Upregulation of renal endothelin receptors in rats with cyclosporine A-induced nephrotoxicity

Measurement of endothelin receptors by binding assay was performed in rats treated with cyclosporine A (CYA). Cyclosporine A administration at 50 mg/kg i.p. for 4 days resulted in renal function impairment as indicated by a significant increase in serum creatinine concentration (from 0.46 +/- 0.02 to 0.61 +/- 0.03 mg/dl. P less than 0.01) and a significant decrease in 24 h creatinine clearance (from 0.65 +/- 0.04 to 0.41 +/- 0.02 ml/min per 100 g, P less than 0.01). Renal endothelin (ET) receptor density was significantly higher in CYA-treated rats (312 +/- 34 vs. 196 +/- 26 fmol/mg protein, P less than 0.01). These data support the possible involvement for endothelin in the increased renal vascular resistance associated with CYA-induced nephrotoxicity.     

Effects of nadolol and propranolol on renal function in hypertensive patients with moderately impaired renal function.

Effects of oral administration of equipotent antihypertensive doses of propranolol and nadolol on renal function were examined in 20 hypertensive patients with moderately impaired renal function. Creatinine clearance increased, and serum beta 2-microglobulin concentrations decreased, when patients were switched from propranolol to nadolol therapy (creatinine clearance = 46.7 +/- 4.9 ml min-1 on propranolol and 52.7 +/- 5.9 on nadolol; beta 2-microglobulin = 6.14 +/- 0.66 mg l-1 on propranolol and 5.62 +/- 0.62 on nadolol). When patients were put back on propranolol, their creatinine clearances (45.9 +/- 5.0 ml min-1) and serum beta 2-microglobulin concentrations (6.51 +/- 0.67 mg l-1) returned to values comparable to those obtained before the change to nadolol was made. Serum beta 2-microglobulin concentrations correlated significantly with creatinine clearance (r = -0.819, P less than 0.001).     

Beta-adrenergic receptors in guinea-pig liver plasma membranes and thermal lability of [3H]dihydroalprenolol binding sites

beta-Adrenergic receptors in guinea-pig liver plasma membranes were characterized by radioligand binding, using l-[3H]dihydroalprenolol ([3H]DHA), l-3-[125I]iodocyanopindolol ([125I]CYP) and dl-[3H]4-(3-tertiarybutylamino-2-hydroxypropoxy)-benzimidazole-2- one hydrochloride [( 3H]CGP-12177). The binding of both [125I]CYP and [3H]CGP-12177 to membranes exhibited high affinity (Kd = 3.5 +/- 0.2 pM for [125I]CYP and 0.75 +/- 0.10 nM for [3H]CGP-12177) and stereospecificity; the maximal binding sites were 130 +/- 15 and 137 +/- 8 fmoles/mg protein respectively. Catecholaminergic agonists competed for these binding sites in the order l-isoproterenol greater than l-epinephrine greater than l-norepinephrine, which is typical for beta 2-adrenergic receptors. The binding data are supported by parallel experiments on adenylate cyclase activation by catecholamines, and on antagonism of this activation by beta 1- and beta 2-selective blockers. The binding of [3H]DHA was excessive (Bmax = 21.4 pmoles/mg protein), exhibited low affinity (Kd = 34.6 nM), and lacked stereospecificity. When liver membranes were incubated at 50 degrees for 40 min in the presence of an agonist, l-isoproterenol, the binding of [3H]DHA to the heat-treated membranes exhibited high affinity (Kd = 1.07 +/- 0.17 nM) and the Bmax was reduced to 139 +/- 22 fmoles/mg protein. In such membranes, as opposed to native membranes, stereospecificity was evident and catecholaminergic agonists competed for the binding sites in the order typical for beta 2-adrenergic receptors. However, agonist competition of the binding to the heat-treated membranes could not be modulated by guanine nucleotides, indicating a loss of communication between the receptor and the guanine nucleotide regulatory protein.     

Stereospecific pharmacokinetics of rac-5-methyltetrahydrofolic acid in patients with advanced colorectal cancer.

