Decline In Plasma Concentration Research Articles

Clinical pharmacokinetics of the depot antipsychotics.

The clinical pharmacokinetics of the 4 depot antipsychotics for which plasma level studies are available (i.e. fluphenazine enanthate and decanoate, haloperidol decanoate, clopenthixol decanoate and flupenthixol decanoate) are reviewed. The proper study of these agents has been handicapped until recently by the necessity of accurately measuring subnanomolar concentrations in plasma. Their kinetic properties, the relationship of plasma concentrations to clinical effects, and conversion from oral to injectable therapy are discussed. The depot antipsychotics are synthesised by esterification of the active drug to a long chain fatty acid and the resultant compound is then dissolved in a vegetable oil. The absorption rate constant is slower than the elimination rate constant and therefore, the depot antipsychotics exhibit 'flip-flop' kinetics where the time to steady-state is a function of the absorption rate, and the concentration at steady-state is a function of the elimination rate. Fluphenazine is available as both an enanthate and decanoate ester (both dissolved in sesame oil), although the decanoate is more commonly used clinically. The enanthate produces peak plasma concentrations on days 2 to 3 and declines with an apparent elimination half-life (i.e. the half-time of the apparent first-order decline of plasma concentrations) of 3.5 to 4 days after a single injection. The decanoate produces an early high peak which occurs during the first day and then declines with an apparent half-life ranging from 6.8 to 9.6 days following a single injection. After multiple injections of fluphenazine decanoate, however, the mean apparent half-life increases to 14.3 days, and the time to reach steady-state is 4 to 6 weeks. Withdrawal studies with fluphenazine decanoate suggest that relapsing patients have a more rapid plasma concentration decline than non-relapsing patients, and that the plasma concentrations do not decline smoothly but may exhibit 'lumps' due to residual release from previous injection sites or multicompartment redistribution. Cigarette smoking has been found to be associated with a 2.33-fold increase in the clearance of fluphenazine decanoate. In 3 different studies, fluphenazine has been proposed to have a therapeutic range from less than 0.15 to 0.5 ng/ml with an upper therapeutic range of 4.0 ng/ml. Plasma concentrations following the decanoate injection are generally lower than, but clinically equivalent to, those attained with the oral form of the drug. Haloperidol decanoate plasma concentrations peak on the seventh day following injection although, in some patients, this peak may occur on the first day.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of alcohol on the release of cholecystokihin and pancreatic enzyme secretion

Ethanol is often implicated in the pathogenesis of acute pancreatitis, but the pathophysiologic processes of alcohol-induced acute pancreatitis remains poorly understood. We found that ingestin of alcohol by healthy volunteers did not stimulate release of cholecystokinin, which is the chief hormonal stimulant of pancreatic enzyme secretion, nor did it significantly alter fasting levels of pancreatic polypeptide, a hormonal inhibitor of pancreatic enzyme secretion. In conscious dogs prepared with chronic pancreatic fistulas, direct intraduodenal instillation of ethanol significantly reduced pancreatic protein output, and this reduction corresponded to a decline in plasma concentrations of cholecystokinin that was similar in the percentage of diminution and in duration. These data suggest that, in patients who do not have chronic pancreatitis, alcohol does not induce acute pancreatitis, either by stimulating cholecystokinin release or by stimulating enzyme secretion directly.

Diurnal changes in peripheral melatonin concentration in goats and effects of light or dark interruption.

