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J H Lin

Publications and source records attributed to J H Lin.

At least 379 records · Page 21Linked to original sources
PubMedDate not supplied

Species-dependent enantioselective plasma protein binding of MK-571, a potent leukotriene D4 antagonist.

The plasma protein binding of the enantiomers of MK-571 was stereoselective and the stereoselectivity was species dependent. The 12 mammalian species studied could be classified into three groups: those that bind the S-(+)-enantiomer to a greater extent than the R-(-)-enantiomer (human, baboon, monkey, cow, dog, and cat); those that bind the R-(-)-enantiomer more extensively (rat, guinea pig, and sheep); and those that show no stereoselectivity (rabbit, hamster, and mouse). The stereoselective binding appears to have no phylogenetic relationship. Using serum albumin instead of plasma, a similar degree of stereoselective binding was observed for human, dog, sheep, and rat, suggesting that albumin is the major binding component for MK-571 enantiomers, and that species differences in stereoselective binding are likely due to structural differences in the albumin molecule. Displacement studies with [14C] diazepam, [14C]warfarin, and [3H]digitoxin indicated that the enantioselective differences in protein binding are most likely due to the differences in binding affinity rather than to different binding sites.

Animals↗
PubMedDate not supplied

Dose-dependent pharmacokinetics of MK-417, a potent carbonic anhydrase inhibitor, in rabbits following single and multiple doses.

MK-417, a potent carbonic anhydrase inhibitor capable of reducing intraocular pressure after topical application, is currently under investigation for the treatment of glaucoma. The purposes of this study were to characterize dose-dependent pharmacokinetics of MK-417 and to determine the accumulating effect of the drug during chronic topical administration in rabbits. Because the drug resided primarily in the erythrocytes, kinetic analyses were performed on whole blood concentration data. Following i.v. administration, both total blood clearance and apparent volume of distribution for MK-417 increased disproportionately between the low and high dose, while the half-life of the drug appeared to be independent of dose. Total blood clearance and apparent volume of distribution increased from 0.993 +/- 0.224 ml/hr/kg (mean +/- SD) and 88.6 +/- 9.4 ml/kg at a dose of 0.05 mg/kg to 2.73 +/- 0.17 ml/hr/kg and 272 +/- 5.5 ml/kg at a dose of 1 mg/kg. The dose-dependent kinetics of MK-417 are probably due to the saturable binding of carbonic anhydrase. Upon instillation of MK-417 into the eyes, the drug was rapidly and well absorbed. At the low dose of 0.05 mg/kg, the bioavailability varied from 58% to 98.5% with a mean value of 76.5 +/- 20.5%. Prediction of concentrations of MK-417 during chronic topical administration were performed based on the corresponding concentrations after a single topical dose using an overlay technique. Good agreement between the experimental data and the predicted blood concentrations of MK-417 during chronic dosing at 0.05 mg/kg, but not at 1 mg/kg, strongly suggests that linear kinetics apply in the case of the low dose but not in the case of the high dose.

Animals↗
PubMedDate not supplied

Effect of experimental diabetes on elimination kinetics of diflunisal in rats.

The effects of insulin-deficient diabetes on the elimination of diflunisal were investigated in streptozotocin-treated rats. Diflunisal, a fluorinated salicylate with nonsteroidal antiinflammatory properties, is eliminated primarily as the ester and ether glucuronides. After an iv injection of a 10 mg/kg dose, diabetic rats cleared diflunisal more rapidly than control rats; time-averaged total body clearances were 1.96 +/- 0.29 and 1.10 +/- 0.12 ml/min/kg, respectively. For a low clearance drug such as diflunisal, changes in the total body clearance can result from changes in the extent of plasma protein binding and/or drug metabolic rate. To determine whether the pronounced changes in elimination clearance in diabetic rats were due to the changes in plasma protein binding or enzyme activity, diflunisal was infused to obtain steady state kinetics. At steady state, the unbound intrinsic clearance increased from 43.4 +/- 16.4 ml/min/kg in the control rats to 82.5 +/- 21.1 ml/min/kg in diabetic rats at a high infusion rate (72 micrograms/min). When the infusion rate was lowered to 4.5 micrograms/min, the respective values for the unbound intrinsic clearance were 353 +/- 101 ml/min/kg and 561 +/- 112 ml/min/kg. Diabetic rats, however, showed no changes in plasma protein binding of diflunisal. The data suggest that the elimination of diflunisal was increased as a result of increased enzyme activity. Insulin treatment appeared to reverse the diabetic effect, suggesting that the effect on drug metabolism was the result of insulin deficiency and not a secondary or nonspecific effect of streptozotocin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Dose-dependent kinetics of cilastatin in laboratory animals.