1. The pharmacokinetics and toxicity of racemic 5-methyltetrahydrofolic (rac-5-MTHF) acid after i.v. infusion were investigated in 18 patients with advanced colorectal cancer. Doses of 100-600 mg rac-5-MTHF/m2 were administered over 2 h together with a bolus of 500 mg/m2 5-fluorouracil (5-FU) as a midpoint injection. 2. The pharmacokinetics of both diastereoisomers were linear in the range from 100-600 mg 5-MTFH/m2. Independent of the administered dose, the maximal plasma concentration of [R]-5-MTHF was nearly twice that of [S]-5-MTHF. The elimination of [S]-5-MTHF from plasma was considerably faster than that of the [R]-isomer (elimination half-life: 3.1 +/- 1.0 h vs 8.3 +/- 3.2 h). No metabolites were detected in plasma and in urine samples. 3. The plasma protein binding was stereoselective ([R]-5-MTHF bound: 88.2 +/- 2.7%; [S]-5-MTHF bound: 59.9 +/- 6.8%; P < 0.001), causing a significantly higher renal clearance for [S]-5-MTHF when compared with the [R]-isomer (37.5 +/- 23.7 ml min-1 vs 12.7 +/- 11.2 ml min-1, P < 0.001). There was no dose dependence, but gender influenced renal clearance (CLren[R]-5-MTHF: male vs female: 20.5 +/- 14.5 ml min-1 vs 7.8 +/- 4.7 min-1, P = 0.03; CLren [S]-5-MTHF: male vs female: 57.2 +/- 21.7 ml min-1 vs 25.7 +/- 16.2 ml min-1, P = 0.006). 4. Toxic side effects of the combination 5-FU/5-MTHF were rare and generally mild, and included stomatitis, nausea/emesis, diarrhoea, anaemia, leukopenia, and thrombocytopenia. 5. In combination with 500 mg 5-FU/m2 a single dose of 600 mg rac-5-MTHF/m2 can safely be administered to patients with colorectal cancer. A similar therapeutic benefit of 5-MTHF to folinic acid in the biochemical modulation of 5-FU is supported by the comparison of in vitro and in vivo data.     

Pharmacokinetics and toxicity of high-dose human alpha 1-acid glycoprotein infusion in the rat

The pharmacokinetics of high-dose human alpha 1-acid glycoprotein (AAG) was studied in rats to determine the feasibility of using AAG to alter the tissue distribution of basic drugs. alpha 1-Acid glycoprotein (2.2 g/kg) was administered iv to six male Holtzman rats over a period of 30 min, and serum AAG concentrations were measured by a specific radial immunodiffusion assay. The AAG concentrations were computer fit to a biexponential equation to generate pharmacokinetic constants for an open two-compartment model. The peak serum AAG concentration was 1830 +/- 180 mg/dL at the end of infusion; greater than 20 times the normal value for rats. The central volume of distribution and steady state volume of distribution were 0.09 +/- .02 and 0.15 +/- 0.02 L/kg, respectively. Total body clearance of AAG was 0.065 +/- 0.005 L/kg/h, and the terminal elimination half-life was 19.3 +/- 1.5 h. The AAG administration was tolerated without adverse effect and did not alter systolic blood pressure, the electrocardiogram, creatinine clearance, weight gain, or survival. The results of the histologic examination of various tissues by light microscopy at 30 d post AAG treatment were normal. These data demonstrate that high doses of human AAG can be safely administered to rats and that they produce supraphysiologic serum AAG concentrations.     