Diurnal changes in peripheral plasma concentrations of melatonin (MLT) and effects of 2 hr light exposure during the nighttime and 2 hr dark exposure during the daytime on MLT concentrations in goats were examined in natural lighting condition. Two breeds of goats, the Saanen goat as a seasonal breeder at the breeding season, and the Shiba goat as a non-seasonal one, were used while they were at luteal phase. Plasma concentrations of MLT showed a marked diurnal change in both breeds of goats, which was high during the nighttime (20-120 pg/ml) and low during the daytime (<20 pg/ml). Light exposure during the nighttime (for 2 hr) caused an abrupt decline in plasma concentrations of MLT to the basal level; and when the light was turned off, plasma MLT began to increase. On the contrary, 2 hr dark treatment during the daytime did not induced a rapid increase in plasma MLT as observed at the onset of the night. The pattern and the magnitude of the nocturnal elevation in plasma MLT and the responses to the dark or light interruption were virtually identical between the two breeds. These results suggest that the secretion of MLT in goats is driven by the endogenous rhythm, though the lighting stimulus temporarily suppresses the MLT secretion.

Dose-Dependent Pharmacokinetics and Biliary Excretion of Bromophenol Blue in the Rat

□ Concentrations of bromophenol blue (I) in plasma, urine, and bile were determined spectrophotometrically after intravenous bolus injections and infusions in rats. The plasma concentrations were found to decrease monoexponentially after all doses except the highest, where the decrease was biexponential. Although the disposition kinetics of I were apparently first-order at all doses, the half-life increased with increasing dose. The area under the plasma concentration–time curve (AUC0-∞) increased disproportionately with increasing dose. The binding of I to rat plasma proteins, as determined by equilibrium dialysis, showed that the fraction bound (96%) remained constant in the concentration range of 10-300 μg/ml. Plasma concentrations were determined at time zero after intravenous administration and after a second dose administered 20 min later when plasma concentrations from the first dose were minimal. The apparent first-order elimination rate constant for the plasma concentration decline following the second dose was significantly less than after the first dose, indicating that the residual dye in the liver altered the elimination of I after the second dose. The fraction of the dose in the liver decreased with increasing dose, indicating a saturable uptake process. The biliary excretion profile reflected the uptake saturation that occurred in the liver and demonstrated that the biliary excretion of I depended on the amount present in the liver. When liver damage was induced by exposure to carbon tetrachloride, dye concentrations in the plasma, liver, and kidney increased markedly.

Physiologically Based Pharmacokinetic Modeling: Principles and Applications

Concentrations of bromophenol blue (I) in plasma, urine, and bile were determined spectrophotometrically after intravenous bolus injections and infusions in rats. The plasma concentrations were found to decrease monoexponentially after all doses except the highest, where the decrease was biexponential. Although the disposition kinetics of I were apparently first-order at all doses, the half-life increased with in- creasing dose. The area under the plasma concentration-time curve (AUCs,) increased disproportionately with increasing dose. The binding of I to rat plasma proteins, as determined by equilibrium dialysis, showed that the fraction bound (96%) remained constant in the concentration range of 10-300 pg/ml. Plasma concentrations were determined at time zero after intravenous administration and after a second dose adminis- tered 20 min later when plasma concentrations from the first dose were minimal. The apparent first-order elimination rate constant for the plasma concentration decline following the second dose was significantly less than after the first dose, indicating that the residual dye in the liver altered the elimination of I after the second dose. The fraction of the dose in the liver decreased with increasing dose, indicating a saturable uptake process. The biliary excretion profile reflected the uptake saturation that occurred in the liver and demonstrated that the biliary excretion of I depended on the amount present in the liver. When liver damage was induced by exposure to carbon tetrachloride, dye concentrations in the plasma, liver, and kidney increased markedly. Keyphrases 0 Bromophenol blue-in rat urine, plasma, and bile, dose-dependent pharmacokinetics, biliary excretion 0 Pharmacoki- netics-bromophenol blue, rat plasma, urine, and bile, biliary excretion I I Biliary excretion-bromophenol blue, rat urine, plasma, and bile, dose-dependent pharmacokinetics Bromophenol blue (I) is a high molecular weight anionic sulfonephthalein dye (670 g/mole, pK, 4.0). Several re- ports (1-3) have shown that I is extensively excreted in the bile and is not metabolized in a variety of species including the rat. Takada et al. (4, 5 ) conducted studies aimed at char- acterizing the role of the intracellular protein fractions Y and Z in the uptake and transport of I in rat hepatocytes, and also developed a linear pharmacokinetic model for the biliary excretion of I after intravenous administration in rats (6). The model adequately described a single low-dose plasma and bile profile, but could not describe the ob- served nonlinearity a t higher doses. The overall aim of these authors was to evaluate I as a model organic anionic compound by characterizing the pharmacokinetics at three different doses. Their report did not fully characterize the pharmacokinetics at any dose. Liver concentrations and plasma protein binding were not measured, and the ob- served nonlinearity was not addressed. Studies on the pharmacokinetics of drugs excreted in the bile have increased in recent years as investigators have become more interested in the effects of liver disease on drug clearance, the effects of first-pass liver clearance on drug bioavailability, the effects of enterohepatic recircu- lation on drug disposition, and the nonlinear excretion of drugs (7-11). Usually these studies have not considered the extent of protein binding, liver-to-plasma and bile- to-liver drug concentration ratios, hepatic blood flow, and bile flow. These factors contribute to the interpretation of hepatobiliary elimination. In addition, the interpreta- tion has been complicated by the use of compounds such as sulfobromophthalein that undergo metabolism. Ideally, a model compound used in studying hepatobiliary elimi- nation would not undergo metabolism, nor enterohepatic recirculation, and would not be pharmacologically ac- tive. The organic anion, bromophenol blue (I), possesses these qualities (2, 4). Therefore, the present investigation was undertaken to: (a ) determine the pharmacokinetic profile 0022-3549/83/ 1000-1 127$01.00/0 @ 1983, American Pharmaceutical Association Journal of Pharmaceutical Sciences I 1127 Vol. 72, No. 10. October 1983