Cilastatin, a potent inhibitor of renal dehydropeptidase I, was specifically designed to inhibit renal metabolism of the antibiotic imipenem in order to achieve therapeutically relevant imipenem concentrations in the urinary tract. In this study the elimination kinetics of cilastatin in rats at doses of 5, 10, 20, 50, 100, and 200 mg/kg iv were demonstrated to be dose dependent, with total plasma clearance and non-renal clearance falling from 20.2 +/- 3.1 ml/min/kg and 17.7 +/- 3.3 ml/min/kg (mean +/- S.D.) at the 5 mg/kg dose to 11.4 +/- 1.2 ml/min/kg and 5.30 +/- 1.2 ml/min/kg, respectively, at the 200 mg/kg dose, whereas the volume of distribution of the drug remained unchanged. Since cilastatin is mainly eliminated by renal excretion as well as by N-acetylation, the non-renal clearance may reasonably reflect the N-acetylation process. Thus, the dose-dependent kinetics of cilastatin might be explained, at least partly, by the saturation of the N-acetylation of the drug. The dose-related decrease in the fraction (fm) of cilastatin converted to its N-acetylated metabolite provided further evidence for the saturable N-acetylation. The fm values decreased from 0.915 at the 10 mg/kg dose to 0.626 at the 100 mg/kg dose. Although both the total plasma clearance and non-renal clearance decreased with increasing dose, the dose had an opposite effect on the renal clearance of cilastatin. The renal clearance of cilastatin increased from 2.50 +/- 0.40 ml/min/kg at the lowest dose to 6.10 +/- 0.50 ml/min/kg at the highest dose as the dose increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Effect of enterohepatic circulation on the pharmacokinetics of diflunisal in rats.

The purpose of this study was to examine the effect of enterohepatic circulation on the pharmacokinetics of diflunisal in rats. The "linked animals" experiments provided evidence that diflunisal exhibits an enterohepatic circulation. Within 26 hr after iv administration of diflunisal (10 mg/kg) to rats, excretion was as follows: 42.2% of the dose, bile; 2.3%, unchanged drug; 27.8%, ester glucuronide; and 12.1%, ether glucuronide. On the average, approximately 65% of the amount of the drug and its glucuronides excreted in bile was reabsorbed from the gut. Biliary excretion and plasma data showed that biotransformation of diflunisal to its glucuronides is the rate-limiting step in their elimination. A concentration-dependent decrease in the partial formation clearance to ester glucuronide was observed with decreased concentration of diflunisal. These concentration-dependent kinetics can be at least partly explained by the nonlinear protein binding of diflunisal.

Acylation↗
PubMedDate not supplied

Effect of uremia and anephric state on the pharmacokinetics of sulindac and its metabolites in rats. I. An application of pharmacokinetic model for reversible metabolism.