Adrenergic receptors in rat spinal cord

Radioligand binding assays were used to demonstrate the presence of alpha 1, alpha 2 and beta receptors in rat spinal cord. Specific and saturable binding was exhibited for [3H]-WB 4101 (alpha 1), [3H]-aminoclonidine (alpha 2) and [3H]-dihydroalprenolol (beta). Binding was of high affinity and the total number of binding sites (Bmax) were: alpha 1, 66.5 +/- 1.0 fmol/mg protein; alpha 2, 20.0 +/- 0.6 fmol/mg protein; beta, 10.2 +/- 0.3 fmol/mg protein. The data confirms the existence of adrenergic receptors in spinal cord and provides further evidence of the role of catecholaminergic neurons in regulating spinal cord physiology     

Adrenergic receptors in rat spinal cord

Radioligand binding assays were used to demonstrate the presence of alpha 1, alpha 2 and beta receptors in rat spinal cord. Specific and saturable binding was exhibited for [3H]-WB 4101 (alpha 1), [3H]-aminoclonidine (alpha 2) and [3H]-dihydroalprenolol (beta). Binding was of high affinity and the total number of binding sites (Bmax) were: alpha 1, 66.5 +/- 1.0 fmol/mg protein; alpha 2, 20.0 +/- 0.6 fmol/mg protein; beta, 10.2 +/- 0.3 fmol/mg protein. The data confirms the existence of adrenergic receptors in spinal cord and provides further evidence of the role of catecholaminergic neurons in regulating spinal cord physiology.     

Propranolol disposition in renal failure.

1 Previous studies of propranolol disposition in renal failure have been conflicting. 2 Using simultaneous administration of [3H]-propranolol intravenously and unlabelled propranolol orally the principal determinants of drug distribution were calculated in normals, patients with severe renal impairment (creatinine clearance 14.5 +/- 2.8 ml/min) but not on haemodialysis and patients on haemodialysis (creatinine clearance less than 5 ml/min). 3 The effect of haemodialysis on propranolol binding and free fraction was also examined. The percentage of propranolol unbound rose from 7.1% to 9.9%. (P less than 0.001) 20 min following heparinization and beginning haemodialysis. This was accompanied by a large rise in free fatty acids from 0.567 +/- 0.059 to 3.326 +/- 0.691 mumol/ml (P less than 0.005). 4 The blood to plasma concentration ratios of propranolol were significantly higher in patients with renal failure (P less than 0.02) and on haemodialysis (P less than 0.001) and were significantly negatively correlated (P less than 0.001) with the haematocrit. 5 Although the half-life propranolol was significantly shortened in the patients with renal failure (P less than 0.02), there was no change in the apparent liver blood flow, extraction ratio or the principal determinants of steady-state drug concentrations in blood namely oral and intravenous clearance from blood. 6 There is, therefore, no pharmacokinetic basis to adjust the dosage of propranolol in patients with renal failure.     

The pharmacokinetics of [3H]1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) in Sprague-Dawley rats

Using adult male Sprague-Dawley rats, we examined the blood protein binding and pharmacokinetics of the potent phencyclidine (PCP) receptor ligand 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP). The average percentage of unbound [3H]TCP in rat serum was 42 +/- 6% and the [3H]TCP blood to plasma ratio was 0.98 +/- 0.03 (mean +/- SD, n = 5 in both studies). For the pharmacokinetic studies, [3H]TCP and 1 mg/kg unlabeled TCP were administered as an iv bolus dose. The average [3H]TCP elimination half-life was 2.1 hr. In contrast, total radioactivity in the plasma had a much longer half-life, suggesting much slower metabolite elimination. The average distribution volumes were 27 +/- 17, 15.6 +/- 6.2, and 5.6 +/- 3.0 liters/kg for V beta, Vss, and Vc, respectively. Total body and renal clearance values were 132 +/- 45 and 1.1 +/- 0.4 ml/min/kg, respectively. When TCP pharmacokinetic parameters were compared to PCP pharmacokinetic data in rats from a previous study, a strikingly similar pharmacokinetic profile was found. These data indicated that TCP and PCP are equivalent, from a pharmacokinetic point of view, and that the higher pharmacological potency of TCP over PCP is probably due to receptor-mediated differences.     

The influence of vitamin K3 treatment on the pharmacokinetics and metabolism of (+)-propranolol in the rat.