Role of Insulin in Regulating Amino Acid Metabolism in Normal and Alloxan-Diabetic Cattle

Experimental diabetes was induced in the bovine in two experiments by intravenous injection of alloxan (110 mg/kg or 60 mg/kg) in order to determine the role of insulin on nitrogen and amino acid metabolism. In experiment 1, insulin was injected to control hyperglycemia in one group of steers immediately after alloxan treatment (110 mg/kg). In experiment 2, insulin was injected beginning 6 days following alloxan treatment (60 mg/kg) to control hyperglycemia. Plasma glucose increased to 800–1400 mg/100 ml within 5–6 days following alloxan administration (experiment 1). A large surge of insulin release occurred immediately after alloxan administration, which was followed by a decrease in insulin concentrations to subnormal levels in those animals not treated with insulin. Alloxan-treated steers became acidotic by day 2 as indicated by a drop in blood pH, bicarbonate and base excess. Acid-base status improved in steers treated with alloxan plus insulin but did not return to normal. Alloxan treatment caused a marked increase in serum urea-N and creatinine concentrations and insulin treatment of the alloxanized animal decreased both serum urea-N and creatinine concentrations. Treatment with alloxan caused a two- to threefold increase in the plasma concentrations of valine, isoleucine, leucine, lysine and 3-methylhistidine and a decrease in alanine, threonine, citrulline and arginine. Insulin treatment of the alloxanized bovine maintained normal plasma concentrations of valine, isoleucine and leucine. In a third experiment, the injection of insulin (6 U/kg) into normal cattle caused a transient decline in plasma concentrations of branched-chain amino acids (BCAA); however, if glucose was continuously infused (125 mmol/hour) in addition to insulin injection, a sustained decrease in plasma BCAA concentrations was observed. These data support the concept that insulin promotes decreased plasma concentrations of BCAA either by promoting tissue anabolism by stimulating tissue uptake and protein synthesis or decreasing proteolysis and BCAA release.

