Plasma protein binding interaction between valproic and salicylic acids in rhesus monkeys

The effects of three levels of salicylic acid on the steady-state plasma concentrations of free and total valproic acid were examined in catheterized rhesus monkeys. Valproate was infused intravenously for a total of 41 hr, and salicylate was added after the first 8 hr. The three salicylate infusions were randomly assigned to each monkey. Valproate free fraction was determined by equilibrium dialysis. Statistically significant increases in valproate free fraction and total body clearance were observed after addition of salicylic acid. The increase in valproate clearance was positively correlated with the molar ratio of salicylate to valproate steady-state plasma concentrations. There was no significant change in valproate free concentration after salicylate treatment. The proposed mechanism of this in vivo interaction includes plasma protein binding displacement with no change in valproate intrinsic clearance.     

Comparative in vivo and in vitro studies of phenytoin protein binding and in vitro lipolysis in plasma of pregnant and nonpregnant rats

This investigation was designed to determine the cause of the changes in drug protein binding that occur in rat plasma, particularly in plasma from pregnant animals, during in vitro drug-protein binding measurements. In vivo estimates of phenytoin binding in plasma were obtained from steady-state CSF-plasma concentration ratios in pregnant and nonpregnant rats. Immediate ultrafiltration of heparin- or EDTA-anticoagulated plasma yielded phenytoin free fraction values that were in good agreement with in vivo estimates for nonpregnant rats but that were about one-third higher than in vivo estimates for pregnant animals. In vitro free fraction values tended to increase during incubation of plasma and/or during equilibrium dialysis. The concentrations of the four major endogenous free fatty acids were similar in plasma of pregnant and nonpregnant rats if determined immediately after blood collection. Six hours of incubation at 37 degrees C caused fatty acid concentrations to increase about fivefold and twofold in heparin-anticoagulated plasma from pregnant and nonpregnant animals, respectively. The corresponding increases in EDTA-anticoagulated plasma were only about twofold and 1.14-fold, respectively. These changes were associated with decreased plasma protein binding of phenytoin. The in vivo differences between pregnant and nonpregnant rats with respect to phenytoin binding in plasma are not due to differences in fatty acid concentrations, but the in vitro differences are due primarily to corresponding differences in free fatty acid concentrations if extensive in vitro lipolysis occurs.     

The pharmacokinetics of salicylate in the pregnant Wistar rat

Sodium salicylate, in a single dose of 50 mg/kg, was administered by iv injection to nonpregnant female and 20-day pregnant Wistar rats. Blood samples (for serum) and urine were collected and analyzed for salicylate, gentisic acid, salicyluric acid, and salicyl glucuronides by HPLC. Pregnant rats showed a significant decrease in body weight-normalized total clearance but no change in absolute total clearance of salicylate. On a body weight-adjusted basis there was a slight increase in the apparent volume of salicylate distribution in pregnancy but this increase becomes highly significant if expressed in absolute terms. The biological half-life of salicylate was significantly increased in late pregnancy. Serum protein binding of salicylate is decreased in pregnancy relative to nonpregnant females but in both groups binding shows a concentration dependence. The partial clearances of both salicyluric and gentisic acids were reduced by pregnancy in the rat whereas that of the salicyl glucuronides appeared unchanged. This latter result in intact pregnant animals contrasts with previously reported decreases in glucuronyltransferase activity in isolated liver preparations from pregnant rats.     

Influence of pregnancy on the pharmacokinetic disposition of two aromatic retinoids (etretinate and acitretin) in the rat. I. Intravenous studies