Plasma levels of sulindac and its metabolites, sulfide and sulfone, were measured in normal, uremic, and anephric rats following concurrent administration of 11C-sulindac and 3H-sulfide (5 mg-eq/kg). A marked decrease in plasma concentration of sulfide was found in uremic rats, while sulindac concentration in these rats was unchanged. In contrast, anephric rats cleared sulindac more slowly than control rats, but had no effect on the sulfide. A pharmacokinetic model for reversible metabolism was used to characterize the kinetic parameters for sulindac----sulfide interconversion system. The intrinsic clearances of unbound drug were calculated for the interconversion and elimination processes. The results indicated that the reduction of sulindac to sulfide is impaired in uremic and anephric rats. The oxidation of sulfide to sulindac was increased in uremic rats, but decreased in anephric rats. Experimental uremia caused a decrease in plasma protein binding of sulindac and sulfide and an increase in the apparent volumes of distribution of the redox species. Anephric state has less effect on plasma protein binding and volume distribution.

Animals↗
PubMedDate not supplied

Effect of uremia and anephric state on the pharmacokinetics of sulindac and its metabolites in rats. II. Differential effects on the biliary excretion.

The differential effects of experimental uremia and surgical anephric state on the biliary excretion of sulindac and its metabolites in rats were investigated. After concurrent administration of 14C-sulindac and 3H-sulfide (5 mg-eq/kg iv), the apparent biliary clearance of sulindac was significantly decreased in anephric rats relative to control rats, whereas the apparent biliary clearance of sulfide was increased in uremic rats as compared to that in control rats. There was a strong positive correlation between the irreversible elimination of sulindac (CLox) and the apparent biliary clearance (r = 0.942). Similarly, the irreversible elimination of sulfide (CLide) was positively correlated with the apparent biliary clearance of sulfide (r = 0.961). A partial explanation is thus provided for differences in the respective effects of uremic and anephric state upon observed CLox and CLide.

Animals↗
PubMedDate not supplied

Comparative effects of H2-receptor antagonists on drug interaction in rats.

The most widely used H2-receptor antagonist, cimetidine, is known to interact with cytochrome P-450 drug-metabolizing enzymes and, therefore, interacts with other drugs which may be administered concurrently. In this study, effects of three H2-receptor antagonists, famotidine, ranitidine, and L-643,441, on drug interaction were studied using cimetidine as a positive control. Cimetidine and L-643,441, but not famotidine or ranitidine, prolonged antipyrine elimination and hexobarbital-induced sleeping time. The effect of cimetidine and famotidine on the anticoagulant effect on warfarin in rats was also investigated. Pretreatment of rats with cimetidine produced a significant depression of plasma prothrombin complex activity, whereas concomitant administration of famotidine did not alter the plasma prothrombin complex activity. Whereas cimetidine is known to impair the elimination of a number of drugs metabolized by microsomal mixed function oxidase enzyme systems, the results of the present study suggest that famotidine and ranitidine have little effect on these enzyme systems.

Animals↗
PubMedDate not supplied

Urinary excretion kinetics of famotidine in rats.

Famotidine is a new histamine H2-receptor antagonist which has been demonstrated to be more potent than cimetidine and ranitidine in inhibiting gastric acid secretion. Nine groups of adult male Sprague-Dawley rats received an ia injection of various loading doses of famotidine followed immediately by a constant infusion of the drug at different rates for 6 hr. When steady state famotidine concentrations in plasma were low, renal clearance of the drug (CLR) was greater than glomerular filtration (GFR), and the ratio CLR/GFR was about 4.5 at plasma concentrations of 0.2-1.8 micrograms/ml, suggesting that famotidine was actively secreted by the renal tubules. The CLR decreased as famotidine concentration in plasma increased, and the ratio CLR/GFR approached 1 in the concentration range of 25-76 micrograms/ml, thus providing evidence for saturation of the secretory mechanism. The maximum rate of secretory transport (Tm) of famotidine averaged 180 micrograms/min/kg. On average, some 50-70% of an ia bolus dose was excreted in the urine as unchanged drug within 24 hr of administration. Over the dose range of 0.3-30 mg/kg famotidine, there was no dose-dependent effect on total or renal clearance. Since the lowest dose level, 0.3 mg/kg, is below the recommended human therapeutic dose for famotidine (0.6 mg/kg), the saturation of the renal excretion process observed here in rats is not likely to be of clinical significance.