Studies on non-linear pharmacokinetics of sulfamono-methoxine in pigs

The drug disposition after intravenous injection of sulfamono-methoxine(SMM: 10,50 and 100mg/kg) in pig was studied by analysis of plasma and urine data. Blood and urine were serially collected for 12-36 hrs and for 72 hrs after dosing, respectively. SMM and its metabolites were determined by the modified method of Bratton & Marschall and a fluorometric method. The time course of drug concentration in plasma appeared to be linear on semilog paper after injection of 10mg/kg of SMM. On the other hand, after 100mg/kg, the decline of plasma concentration was slow at early stage and afterward,tended to curve inward and with further time,appeared to be linear,suggesting that the disposition of a high dose of SMM was by non-linear kinetics with capacity limited elimination. The non-linear drug disposition was observed 3/5 of pigs after 50mg/kg. About 80% of the total SMM excreted was recovered as acetyl deriva-tives(AcSMM) from urine at each SMM dose. Renal clearance of AcSMM at each urine sampling time was constant throughout the experiment at 10mg/kg;but at 50 and 100mg/kg, different values were obtained according to the experimental stage,that is, low in the early stage and high afterwards. While much AcSMM was observed in plasma after the drug injection, the ratio of appearance of AcSMM and that of SMM was not different with the administered doses(about 1/2). This fact showed that the saturation of renal clearance capacity of AcSMM may be the causal factor for the non-linear kinetics of SMM at a high dose.

Decline of plasma concentrations of etretinate and its main metabolite after treatment.

Decline of plasma concentrations of etretinate and its main metabolite after treatment.

Dose-Dependent Pharmacokinetics of the Antihypertensive 2,3,4,4a-Tetrahydro-lH-pyrazino[l,2a]quinoxalin-5-(6H)-one in Dogs and Rats

A sensitive and reproducible GLC assay was developed for determining 2,3,4,4a-tetrahydro-lH-pyrazino[l,2a]quinoxalin-5(6H)-one (I) in biological fluids, utilizing the electron-capturing capability of the heptafluorobutyryl derivative. After single 2.5- and 10-mg/kg oral and intravenous doses to three dogs, plasma concentration-time data for I were fitted to a biexponential equation and pharmacokinetic parameters were calculated. A dose-dependency for certain parameters, most notably total body clearance (Clt),was indicated. The difference in Clr for the low and high dose was statistically significant. After single 5-, 25-, and 50-mg/kg intragastric doses were given to rats, the decline in plasma concentrations of I with time followed a monoexponential equation. As with dogs, there was a disproportionate change in kinetic parameters with increasing dose for rats. While simple Michaelis-Mentenc kinetics were not evident, nonlinearity in biotransformation (intrinsic clearance) appeared to be the cause for the dose-dependent pharmacokinetics.

Effects of 2-deoxy-D-glucose on plasma and adrenal concentrations of corticosterone and aldosterone in standard diet fed and potassium loaded rats.

The concentrations of corticosterone, aldosterone and electrolytes (Na+ and K+) were measured in the plasma and adrenal glands, following 2-deoxy-D-glucose (2-DG) treatment (2 injections of 50 mg/ml/100 g body weight) in standard diet fed and potassium loaded rats. In both regimens, 2-DG increased the concentrations of corticosterone mainly in the plasma (+144.8% and 229.5%) and to a lesser extent, in the adrenal glands (+50.9% and 62.5%). Conversely, 2-DG treatment was followed by a steep decline in plasma concentrations of aldosterone both in standard diet fed rats (-65.2%) and in potassium loaded rats (-83.9%), in spite of a marked increase in plasma (+233.3%) and in adrenal (+54.9%) levels of aldosterone after potassium loading; adrenal aldosterone content was essentially the same. Plasma and adrenal electrolytes concentrations and hematocrit varied very little after 2-DG treatment.

Insulin effectiveness in hypovolemic dogs.