The influence of pregnancy on the disposition of two related aromatic retinoids (etretinate and its metabolite, acitretin) was evaluated in a rodent model. The plasma concentrations of etretinate and acitretin were monitored by a specific HPLC method following iv bolus doses to 17-day pregnant and nonpregnant Sprague-Dawley rats. The systemic clearance of etretinate was significantly lower in the pregnant rats compared to nonpregnant controls (129 vs. 185 ml/hr, respectively; p less than 0.05). This decrease was entirely due to a lower formation clearance of acitretin (acid) from etretinate (ester) in the pregnant animals (96 vs. 146 ml/hr; p less than 0.05). The in vitro plasma hydrolysis rate of etretinate was also lower in the pregnant animals. By contrast, the systemic clearance of acitretin was greater in the pregnant compared to the nonpregnant control animals (184 vs. 145 ml/hr, respectively; p less than 0.05). The apparent volumes of distribution for both retinoids were comparable in the pregnant and nonpregnant animals. Etretinate infusions in nonpregnant animals yielded systemic clearances (mean = 164 ml/hr) which were similar to those obtained for bolus dose experiments. Acitretin clearance increased (plasma levels decreased) following acitretin infusion to nonpregnant rats over the time course of the infusion. The results illustrate the marked effect of pregnancy on the disposition of these retinoids and suggest that acitretin may pose less of a teratogenic hazard than the parent compound etretinate.     

Decreased binding of drugs and dyes to plasma proteins from rats with acute renal failure: effects of ureter ligation and intramuscular injection of glycerol.

1 The decreased binding of drugs and dyes to plasma proteins from male and female rats with acute renal failure has been investigated using equilibrium dialysis at 37 degrees C. 2 Acute renal failure induced by bilateral ligation of the ureters produced a greater than threefold increase in the unbound fraction of o-methyl red relative to normal rat plasma. Unbound dye concentration in plasma from sham-operated control rats was also significantly increased but to a lesser extent. 3 Glycerol-induced acute renal failure produced a significant increase in the unbound fractions of o-methyl red, methyl orange, bromocresol green (BCG), 2-(4'-hydroxybenzeneazo) benzoic acid (HABA), phenytoin and salicylic acid. A marginally significant increase in unbound warfarin concentration was observed. 4 Glycerol-induced renal failure had no effect on total plasma protein concentration and experiments with o-methyl red and salicylic acid indicated that a direct effect of glycerol was not responsible for the diminution of binding. 5 Glycerol-induced acute renal failure, which produced decreases in drug and dye binding similar to those reported for human uraemic plasma, provides a convenient non-surgical animal model for the investigation of this phenomenon.     

Pharmacokinetics, metabolism and disposition of salicylate in protein-deficient rats

The influence of dietary protein deficiency on the pharmacokinetics, metabolism, and disposition of sodium salicylate was investigated in Sprague-Dawley male rats. Animals were fed for 3 weeks a 21% (control) or a 5% (deficient) protein diet ad lib.; an additional group of rats (pair-fed controls) was fed for 3 weeks the control 21% protein diet in a restricted quantity (10 g/day/rat), which was approximately equal to the quantity (9.8 g/day) consumed by rats receiving the 5% protein diet ad lib. Sodium salicylate (in salicyclic acid equivalents) and its metabolites were assayed by HPLC. In both control and protein-deficient rats, sodium salicylate kinetics were dose-dependent and the decline in its plasma concentration proceeded according to a first-order process; no differences in the two groups of animals were found with respect to the following features of the biological fate of salicylate: plasma half-life and clearance at a 2-mg/kg (iv) dose level, volume of distribution at all dose levels (2, 10, and 100 mg/kg, iv), relative bioavailability by oral route, tissue distribution, and the rate of urinary excretion of salicyl glucuronides at 10-mg/kg dose level. However, at high dose levels (10 and 100 mg/kg, iv), the plasma half-life of salicylate was shorter and its clearance greater in protein-deficient than in control rats. The following additional changes were caused by dietary protein deficiency: a decrease in salicylate binding to serum protein, an increase in the metabolic transformation of salicylic acid to its glycine conjugate, salicyluric acid, by kidney mitochondrial preparations, an increase in the urinary excretion of salicyluric acid and salicylic acid, and a decrease in the elimination half-life of salicylic acid; the excretion of salicyluric acid proceeded according to a first-order process in protein-deficient rats but according to an apparent zero-order process in the controls. The changes in the plasma half-life and clearance of salicylate in pair-fed controls were not significant; it appears that a deficiency of both proteins and calories (protein-deficient rats) exerts greater influence on the biological fate of salicylate than does a deficiency mainly of calories (pair-fed controls). It is suggested that the decrease in the plasma half-life of salicylate in protein-deficient rats is the result of an increase in its clearance, which in turn is caused by a decrease in protein-salicylate binding and an increase in the metabolism of salicylic acid to salicyluric acid. These results point to the desirability of a systematic study of the biological fate of salicylate during clinical malnutrition, which is common in developing countries.     