Animals↗
PubMedDate not supplied

Kinetic studies on the competition between famotidine and cimetidine in rats. Evidence of multiple renal secretory systems for organic cations.

The H2-receptor antagonists famotidine and cimetidine are both basic drugs that are predominantly eliminated by the kidneys. Cimetidine has been shown to inhibit the renal secretion of tetraethyl-ammonium bromide (TEAB) but not p-aminohippuric acid (PAH), suggesting that cimetidine is secreted by an organic cation transport system [Weiner and Roth: J. Pharmacol. Exp. Ther. 216: 516 (1981)]. The present study shows that famotidine behaves like cimetidine in that it also inhibits TEAB but not PAH excretion. Where a high concentration of cimetidine in plasma has an inhibitory effect on the renal excretion of famotidine, the reverse is not true, i.e. high plasma levels of famotidine have no effect on the excretion of cimetidine. Further evidence that additional transport systems are involved in the renal tubular secretion of cimetidine is as follows. Quinine, a potent competitor of the organic cation transport system, inhibits the secretory component of famotidine renal clearance but not that of cimetidine. Probenecid, a classic competitor for the organic anion transport system, inhibits the renal excretion of cimetidine but not famotidine. However, the effect of probenecid is minor and not sufficient to account for other components of cimetidine secretion not affected by famotidine and quinine.

Animals↗
PubMedDate not supplied

Differential renal handling of angiotensin-converting enzyme inhibitors enalaprilat and lisinopril in rats.

Enalaprilat, the active metabolite of enalapril, and its lysine analogue lisinopril are potent nonsulfhydryl angiotensin-converting enzyme inhibitors. Earlier studies from our laboratories demonstrated that neither drug is significantly metabolized, and both are almost exclusively eliminated by renal excretion. This report compares the renal excretory mechanisms for these structurally related compounds in the rat. After an iv, 1-mg/kg dose, ratios of renal clearance (CLR) of unbound drug to glomerular filtration rate (GFR) for enalaprilat and lisinopril were 2.72 +/- 0.70 and 1.01 +/- 0.18, respectively, suggesting that enalaprilat, but not lisinopril, was actively secreted by the kidneys. Treatment with probenecid and p-aminohippuric acid, potent competitive inhibitors for the renal anionic transport system, caused a profound decrease in the renal clearance of enalaprilat to the level of GFR. The CLR/fu.GFR, where fu is the unbound fraction, became 1.10 +/- 0.09 and 1.25 +/- 0.25, respectively. These results and the fact that quinine, a potent inhibitor for the cationic transport system, had little effect on the renal clearance of enalaprilat indicated that enalaprilat is secreted by the organic anion transport system. On the other hand, probenecid, p-aminohippuric acid, and quinine had no effect on the renal clearance of lisinopril, suggesting that lisinopril is eliminated exclusively by glomerular filtration.

Angiotensin-Converting Enzyme Inhibitors↗
PubMedDate not supplied

Enantioselective disposition and protein binding of [(5,6-dichloro-9a-propyl-3-oxo-2,3,9,9a-tetrahydro-1-H-fluoren-7 -yl)-oxy] acetic acid, a new cerebral antiedemic agent, in rats.