The question addressed in this study was whether exogenous insulin can enhance the rate of assimilation of blood glucose after prolonged hypovolemia when homeostasis is waning. Twenty-three well-fed mongrel dogs were maintained at a mean arterial blood pressure of 50 mm Hg by bleeding. Periodic analyses were made of arterial and venous plasma concentration of glucose, femoral blood flow, arterial plasma concentration of insulin, and hematocrit. At the onset of physiologic deterioration signaled by the need to reinfuse 50 ml of shed blood to maintain 50 mm Hg blood pressure, dogs received either 10 ml saline (control; n=15) or 10 ml saline containing 2 units insulin (treated; n=8). Administration of 2 units of insulin to eight of the dogs caused a significantly faster decline of blood glucose than that observed in saline-treated animals. Despite the more rapid decline in plasma concentration of glucose in animals that received insulin, there was no significant difference in glucose uptake between the two groups of animals. The hemoconcentration reflected by a rising hematocrit that develops when hypovolemia persists was accentuated by the administration of insulin without supplementary fluids. The absence of any effect of insulin on glucose uptake in the hindlimb in the late phase of hypovolemic shock suggests that the accelerated decline in arterial glucose levels may be due to inhibitory effects of insulin on hepatic glucose release. These results are not consistent with the resistance of plasma glucose to insulin in the late phases of hypovolemic shock.

Verapamil kinetics in normal subjects and patients with coronary artery spasm.

Verapamil kinetics after intravenous and single and long-term oral dosing were studied in 12 patients with coronary artery spasm and four normal subjects. The decline in plasma concentration after intravenous doses was described by triexponential decay equation, with a terminal half-life (t1/2) of 5 hr. After a single oral dose the bioavailability was only 24%, probably because of the first-pass metabolism. During long-term oral doses of 80 mg every 6 hr, mean peak and trough concentrations were 255 +/- 90 and 105 +/- 38 ng/ml, and mean time at which peak concentration occurred was 1.2 +/- 0.5 hr. Norverapamil, the major active metabolite of verapamil, cumulated during oral dosing and may account for a small proportion of the overall pharmacologic effect. Mean elimination t1/2 during long-term oral dosing was longer than after a single dose (9.6 and 5.7 hr, P less than 0.05). Also, during long-term dosing the area under the curve was more than double that of a single dose, and the apparent oral clearance fell from 4.2 to 1.8 l/min (P less than 0.01). These changes may partly be explained by reduction in presystemic metabolism during long-term therapy. Kinetic predictions based on single doses will not give reliable estimates for long-term oral dosage. Less frequent dose schedule may be possible for prolonged therapy.

The pharmacokinetics of cyclophosphamide, phosphoramide mustard and nor-nitrogen mustard studied by gas chromatography in patients receiving cyclophosphamide therapy.

Abstract 1 Simple, accurate and specific gas-chromatographic methods for the estimation of derivatized phosphoramide and non-nitrogen mustards utilizing alkali-flame ionization detection are described. 2 The pharmacokinetics in plasma of cyclophosphamide, phosphoramide mustard, nor-nitrogen mustard and nitrobenzyl pyridine alkylating activity were investigated following administration of cyclophosphamide by intravenous and oral routes to patients with malignant disease 3 The mean T½ for cyclophosphamide was 8.88 h (s.d. 1.25 h) and the apparent volume of distribution (Vdβ) was 0.74 l kg-1 (s.d. 0.16 l kg-1). 4 The decline in plasma concentration of phosphoramide mustard was biphasic, the longer T½ being 8.68 h (s.d. 2.50 h). This was not significantly different from that of cyclophosphamide. This could indicate that the true biological T½ for phosphoramide mustard is identical with or shorter than that of cyclophosphamide. 5 The plasma concentrations of phosphoramide mustard following cyclophosphamide doses of known therapeutic efficacy are probably insufficient to produce important cytotoxic effects. This suggests that if phosphoramide mustard is the major alkylating metabolite derived from cyclophosphamide, it is transported in the blood in precursor form. 6 The mean plasma T½ of nor-nitrogen mustard was 3.31 h (s.d. 1.60 h) which was significantly different from that of cyclophosphamide. 7 The mean plasma T½ of the nitrobenzylpyridine alkylating activity was 9.81 h (s.d. 4.18 h) and did not significantly differ from that of cyclophosphamide. Although the area under the plasma alkylating activity concentration, time curve is related to the T½ of cyclophosphamide, the alkylating activity does not reflect the concentrations of the two plasma metabolites measured.