Effects of salicylates and paracetamol compared to lidocaine on nerve conduction in vitro

The effects of acetylsalicylic acid, salicylic acid, sodium salicylate and paracetamol on the compound action potentials of the isolated left phrenic nerve of the rat were observed, and compared to that of lidocaine. All drugs depressed the compound action potential in a reversible, dose-dependent way. Lidocaine (inhibition between 0.05 and 10 mM) was more potent than the other drugs and the depression occurred faster. The inhibitory effects of acetylsalicylic acid and salicylic acid were similar to each other (between 1 and 20 mM). Sodium salicylate was less potent (inhibition between 5 and 70 mM). These concentrations cover the plasma levels reported after therapeutic and toxic doses for the salicylates. Inhibition of nerve conduction may therefore contribute to the adverse nervous effects seen after intoxication with salicylates. In contrast, the observed concentrations for inhibition of the compound action potential caused by paracetamol (between 6.7 and 53 mM) were far greater than the plasma concentrations reported after therapeutic doses or after intoxication with paracetamol. Thus, the inhibition of the compound action potential, caused by paracetamol does not contribute to the therapeutic analgesic effects of paracetamol.     

Metabolism and disposition of a potent group II metabotropic glutamate receptor agonist, in rats, dogs, and monkeys.

Metabolism and disposition of MGS0028 [(1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate], a potent group II metabotropic glutamate receptor agonist, were examined in three preclinical species (Sprague-Dawley rats, beagle dogs, and rhesus monkeys). In rats, MGS0028 was widely distributed and primarily excreted in urine as parent and as a single reductive metabolite, identified as the 4R-isomer MGS0034 [(1R,2S,4R,5S,6S)-2-amino-6-fluoro-4-hydroxybicyclo[3.1.0]-hexane-2,6-dicarboxylic acid]. MGS0028 had a low brain to plasma ratio at efficacious doses in rats and was eliminated more slowly in rat brain than in plasma. Exposure increased proportionally (1--10 mg/kg p.o.) in rats, with bioavailability>60% at all doses. However, bioavailability was only approximately 20% in monkeys, and MGS0034 was found in relatively high abundance in plasma. In dogs, oral bioavailability was >60%, and the metabolite was not detected. In vitro metabolism was examined in liver subcellular fractions (microsomes and cytosol) from rat, dog, monkey, and human. Reductive metabolism was observed in rat, monkey, and human liver cytosol incubations, but not in dog liver cytosol incubations. No metabolism of MGS0028 was detected in incubations with liver microsomes from any species. Similar to in vivo results, MGS0028 was reduced in cytosol stereospecifically to MGS0034. The rank order of in vitro metabolite formation (monkey > rat approximately human > dog) was in agreement with in vivo observations in rats, dogs, and monkeys. Based on the observation of species difference in reductive metabolism, rat and monkey were recommended to be the preclinical species for further characterization prior to testing in humans. Finally, allometric scaling predicts that human pharmacokinetic parameters would be acceptable for further development.     

Influence of age, sex, pregnancy and protein-calorie malnutrition on the pharmacokinetics of salicylate in rats