[(5,6-Dichloro-9a-propyl-3-oxo-2,3,9,9a-tetrahydro-1-H-fluoren-7-y l)-oxy] acetic acid (DPOFA) is an agent capable of reducing the swelling of astroglial cells in brain tissues. In vitro studies have demonstrated that the (R)-(+)-form of DPOFA is more effective than its (S)-(-)-form in inhibiting tissue swelling. The purpose of this study is to compare the elimination kinetics of the enantiomers. A new stereoselective HPLC procedure was developed for the simultaneous quantitation of (R)-(+)- and (S)-(-)-enantiomers in plasma and bile samples. After iv administration of the racemic mixture (40 mg/kg), rats cleared the (R)-(+)-enantiomer more rapidly than the (S)-(-)-isomer; time-averaged total plasma clearances were 8.88 +/- 0.55 and 4.20 +/- 0.70 ml/min/kg (mean +/- SD), respectively. Similar results were observed when the individual isomers were administered (20 mg/kg iv). Both (R)-(+)- and (S)-(-)-enantiomers were highly bound to plasma protein. The (R)-(+)-isomer had a higher unbound fraction (2%) than did the (S)-(-)-enantiomer (0.8%). The intrinsic clearance of unbound drug for (R)-(+)- and (S)-(-)-enantiomers were 434 +/- 27 and 490 +/- 84 ml/min/kg, respectively, suggesting that the differences in the elimination of the enantiomers in rats were attributable to stereoselectivity in plasma protein binding rather than to enzyme activity. In vitro studies with isolated hepatocytes supported the hypothesis that there was no stereoselectivity in metabolism of the enantiomers.

Animals↗
PubMedDate not supplied

Effect of product inhibition on elimination kinetics of ethoxybenzamide in rabbits. Analysis by physiological pharmacokinetic model.

In our previous study [Lin, Sugiyama, Awazu, and Hanano: J. Pharmacokin. Biopharm. 10,649 (1982)], we successfully applied a physiological pharmacokinetic model to quantitative prediction of the elimination and distribution kinetics of ethoxybenzamide in rats and rabbits. The predictions of the time course of ethoxybenzamide concentrations in plasma were good at lower doses (10 and 20 mg/kg), whereas those at high dose (80 mg/kg) were poor. In the present study, therefore, product inhibition was suspected and examined. Product inhibition of ethoxybenzamide deethylation by its metabolite, salicylamide, was demonstrated both in vivo and in vitro studies. The plasma disappearances of ethoxybenzamide after a 20 mg/kg iv injection were determined both in the control and the salicylamide-treated rabbits. In the salicylamide-treated rabbits, the plasma disappearance of ethoxybenzamide was significantly delayed compared to that in control rabbits. This delay was quantitatively explained by the physiological pharmacokinetic model taking the competitive-type of product inhibition into consideration. The apparent dissociation constant for the salicylamide-enzyme complex in vivo was estimated as 0.14 mM. The inhibition of ethoxybenzamide de-ethylation by salicylamide was observed also in in vitro study using liver microsome of rabbits.

Animals↗
PubMedDate not supplied

Physiological disposition of L-663,581, a partial agonist of the benzodiazepine receptor, in laboratory animals.

L-663,581, 7-chloro-4,5-dihydro-5-methyl-3-(5-(1-methylethyl)-1,2,4-oxadiazol -3-yl)6H-imidazo(1,5-A)(1,4)benzodiazepin-6-one, is an investigational partial agonist for benzodiazepine receptors. This study was designed to characterize the absorption and disposition of the drug and its active metabolites in rats, dogs, and rhesus monkeys. Following intravenous administration (5 mg/kg), L-663,581 was cleared rapidly in all species. The plasma clearance was approximately 95, 40, and 48 ml/min/kg for rats, dogs, and monkeys, respectively. Comparison of urinary recoveries of radioactivity after oral and intravenous dosing indicated that approximately 80-90% of the dose was absorbed in rats and dogs, and 50% in monkeys. The bioavailability was approximately 45% in dogs, 23% in rats, and very low in monkeys after oral administration (5 mg/kg), suggesting an extensive first-pass metabolism in all species. HPLC radiohistograms of urine from all species after intravenous administration revealed that only a trace amount of intact drug was present, indicating that the drug was mainly eliminated by biotransformation. NMR and mass spectral analyses showed that hydroxylation is a major biotransformation pathway. Two active metabolites have been identified as mono- and bis-hydroxy analogs. In addition, the disposition of the monohydroxylated metabolite was also studied in these species. Elimination of the metabolite from plasma was much slower than that of the parent drug in all species. Systemic conversion of L-663,581 to the monohydroxylated metabolite was approximately 43% in rats, 52% in dogs, and only 11% in monkeys.