The effects of vitamin K3 treatment on the pharmacokinetics and metabolism of (+)-propranolol and the consequences of hepatic injury associated with vitamin K3 treatment were examined in groups of male Sprague-Dawley rats. When vitamin K3 (20 mg/kg) in polyethylene glycol 300 (PEG 300) was coinfused with (+)-propranolol (2 mg/kg) into the pyloric vein (a tributary flowing directly into the hepatic portal vein), a significant decrease in the intrinsic clearance of total drug (CLint) from 94.1 +/- 50.1 to 32.9 +/- 11.5 ml/min/kg was observed (p less than 0.01 vs. vehicle control). However, a lower dose of vitamin K3 (2 mg/kg in PEG 300) had little effect on this parameter. Interestingly, the PEG 300 vehicle control group exhibited a significantly (p less than 0.05) higher CLint than that observed in a saline control group (94.1 +/- 50.1 vs. 45.9 +/- 13.7 ml/min/kg). This difference appeared to be due to an increase in the free fraction of propranolol caused by PEG 300, because in vitro addition of this solvent to serum (at estimated in vivo concentrations) with or without added vitamin K3 doubled propranolol free fraction. Furthermore, rats that received the high dose vitamin K3 (20 mg/kg) treatment exhibited a pronounced increase in the serum concentration of enzymes of hepatic origin (alanine aminotransferase and sorbitol dehydrogenase) and in the incidence of hepatic necrosis. It was also observed that high-dose vitamin K3 treatment caused only minor changes in the urinary recovery of propranolol metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)     

Azotemia during chronic converting enzyme inhibition with enalapril in sodium-depleted rats: role of renal circulatory changes

Chronic administration of the angiotensin-converting enzyme inhibitor enalapril to sodium-restricted rats causes azotemia and elevations in serum creatinine. This study was undertaken to determine the contribution of altered systemic and renal hemodynamics to the reductions in renal function in sodium-restricted rats treated with enalapril. Animals were maintained for 21 days on a sodium-restricted diet (0.04 +/- 0.01 mEq Na+/24 h). Enalapril was administered in the drinking water (300 mg/L) to half the rats. Regional blood flows were measured in animals anesthetized with pentobarbital (50 mg/kg, i.p.) using the radioactive microsphere technique. Converting enzyme inhibition (CEI) reduced mean arterial pressure (130.8 +/- 5.9 vs 60.3 +/- 6.1 mm Hg, p less than 0.001), and increased cardiac index (346 +/- 33 vs. 437 +/- 28 ml/min/kg, p less than 0.05). Total peripheral resistance was significantly lower in enalapril-treated rats [0.406 +/- 0.049 vs. 0.166 +/- 0.013 arbitrary resistance units (RU), p less than 0.001]. Renal blood flow was maintained (control, 2.93 +/- 0.21 vs. enalapril, 2.55 +/- 0.28 ml/min/100 g, p = NS) despite a 54% decrease in perfusion pressure due to decreased renal vascular resistance (42.6 +/- 1.7 vs. 25.2 +/- 2.9 RU, p less than 0.001). CEI reduced coronary blood flow (2.76 +/- 0.22 vs. 1.59 +/- 0.19 ml/min/100 g, p less than 0.001), but did not change coronary vascular resistance (50.2 +/- 4.6 vs. 44.0 +/- 4.3 RU, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

The pharmacokinetics and pharmacodynamics of quinidine and 3-hydroxyquinidine.

1. The pharmacokinetics and pharmacodynamics of quinidine and 3-hydroxyquinidine based upon measurements of total and unbound serum concentrations were determined after a single dose (400 mg) and at steady state (200 mg every 6 h). 2. The oral clearance (7.6 +/- 1.9 vs 4.8 +/- 2.0 ml min-1 kg-1; P less than 0.05) and renal clearance (1.2 +/- 0.3 vs 0.63 +/- 0.25 ml min-1 kg-1; P less than 0.005) or quinidine were lower during steady state than after the single dose. 3. The area under the serum concentration vs time curve (AUC) of 3-hydroxyquinidine was greater at steady state than after the single dose (2.0 +/- 0.7 vs 3.0 +/- 0.6 mg l-1 h; P less than 0.05) and its renal clearance was less (3.0 +/- 1.1 vs 1.54 +/- 0.38 ml min-1 kg-1; P less than 0.05). 4. The slope of the relationship between quinidine concentration and change in QTc interval was greater at steady state (40.1 +/- 21.7 vs 72.2 +/- 41.7 ms/(mg l-1); P less than 0.05).     