The influence of age, sex, pregnancy and protein-calorie malnutrition (PCM) on the plasma t1/2, plasma clearance (Clp) and apparent volume of distribution (Vd) of sodium salicylate (62 mumol kg-1) was determined in Sprague-Dawley rats. Female and male rats of five different age groups (ages in weeks: pups 1, weanling 3, young 8-9, adult including pregnant 14-15, old 56-60) including three age groups with PCM (8-9, 14-15 and 56-60 weeks old) were used. Plasma and urinary salicylates were assayed by h.p.l.c. Plasma t1/2 was longer and Clp smaller in pups than in weanling and young rats and comparable to values for old rats; Vd of salicylate in pups was larger than in any other group of rats. Plasma t1/2 was longer and Clp as well as Vd of salicylate were smaller in adult females than in males of comparable age. Relative to nonpregnant adult females, Vd of salicylate in pregnant rats was larger but plasma t1/2 and Clp were unchanged. In all groups of rats studied, PCM decreased the plasma t1/2 and increased the Clp of salicylate; Vd was unchanged. Changes in salicylate pharmacokinetics were not due to any differences in serum protein-salicylate binding or to serum testosterone levels. Ovariectomy decreased the plasma t1/2 of salicylate but castration of male rats had no significant effect. Administration of testosterone to ovariectomized female rats exerted no significant effect on salicylate pharmacokinetics. It is concluded that the physiological state and the nutritional status can modify salicylate pharmacokinetics; in so far as the rat model reflects the human situation, these variables should be taken into account for a rational salicylate therapy.     

Extensive biliary excretion of the sulfasalazine analogue, susalimod, but different concentrations in the bile duct in various animal species correlating to species-specific hepatobiliary toxicity.

Studies on biliary concentrations of susalimod were conducted in rat, dog and monkey to clarify the interspecies differences observed in toxicology studies with respect to hepatobiliary toxicity after long-term administration of the compound. Dose-related bile duct hyperplasia appeared only in dogs at doses > or =75 mg/kg/day, while in rats and monkeys it did not appear at doses up to 1500 and 2000 mg/kg/day respectively. Biliary excretion was investigated after intraduodenal administration of susalimod in anaesthetised animals. In addition excretion routes were determined by collecting urine and faeces following a radiolabelled intravenous dose. Susalimod was extensively excreted via the bile in all animal species, > or =90%, mainly as non-conjugated parent compound. However, the local concentrations in bile varied between the species. Highest concentrations were obtained in the dog. The bile/plasma concentration ratio was 3400 in the dog, 300 in the monkey and 50 in the rat. In the dog, bile duct concentrations of susalimod about 30,000 micromol/l was obtained at plasma concentrations approximately similar to those at which hepatobiliary toxicity occurred, while in rat and monkey the levels were < or =7000 micromol/l at plasma concentrations similar to those obtained at the highest doses in the toxicology studies. From these results supported by a previous biliary excretion study in conscious dogs with chronic bile fistula receiving repeated administration of susalimod (P?hlman et al. 1999), it is likely that the hepatotoxic findings in dog are induced by the high concentrations of susalimod in the bile duct.     

Determination of salicylic acid by HPLC in plasma and saliva from children with juvenile chronic arthritis.

A high performance liquid chromatography (HPLC) method has been developed for measuring salicylic acid in the plasma and saliva of children with juvenile chronic arthritis (JCA). Samples were extracted with diethyl ether and, after drying, redissolved in methanol to be chromatographed. Quantitation of salicylic acid was performed by reverse phase HPLC on a spherisorb ODS-2 column, using methanol: water: acetic acid as mobile phase. Phenolic was monitored by absorbance at 237 nm. Linearity between the amount of mass injected and the response in the detector was determined. This method was applied to compare concentrations of salivary and plasma salicylic acid. The method also permitted the quantitation of salivary salicylate as a non-invasive, indirect method for monitoring the concentration of plasma salicylate in patients with JCA.     

Comparison of the effects of N-nitrosodimethylamine on pregnant and nonpregnant Holtzman rats