Administration, Oral↗
PubMedDate not supplied

Uptake of alendronate by bone tissue in hypocalcemic and hypercalcemic rats.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation in the treatment of osteoporosis. Earlier studies in rats from this laboratory have demonstrated that systemically administered alendronate was taken up by bone tissues to the extent of 60-70% of the dose and excreted by the kidneys, 30-40%, and that renal excretion was the only route of elimination of the drug. In this study, a classic three-compartment model was used to determine the kinetics of bone uptake of alendronate in hypo- and hypercalcemic rats. Following intravenous administration (1 mg/kg), the apparent uptake clearance (CL,up) by tibia was approximately 0.18 ml/min/g of bone for control rats, 0.25 ml/min/g for hypocalcemic rats, and 0.05 ml/min/g for hypercalcemic rats. Like other organs, uptake of drugs by bone tissues would be controlled by the plasma flow rate (Q), the fraction of unbound drugs in plasma (fp), and the intrinsic ability of bone uptake (CLin) as described by the equation: CL,up = Q(1 - e-fp.CLin/Q). The plasma flow rate to the tibia of rats was reported to be approximately 0.25 ml/min/g. The unbound fraction of alendronate in plasma of control, hypo-, and hypercalcemic rats was 0.03, 0.45, and 0.035, respectively. By applying the equation, the intrinsic ability (CLin) of bone uptake was estimated to be approximately 10, 2.3, and 1.6 ml/min/g for control, hypo-, and hypercalcemic rats, respectively, indicating that the intrinsic ability of bone to bind alendronate was decreased in both hypo- and hypercalcemic rats.

Alendronate↗
PubMedDate not supplied

Nonlinear kinetics of alendronate. Plasma protein binding and bone uptake.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation in the treatment of osteoporosis. The purpose of this study was to examine the plasma protein binding and the ability of bone to bind alendronate, and their effects on the distribution of the drug to bone tissues. In addition, the species differences in plasma protein binding and bone uptake between rats and dogs were studied. Following intravenous administration (0.8 or 1 mg/kg), the apparent uptake clearance (CL,up) by tibia in dogs and rats was approximately 0.075 and 0.18 ml/min/g bone tissue, respectively. The binding of alendronate to plasma protein was species-dependent; the drug was highly bound to rat plasma, but not to dog plasma. The unbound fraction of alendronate was approximately 0.03 for the rat and 0.53 for the dog. Binding studies with purified serum albumin revealed the presence of displacer(s) in dog plasma. This may explain the low binding of alendronate in dog plasma. Like other organs, uptake of drugs by bone tissue is controlled by the plasma flow (Q), the fraction of unbound drug in plasma (fp), and the intrinsic ability of bone to bind the drug (CLin) as described by the equation: CL,up = Q(1-e-tp.CLin/Q). Plasma flow to the tibia of dogs and rats is reported to be approximately 0.09 and 0.25 ml/min/g, respectively. By applying the equation, the CLin was estimated to be approximately 10 ml/min/g for the rat and 0.3 ml/min/g for the dog. These results indicate that both plasma protein binding and bone uptake were species-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Alendronate↗
PubMedDate not supplied

Intestinal obstruction in asplenia syndrome: report of three cases.

Congenital absence of spleen is rare. When it does occur, it may be associated with a characteristic group of anomalies of the cardiovascular and gastrointestinal system. Fifteen neonates of asplenia syndrome were seen in our hospital from April 1989 to November 1992, three of these fifteen cases were associated with intestinal obstruction and malrotation. All of the three neonates were noted to have cyanosis, heart murmur and abdominal distention soon after birth. Absence of spleen, heterotaxia and complex cardiac malformations were detected by sonography. Howell-Jolly bodies were found in their peripheral blood smear. The barium examinations of gastrointestinal tract showed intestinal obstruction and malrotation. All of them died in the first month of life. One of them received an autopsy.

Abnormalities, Multiple↗