Age- and gender-related differences in carbohydrate concentrations of alpha1-acid glycoprotein variants and the effects of glycoforms on their drug-binding capacities

OBJECTIVE: Alpha(1)-acid glycoprotein (AAG) is a major binding protein for neutral and basic drugs because of its great drug affinity. AAG has three main genetic variants--F1, S, and A variants. Several attempts have been made to elucidate the differences in compositions of the carbohydrate moiety and structure-function relationships such as drug-binding differences. However, there have been few reports on age- and gender-related differences in compositions or concentrations of the carbohydrate moiety of AAG variants. The aim of this study was to clarify the age- and gender-related differences in carbohydrate concentrations and in drug-binding capacities of AAG glycoforms. METHODS: The sera used in this study were obtained from 32 healthy subjects (17 men and 15 women, aged 16-84 years). The AAG glycoforms were isolated by hydroxyapatite chromatography. The binding capacity of AAG to disopyramide (DP), which is a basic drug, was determined using the ultrafiltration method. The concentrations of N-acetylneuraminic acid (NeuAc) and monosaccharides in AAG were determined using high-pH anion-exchange chromatography with pulsed-amperometric detection. RESULTS: The mean plasma AAG concentration in the female subjects was significantly lower than that in the male subjects (0.67 +/- 0.12 mg/ml, mean +/- SD, in females, n = 15, versus 0.81 +/- 0.17 mg/ml in males, n = 17, P < 0.05), but no age-related differences were found (0.75 +/- 0.18 mg/ml in young subjects, n = 24, versus 0.77 +/- 0.12 mg/ml in older subjects, n = 8, n.s.). However, the degree of branching of the glycan chain in the female subjects was significantly lower than that in the male subjects (1.61 +/- 0.17 mol/mol, mean +/- SD, in females, n = 15, versus 1.75 +/- 0.23 mol/mol in males, n = 17, P < 0.05). There was a significant inverse relationship between the binding capacity of AAG to DP (Cb/AAG) and the degree of branching of the glycan chain. The binding capacity (Cb/AAG) decreased as the degree of branching in AAG glycans increased. The binding capacity (Cb/AAG) in the female subjects was significantly higher than that in the male subjects (2.79 +/- 0.59 mg/g AAG in females, mean +/- SD, n = 15, versus 2.37 +/- 0.29 mg/g AAG in males, n = 17, P < 0.05). CONCLUSION. The degree of branching of the glycan chain in AAG plays an important role in drug-binding capacity. Gender-related differences in drug-binding capacity (Cb/AAG) may be caused by differences in the ratios of the extent of branching of the glycan chain in AAG.     

Stereoselective binding of propranolol in the elderly.

The influence of age on the stereoselective serum protein binding of propranolol was investigated. Serum was obtained from 10 young (mean age 23 +/- 2 years) and ten elderly (mean age 68 +/- 2 years) healthy male volunteers. The free fraction of propranolol (fu) was measured by equilibrium dialysis, using tritium labeled (+/-)- and (-)-propranolol. The fu values were 0.159 +/- 0.049 and 0.148 +/- 0.028 (+/-), 0.135 +/- 0.041 and 0.136 +/- 0.04 (-), 0.174 +/- 0.056 and 0.161 +/- 0.028 (+) in the young and elderly subjects, respectively. Serum alpha 1-acid glycoprotein (AAG) concentrations were 81.4 +/- 33.0 and 81.0 +/- 21.6 mg 100 ml-1 in young and elderly respectively (P greater than 0.05). Variability in AAG concentration accounted for most of the observed intersubject variability in the binding of both propranolol isomers. The stereoselective binding of propranolol does not appear to be affected by age.     