Single oral doses of N-nitrosodimethylamine or olive oil were given to nonpregnant and pregnant female Holtzman rats on different days of pregnancy (days 7–18, where day 0 was considered to be the sperm positive day). Serological and histopathological studies were performed on animals killed 2 days after treatment. In comparison with the values obtained in nonpregnant controls, the following parameters in pregnant controls were significantly increased: relative liver weights (days 9–20), liver ascorbic acid concentrations (day 12), blood urea nitrogen (days 16–20), serum triglyceride (days 14–20), serum inorganic phosphorus (days 12–18), and serum glutamic-pyruvic transaminase (days 14–20). The following parameters were decreased in pregnant rats compared with nonpregnant controls: relative organ weights (kidneys, adrenals and thyroids), serum glucose (days 12–20), total serum protein (days 9 and 16–20), and serum alkaline phosphatase (day 20). The serum cholesterol levels in pregnant rats were significantly decreased on days 9–15 of pregnancy and significantly increased on day 20. The numbers of mitotic cells in the livers of pregnant rats were greatly increased compared with nonpregnant rats on all days of pregnancy, while the adrenal cortex contained a significantly higher number of mitotic cells only on days 16 and 18.Compared with control values, NDMA given orally (15 or 20 mg/kg body weight) increased the following in both pregnant and nonpregnant rats: numbers of mitotic cells in the liver and adrenal cortex, relative adrenal weights, serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase. NDMA treatment decreased liver ascorbic acid and total serum protein in both pregnant and nonpregnant rats. In nonpregnant rats NDMA also increased relative liver weights (not significant) and serum alkaline phosphatase levels. NDMA increased serum α-hydroxybutyric dehydrogenase in pregnant rats on day 20 and decreased foetal weights (in rats treated on days 13 and 18). NDMA treatment was not lethal to nonpregnant rats or to pregnant rats up to day 16 of pregnancy, but single oral doses of 15 and 20 mg NDMA/kg killed 9.4 and 35.3%, respectively, of rats treated on day 18 of pregnancy. In general, the acute toxic effect of NDMA, as measured by changes in the above parameters, was greater in pregnant than in nonpregnant rats, especially near the end of pregnancy.     

Extensive Biliary Excretion of the Sulfasalazine Analogue,Susalimod, but Different Concentrations in the Bile Duct in Various Animal Species Correlating to Species-Specific Hepatobiliary Toxicity

Abstract: Studies on biliary concentrations of susalimod were conducted in rat, dog and monkey to clarify the interspecies differences observed in toxicology studies with respect to hepatobiliary toxicity after long-term administration of the compound. Dose-related bile duct hyperplasia appeared only in dogs at doses ≥75 mg/kg/day, while in rats and monkeys it did not appear at doses up to 1500 and 2000 mg/kg/day respectively. Biliary excretion was investigated after intraduodenal administration of susalimod in anaesthetised animals. In addition excretion routes were determined by collecting urine and faeces following a radiolabelled intravenous dose. Susalimod was extensively excreted via the bile in all animal species, ≥90%, mainly as non-conjugated parent compound. However, the local concentrations in bile varied between the species. Highest concentrations were obtained in the dog. The bile/plasma concentration ratio was 3400 in the dog, 300 in the monkey and 50 in the rat. In the dog, bile duct concentrations of susalimod about 30,000 μmol/l was obtained at plasma concentrations approximately similar to those at which hepatobiliary toxicity occurred, while in rat and monkey the levels were ≤7000 μmol/l at plasma concentrations similar to those obtained at the highest doses in the toxicology studies. From these results supported by a previous biliary excretion study in conscious dogs with chronic bile fistula receiving repeated administration of susalimod (Påhlman et al. 1999), it is likely that the hepatotoxic findings in dog are induced by the high concentrations of susalimod in the bile duct.     

Dose‐dependent plasma clearance of MK‐826, a carbapenem antibiotic,arising from concentration‐dependent plasma protein binding in rats and monkeys

After intravenous administration of MK‐826, a new carbapenem antibiotic, the compound exhibited nonlinear pharmaco‐kinetics in rats and monkeys. In both species, time‐averaged plasma clearance (based on total concentrations) increased about 5‐fold over the 10‐ to 180‐mg/kg dose range. MK‐826 was extensively plasma protein bound in rat and monkey plasma, and the extent of binding was concentration dependent at plasma concentrations achieved after administration of these doses. Rosenthal analysis of the plasma protein binding indicated that there were two classes of binding sites. The binding capacity of the primary site was comparable to the plasma albumin concentration, which suggested that this primary site consisted of a single site on albumin. The extent of binding of MK‐826 to rat albumin was similar to that in whole plasma. Clearance values based on unbound concentrations appeared independent of dose from 10 to 180 mg/kg, which is consistent with saturation of protein binding as the primary cause of the nonlinear pharmacokinetic behavior.     