Biopharmaceutics of rectal administration of drugs in man. Absorption rate and bioavailability of glafenine after oral and rectal administration

In this report it will be shown that rectal administration of glafenine and its salt can not be considered as a rotional therapy. Plasma concentrations of glafenine and glafenic acid were measured, by means of HPLC analysis, after single oral and rectal doses of glafenine (400 mg), suspended in aqueous vehicles. After oral administration negligible plasma concentrations of free glafenine could be detected, probably due to a substantial first-pass effect. Peak concentrations of glafenic acid were reached after one hour. The decline in plasma concentrations was observed to be multiphasic. Rectal adsorption of glafenine (from micro-enemas) or glafenine HCl (from fatty suppositories) was extremely slow and incomplete, due to the slight water-solubility of glafenine at the prevailing pH in the rectum lumen.

Pharmacokinetics of cytosine arabinoside in patients with acute myeloid leukaemia.

1 The pharmacokinetics of cytosine arabinoside were studied after a single i.v. bolus of 2 mg/kg ara-C in patients with newly diagnosed untreated AML, using a bioassay and GC-MS method to measure the plasma concentrations. 2 Most patients showed a bi- or tri-phasic decline in plasma concentrations with time. Plasma clearance was 3.9 to 18.1 l/min as measured by the GC-MS method, and terminal half-lives varied from 7--107 min. 3 There was poor correlation of the GC-MS assay with the bioassay, probably because the latter was interfered with by the release of endogenous nucleosides from blasts after after ara-C. 4 Plasma concentrations were measured by GC-MS during continuous infusions in 14 patients. Plasma clearances were much lower than after a bolus, 0.39 to 5.25 l/min. 5 There was no correlation of response (remission or fall in peripheral blast count) with exposure to ara-C calculated from infusion dose, clearance and duration of infusion. 6 This study shows that ara-C pharmacokinetics varies markedly from patient to patient and that there is a wide range in the plasma concentrations associated with therapeutic response.

The plasma half-life of placental hormones.

Blood was collected from 12 women following Caesarean section or normal delivery at term. The decline in plasma concentration of total oestriol, oestriol sulphate, oestriol glucosiduronate, unconjugated oestriol, human placental lactogen and pregnancy specific beta1 glycoprotein following delivery of the placenta was studied for 120 hours. The steroids and human placental lactogen fell very rapidly but pregnancy specific beta1 glycoprotein declined much more slowly. Analysis of the curves of puerperal decline suggests that the oestriol moieties are distributed in many compartments of the mother but that the proteins penetrate only to the plasma and the interstitial fluid.

Antiallergic chromones. I. Disposition of 5-(3- p-cyanophenoxy-2-hydroxy-1-propoxy)-2-(1 H-tetrazol-5-yl) chromone in four mammalian species

The gastrointestinal absorption, plasma concentrations, excretion, and metabolism of the 14C-labeled sodium salt of 5-(3-p-cyanophenoxy-2-hydroxy-1-propoxy)-2-(1H-tetrazol-5-yl) chromone (NaCPTC) were studied in rats, mice, dogs, and monkeys. In addition, tissue distribution of [14C]NaCPTC was studied in rats. All animals received a single po or iv 10 mg/kg dose of [14C]NaCPTC. In each species, the decline of plasma concentrations was rapid after iv dosing and 14C was quickly excreted in urine and bile. The highest tissue 14C concentrations were found in liver. Plasma 14C concentrations after po administration were very low, relative to those after iv administration in all species. The estimated extent of gastro-intestinal absorption was about 10.4, 9.6, 9.9, and 3.6% in the rat, mouse, dog, and monkey, respectively. Fecal excretion was the preferred route of drug elimination, and excretion appeared to be essentially complete in three of the four species within 48 hr. In analyses of plasma and urine samples from the four species conducted by reverse phase high pressure liquid chromatography, no evidence of metabolism of NaCPTC was found.