Nonlinear pharmacokinetics of unbound propranolol after oral administration

After multiple oral doses, propranolol has been reported to accumulate to a greater degree than expected based on its terminal elimination rate constant and dosage interval. To determine whether the decrease in presystemic elimination can be attributed solely to a decrease in unbound intrinsic clearance or possibly a decrease in unbound fraction, we studied the pharmacokinetics of unbound propranolol in nine healthy subjects who were given 160 mg of regular or sustained-release propranolol orally as single doses, and once daily for 7 d. Unbound propranolol concentrations were calculated by HPLC and equilibrium dialysis on each serum sample. With regular propranolol, the mean unbound oral clearance (CLoral) decreased 29%, from 503 +/- 281 after a single dose to 359 +/- 143 mL/min/kg at steady state (p less than 0.05). Similarly, CLoral decreased 33% with sustained-release propranolol from 1077 +/- 514 to 721 +/- 385 mL/min/kg (NS). The corresponding accumulation ratios for regular and sustained-release propranolol were 1.39 +/- 0.49 and 1.61 +/- 0.81, respectively (NS). Therefore, the mean bioavailability of sustained-release relative to that of regular propranolol was 0.52 +/- 0.23 and 0.54 +/- 0.17 for single doses and at steady-state, respectively. The percent unbound of propranolol ranged from 6.8 to 14.0 with an average of 10.1. Neither the percent unbound nor alpha 1-acid glycoprotein (AAG) serum concentrations were statistically different between single and multiple doses. The binding ratio was significantly correlated to AAG concentration (r = 0.776, p less than 0.05). The data support a decrease in unbound intrinsic clearance of propranolol with no change in unbound fraction, leading to an increase in bioavailability at steady state.     

An effect of ischemia on myocardial dihydropyridine binding sites

The [3H]nitrendipine binding activity of sarcolemmal fragments isolated from aerobically perfused or ischemic rat hearts was studied. After 90 min aerobic perfusion, two populations of binding sites were detected--high affinity sites with KD of 0.24 +/- 0.04 nM and Bmax 313 +/- 110 fmol/mg protein, and low affinity sites with KD of 47.6 +/- 8.7 nM and Bmax 12.4 +/- 1.88 pmol/mg protein. Sixty minutes global ischemia significantly reduced the KD of the low (15.8 +/- 2.9 nM, P less than 0.03) but not of the high (0.22 +/- 0.05 nM) affinity sites. Under these same conditions the Bmax of both the high (82.4 +/- 14.5 fmol/mg protein, P less than 0.03) and low (6.1 +/- 1.7 pmol/mg protein, P less than 0.01) affinity binding sites was reduced but the sites retained their selectivity, with nifedipine displacing bound [3H]nitrendipine more potently than D600. Bay K 8644, when added upon reperfusion, promoted a dose-related increase in Ca2+ entry which was reduced by nifedipine, indicating that dihydropyridine binding sites can be activated after 60 min ischemia.     

Chronic treatment with nifedipine does not change the number of [3H]nitrendipine and [3H]dihydroalprenolol binding sites

Possible receptor changes occurring after withdrawal of chronic nifedipine treatment or chronic propranolol treatment were examined by administering nifedipine (100 mg/kg per day) or propranolol (45 mg/kg per day) to rats for 2 weeks and then withdrawing treatment [3H]Nitrendipine and [3H]DHA binding were measured in membrane fragments of the ventricle. In propranolol-treated rats, 8 h after the last administration, the maximum binding for [3H]DHA was significantly increased from 79.9 +/- 8.0 to 139.8 +/- 12.8 fmol/mg protein (mean +/- S.E.); the dissociation constant was significantly increased from 4.9 +/- 0.7 to 10.7 +/- 1.2 nM. On the other hand, in nifedipine-treated rats, 12 and 48 h after the last administration, [3H]nitrendipine binding and [3H]DHA binding had not changed significantly. These results indicate that the mechanism of the calcium antagonist withdrawal syndrome may be different from that of beta-blocker withdrawal syndrome.     