Effect of pregnancy on tissue distribution of salicylate in rats

The effect of pregnancy on tissue distribution of salicylate was studied by comparing both pharmacokinetic and protein-binding parameters between 20-day-pregnant rats and nonpregnant (control) rats. In the pregnant rats, the volume of distribution increased significantly (p less than 0.05) from 164 ml/kg of the control to 225 ml/kg, and the total body clearance also increased significantly (p less than 0.05) from 12.1 ml/hr/kg of the control to 19.8 ml/hr/kg. But these changes did not affect the plasma disappearance half-life of salicylate in the pregnant rats. The serum unbound fraction (fs) of the pregnant rats at 8 hr after iv administration of salicylate increased remarkably from 0.14 of the control to 0.67. The fs in the fetal serum (0.41) was lower than that in the maternal serum in spite of the lower albumin concentration in the fetal serum. A nonlinear serum protein binding was observed both in the control and in the fetal rats, but not observed in the pregnant rats. In the pregnant rats, the tissue-to-serum concentration ratios (Kp) of all tissues studied were larger than those in the control rats, and the values of Kp in the fetal were larger than those in the maternal. To elucidate these difference in Kp values between the pregnant and control rats, a mathematical model was proposed, where salicylate was distributed in the interstitial fluid, bound to the interstitial albumin, and translocated into the intracellular fluid according to the pH partition theory. The Kp values of most tissues in the control and pregnant rats were predicted successfully by using this model.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of cimetidine on the pharmacokinetics of salicylic acid

The pharmacokinetics of the interaction between salicylic acid and cimetidine was investigated in 11 healthy male and female volunteers. The plasma concentrations of total and free salicylic acid were measured. The kinetic disposition of salicylic acid after multiple administration of cimetidine (1 g per day) showed two modifications: the elimination rate was slower and plasma clearance was reduced. The corresponding area under concentration-time curves was always significantly greater. These differences were the same in both sexes. The rate of absorption, peak salicylate concentration and plasma protein binding of salicylic acid in the presence of cimetidine were not changed.     

Anti-platelet actions of salicylates: in vivo, ex vivo and in vitro effects of choline salicylate

Effects of choline salicylate, sodium salicylate, choline chloride and acetylsalicylic acid on platelet aggregation in vivo, ex vivo and in vitro in mice were studied. These drugs all inhibited adenosine diphosphate (ADP)-induced respiratory depression, which is closely related to platelet aggregation in vivo, with choline salicylate showing the strongest inhibitory effect. Choline salicylate had a tendency to reduce the mortality of animals injected intravenously with endotoxin, but the other drugs had no such effect. The inhibitory effects of these drugs on ADP-induced platelet aggregation ex vivo were in the order of choline salicylate greater than acetylsalicylic acid congruent to sodium salicylate greater than choline chloride congruent to no effect, and plasma concentrations of protein-unbound salicylic acid at 1 hr after oral administration of drugs were in the order of choline salicylate greater than acetylsalicylic acid congruent to sodium salicylate. The in vitro effects of these drugs were in the order of choline salicylate congruent to sodium salicylate greater than choline chloride congruent to acetylsalicylic acid congruent to no effect. Therefore, it was considered that salicylic acid played an important role on the in vivo, ex vivo and in vitro effects of choline salicylate and that choline increased plasma concentrations of salicylic acid and consequently enhanced the in vivo and ex vivo effects of salicylic acid. Furthermore, the ex vivo effects of choline salicylate were found when ADP-induced platelet aggregation was measured with platelet-rich plasma prepared from blood collected with heparin as anti-coagulant, but not when blood was collected with citrate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of nimodipine. I. Communication: absorption, concentration in plasma and excretion after single administration of [14C]nimodipine in rat, dog and monkey

