady state. Thereafter, these values approached almost constant levels and their fluctuations became smaller than those following the bolus intravenous administration. These results showing S/P ratio and salivary clearance of 5-FU were affected by the plasma drug concentration, suggested the possibility that non-linear pharmacokinetics may be involved in the salivary excretion of 5-FU.