Effect of beta-adrenergic antagonists on experimentally induced drinking in female rats

The nonspecific beta-adrenergic antagonist d,l propranolol, the specific beta 1-adrenergic antagonist atenolol, and the specific beta 2-adrenergic antagonist butoxamine were administered intraperitoneally (IP) to ovariectomized female rats in order to determine the role of beta-adrenergic receptors in drinking. D,l propranolol and atenolol administered at doses of 6, 12, and 18 mg/kg significantly attenuated the one-hour water intakes of rats administered angiotensin II (200 micrograms/kg, SC) and the water intakes of rats deprived of water for 24 hours. D propranolol, which has little beta-adrenergic blocking ability, administered at doses of 6 and 12 mg/kg, and butoxamine, administered at doses of 25 and 35 mg/kg, had no significant effects on the water intakes of angiotensin II treated or water deprived rats. Regardless of the dose, d,l propranolol, atenolol, and butoxamine failed to significantly alter the water intakes of rats administered 1.0 M NaCl (10 ml/kg, IP) The results provide evidence that beta 1-adrenergic receptors, but not beta 2-adrenergic receptors, are involved in mediating the increased water intakes induced by angiotensin II and water deprivation. On the other hand the increased water intake due to administration of hypertonic saline does not appear to mediated by beta-adrenergic receptors.     

Decreased hepatic elimination of pyrimethamine during malaria infection. Studies in the isolated perfused rat liver

The elimination of the antimalarial drug pyrimethamine was studied in isolated liver preparations from young rats (80-100 g) infected with merozoites of Plasmodium berghei two weeks earlier. Perfusate half-life of pyrimethamine was increased in livers from M.I. rats (t1/2 beta control group = 56 +/- 11 min vs M.I. group = 101 +/- 12, P less than 0.01), reflecting a decrease in hepatic clearance (3.6 +/- 1.1 ml/min vs 1.9 +/- 0.5 ml/min, P less than 0.01). There was no significant difference in volume of distribution between livers from M.I. and control groups. Intrahepatic concentration of unchanged drug at 3 hr was 4-5-fold greater in livers from infected rats (control group = 4725 +/- 2287 ng/ml vs M.I. group = 22,324 +/- 6824 ng/ml), while liver: perfusate concentration ratios were not significantly different (control group = 30.8 +/- 24.1 vs M.I. group = 35.6 +/- 20.3). We conclude that the hepatic elimination of pyrimethamine is substantially impaired in the malaria-infected rat.     

Cyclosporin A treatment enhances angiotensin converting enzyme activity in lung and serum of rats

Nephrotoxicity and arterial hypertension are the most common side effects of treatment with cyclosporin A (CSA). Its effects on angiotensin converting enzyme (ACE) activity in the renal cortex, lung and serum of nephrotoxic rats have been investigated. Wistar rats were treated with CSA (20 mg kg-1 day-1 i.p.) or vehicle (olive oil containing 10% ethanol) for 14 days. On day 15, the rats were killed and ACE activity determined by radiometric assay using [3H]hippuryl-glycyl-glycine as substrate. CSA treatment resulted in a decrease in creatinine clearance, urine flow and body weight and a significant increase in serum and lung ACE activities (436 +/- 9 vs 391 +/- 7 nmol mL-1 min-1, P less than 0.001; 184 +/- 8 vs 142 +/- 10 nmol mg-1 min-1 P less than 0.01, respectively). In contrast, renal cortex ACE activity was reduced in the CSA-treated rats (0.35 +/- 0.02 vs 0.51 +/- 0.02 nmol mg-1 min-1, P less than 0.01). ACE activities in the renal cortex and serum were not affected by treatment with gentamicin (80 mg kg-1 day-1) for 11 days. In rats treated simultaneously with CSA and captopril (50 mg kg-1 day-1) ACE activity in the serum, lung and renal cortex was inhibited by 95, 93 and 92%, respectively. These changes in ACE activity were associated with a decreased systolic blood pressure in the rats receiving CSA and captopril. Therefore, ACE activity in the serum and lung of CSA-treated rats was increased, while its activity in the renal cortex was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)