Studies on absorption, plasma concentrations and excretion with (+/-)isopropyl-2-methoxyethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate (nimodipine, Bay e 9736, Nimotop) have been conducted in rat, dog and monkey using the carbon-14-labelled substance and a wide range of doses (0.05-10 mg/kg) administered via different routes (intravenous, oral, intraduodenal). Nimodipine was well absorbed in all species. Peak plasma concentrations of radioactivity were determined 28-40 min (male rat), 60 min (female rat), about 3 h (dog) and 7 h (monkey) after administration. Dependent on the observation period (24-216 h) terminal half-lives for the elimination of radioactivity from plasma ranging between 4.6 h (female rat) and 157 h (dog) were observed. Comparing the AUC, the concentration of unchanged [14C]nimodipine in plasma represented only a small (maximally 37% in dogs after i.v. dose) to negligible (about 1%, monkey after oral dosing) part of the total radioactivity. Excretion of radioactivity via feces and urine was rapid in all species after both oral and intravenous dosing. Fecal (biliary) excretion was the major excretory route in rat and dog. The monkeys excreted about 40 to 50% via the urine. Residues in the body never exceeded 1.5% of the dose. [14C]nimodipine and/or its radiolabelled metabolites were secreted in milk of orally dosed lactating rats. Binding of [14C]nimodipine to plasma proteins of rat and dog was about 97%.     

Time-course changes of hematology and clinical chemistry values in pregnant rats

The aim of this study is to report how pregnancy alters hematology and clinical chemistry values in rats. Female and male Sprague-Dawley rats were mated; the day of copulation was designated as Day 0. Hematology and clinical chemistry measurements were conducted on Days 7, 14, 17 and 21 in pregnant rats. Measurements were also conducted in non-pregnant rats. Red blood cells (RBC), hemoglobin (Hb), hematocrit (Ht), total protein and albumin decreased on Days 7, 14, 17 and 21; sodium, chloride and glucose decreased on Days 14, 17 and 21; iron decreased on Days 17 and 21; hemoglobin content of reticulocytes (CHr), calcium, inorganic phosphorus and the albumin/globulin ratio decreased on Day 21; and total cholesterol, phospholipid and high-density lipoprotein cholesterol decreased on Day 14 in pregnant rats compared with non-pregnant rats. Reticulocyte increased on Days 7, 14 and 17; mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, neutrophil count and rate increased on Days 14, 17 and 21; platelets, fibrinogen, triglyceride and free fatty acid increased on Days 17 and 21; and activated partial thromboplastin time was prolonged on Days 17 and 21 in pregnant rats compared with non-pregnant rats. The decreased RBC, Hb, Ht, CHr and iron in pregnant rats indicated that they suffered from iron deficiency anemia. These data can be used as background information for effective evaluation in reproductive toxicology studies.     

The metabolism of the anti-inflammatory drug eterylate in rat,dog and man

1. Oral doses of ¹⁴C-eterylate were well absorbed by rat and man and excreted mainly in the urine (94% dose by rat in three days and 91% by man in five days). Oral doses to dogs were excreted in similar proportions in both the urine and faeces, although faecal ¹⁴C was probably derived in part, from biliary-excreted material.

2. Peak plasma ¹⁴C and drug concn. were generally reached between one and three hours after oral doses. In humans, only two metabolites, salicylic acid and 4-acetamido-phenoxyacetic acid, were detected in plasma. The latter was cleared more rapidly than the former and hence plasma salicylate concn. reached a peak (10.9 and 19.8 μg/ml in Subjects 1 and 2, respectively) and initially declined with a half-life of about two-three hours. Plasma 4-acetamidophenoxyacetic acid concn. reached a peak (4.3, 10.0 μg/ml, respectively) and declined with a half-life of about one hour.

3. Tissue concn. of ¹⁴C were generally greater in dogs than in rats. Highest conc. occurred at three hours in dogs and at one hour in rats. Apart from those in the liver and kidneys, tissue concoccurred were lower than those in the corresponding plasma.

4. Unchanged drug was not detected in urine or plasma of any species and was rapidly metabolized in human plasma. The major ¹⁴C components in human urine were identified as salicyluric acid and 4-acetamidophenoxyacetic acid; minor metabolites were salicylic acid, gentisic acid and paracetamol. These metabolites were also detected in rat urine albeit in different proportions to those in human urine. Dog urine contained less of these metabolites and a major proportion of the ¹⁴C was associated with relatively non-polar components. Although salicylic acid and 4-acetamidophenoxyacetic acid were the only major circulating metabolites in man and rat, dog plasma also contained the non-polar urine metabolites.