Relation of Hormonal Variations to Nutritional Studies and Metabolism of Ruminants1,2

Variations in concentrations of growth hormone, insulin, glucagon, prolactin, adrenal corticoids, and thyroid hormones in blood plasma of ruminants as related to circadian rhythms, environmental factors, and nutrition are reviewed. Rhythms in prolactin concentrations are related to light and temperature. Concentrations of prolactin in plasma are higher in warm environments and during longer photoperiods. There is episodic secretion of growth hormone in cattle with frequent peaks in plasma concentrations during 24h. Marked increases in environmental temperature result in greater secretion of growth hormone for short times followed by a decline in plasma concentration with prolonged exposure. Extreme cold temperature also increases growth hormone concentrations in plasma. Secretion of thyroid hormones increases in cold and decreases in warm environments. Circadian rhythms are definite for plasma concentrations of adrenal corticoids in ruminants adjusted to their surroundings. Peaks occur late in dark periods, and lows occur during the end of light periods. Circadian patterns have not been consistent for secretion of insulin. Prolonged subjection to stresses such as noise, handling, and restraint can modify concentrations of prolactin, growth hormone, and adrenal corticoids. Changes in concentrations of insulin may occur if blood glucose is increased. After feeding, concentrations of growth hormone in plasma decrease and concentrations of insulin and glucagon increase. Relationships of these changes with metabolism are discussed.

Renal and bone uptake of tartaric acid in rats: Comparison of L(+) and DL-forms

Plasma concentrations of radioactivity declined biphasically with half-lives of about 15 and 58 h respectively in rats dosed with monosodium DL-[14C] tartrate for 7 days at a dose level of 2.73 g/kg/day. Uptake and retention of radioactivity occurred in blood cells, kidneys and bones where it was detected for at least 12 days after dosing. Renal retention (11202 ± 4469 ppm at 6 h, n = 7) was probably due to precipitation of the poorly soluble calcium DL-tartrate in the tubules leading to increased kidney weight, nephrotoxicity and even death. The more sooluble, naturally-occurring L(+)-[14C] tartrate was not retained in the kidneys (1287 ± 118 ppm at 6 h, n = 8) when administered to rats under the same conditions, and the initial decline of plasma concentrations of radioactivity was more rapid (t0.5approx. 3 h). For this reason, monosodium L(+)-tartrate was non-toxic at 2.73 g/kg/day whereas monosodium DL-tartrate was toxic at this dosage.

Metabolic and pathologic investigation of 1-Aminocyclohexanecarboxylic acid (ACHC), a metabolite of 6-(1-aminocyclohexanecarboxamido)penicillanic acid (cyclacillin)

A nephrotoxic effect was noted in male but not in female COBS-CD rats chronically treated with 1-aminocyclohexanecarboxylic acid (ACHC), a metabolite of 6-(1-aminocyclohexanecarboxamido)penicillanic acid (cyclacillin). The renal changes were qualitatively similar to, but less severe than, those observed with the parent compound. In correlation with the histopathologic findings, the rate of urinary excretion (the primary route of elimination for ACHC) was lower and the accumulation of ACHC in plasma and tissues was higher in males than in females. Following termination of chronic dosing the concentrations in the plasma of females decreased in 2 phases, with a t 1 2 of 14 hr for the first and 31 hr for the second. In similarly treated males, the respective phases were 4 days and 8.5 days. There was no evidence of metabolic breakdown of ACHC in the rat. In the dog there was little sex difference in disposition of ACHC, and both renal excretion and decline in plasma concentrations were between the values for the male and female rat.