Search PubMed⌕ Search

Biomedical subjects

A Rane

Publications and source records attributed to A Rane.

At least 253 records · Page 14Linked to original sources
PubMed1979

Acetaminophen: potentially toxic metabolite formed by human fetal and adult liver microsomes and isolated fetal liver cells.

A reactive metabolite of acetaminophen is hepatotoxic in humans when the drug is ingested in large overdoses. The ability of the human fetal and adult liver to oxidize acetaminophen by trapping the potentially toxic metabolite as a glutathione conjugate has been measured. Oxidation by fetal liver was approximately ten times slower than by adult liver. However, there was a definite increase in acetaminophen oxidation with fetal age. Isolated human fetal liver cells conjugated acetaminophen with sulfate but not with glucuronic acid. The results indicate that the human fetal liver is able to detoxify acetaminophen by conjugation. However, it also catalyzes the formation of an active metabolite of acetaminophen through oxidation. Hence the fetus remains at risk should a large dose of the drug cross into the fetal circulation.

Acetaminophen↗
PubMed1979

Kinetics of placentally transferred phenytoin and its p-hydroxylated metabolites in newborn infants.

1 The kinetics of phenytoin and its main metabolites, unconjugated and conjugated 4-hydroxy-phenytoin were studied in newborn infants of epileptic mothers that were treated with phenytoin during the pregnancy. 2 In two of the infants phenytoin was eliminated by an apparent zero-order process followed by an apparent first-order process. In the other two infants the mode of elimination could not be characterized. 3 The decline of plasma conjugated 4-hydroxy-phenytoin was parallel to that of phenytoin. In contrast, the plasma concentration of unconjugated 4-hydroxy-phenytoin remained grossly constant during the first 3 to 4 days.

Female↗
PubMed1979

Decreased plasma protein binding of phenytoin in patients on valproic acid.

1 Plasma protein binding of phenytoin and of valproic acid were measured in ten epileptic patients on this drug combination. Ten other epileptics not on valproic acid served as controls. All patients had normal kidney function. 2 The measured free fraction of phenytoin among the patients on valproic acid ranged from 12.5 to 23.2% and after recalculation to a plasma albumin level of 45 g/l from 12.5 to 20.0 (median 15.4%). This differed significantly (P = 0.002, Mann- Whitney U-test) from the control patients where the normalized values ranged from 9.9 to 13.9% with a median value of 11.8%. 3 The measured free fractions of phenytoin and of valproic acid showed a significant correlation which, however, was due to the quantitative relation between the degree of binding of both these drugs and the concentration of plasma albumin. There was no discernable relation in this material between the free concentration of valproic acid and the free fraction of phenytoin. 4 It is concluded that patients on combined treatment with phenytoin and valproic acid have an unpredictably raised free fraction of phenytoin. This drug interaction therefore can complicate the important plasma level monitoring of phenytoin in epileptic patients unless the free concentration of this drug can be analysed or estimated.

Adolescent↗
PubMed1978

High incidence of a concentration-dependent skin reaction in children treated with phenytoin.

A particularly high incidence of rash was seen in children with epilepsy treated with phenytoin. Ten children with untreated epilepsy were therefore included in a prospective study and given either 3 (group 1) or 6 (group 2) mg of phenytoin/kg body weight/day for five days followed by 6 mg/kg body weight/day for both groups. Four of the five children in group 2 compared with only one of the five in group 1 developed a rash seven to 12 days after the start of treatment. Patients with rashes had significantly higher plasma phenytoin concentrations. Whenever the phenytoin concentration was higher than 14 micromol/l on day 5 a rash occurred. These findings indicate that the generalised skin reaction is caused by a high body burden of phenytoin, which results from either a high load of the drug or a low clearance rate.

Adolescent↗
PubMed1978

A simplified assay of furosemide in plasma and urine by high-pressure liquid chromatography.

A simplified high-pressure liquid chromatograhic method for determination of furosemide in plasma and urine has been developed using a fluorometric detector directly coupled to the column effluent. The method includes an ether extraction from acidified biologic samples. The mobile phase used for chromatography on a reversed-phase column (C15 hydrocarbon permanently bonded to silica particles) is sufficiently acidic to induce fluorescence of furosemide. The methylester of furosemide is employed as an internal standard. The sensitivity is 0.1 and 0.25 microgram per ml plasma and urine, respectively. The applicability to pharmacokinetic studies of furosemide is shown.

Adult↗
PubMed1978

Relation between plasma concentration of indomethacin and its effect on prostaglandin synthesis and platelet aggregation in man.

The dose and plasma levels of indomethacin correlated with inhibition of prostaglandin synthesis as measured both by urinary excretion of the major metabolite of prostaglandin E2 (PGE-M) and by the release of prostaglandin E2 from thrombin-stimulated platelets. Considerable intersubject variability was observed in the suppression of PGE-M excretion. In some patients 37.5 mg indomethacin daily, usually considered subtherapeutic, caused suppression. Maximal suppression (greater than 90%) occurred in some after a daily dose of 75 mg, whereas 150 mg was required to achieve this level of inhibition in others. Suppression of the excretion of PGE-M by 60% occurred when the end of the dosage interval plasma levels of indomethacin were in the range 0.05 to 0.3 microgram/ml, which implies that a somewhat higher average steady-state concentration during the dosage interval was required to achieve this effect. A similar degree of inhibition of the release of PGE2 on thrombin-stimulated platelets was associated with the same range of plasma levels. Upon discontinuation of the drug, the levels of indomethacin in plasma decreased exponentially; inhibition of the release of PGE2 from platelets by indomethacin declined linearly with time and in parallel with the logarithm of the diminishing plasma levels.

Adult↗
PubMed1978

Pharmacokinetics of oxazepam given during labour.

The transfer across the placenta and the maternal and neonatal kinetics of oxazepam and its conjugate was studied in 12 patients and their newborns. Oxazepam was readily absorbed and peak plasma concentrations were similar to those in healthy non-pregnant volunteers. When meperidine was given within one hour of the dose of oxazepam the absorption was delayed but the bioavailability did not decrease. In the newborns the umbilical vein plasma concentration of oxazepam usually exceeded that of the conjugate. The reverse was true for all subsequent plasma samples from the newborn. The half-life of oxazepam in the newborn averaged 22 hours as compared to 6.5 hours in the mothers. A significant rise of the plasma concentration of oxazepam conjugate was noted in three newborns during the first 6-10 hours of extrauterine life. This shows that the newborn is able to conjugate oxazepam. The Apgar score values were normal.

Administration, Oral↗
PubMed1978

The influence of indomethacin on the pharmacokinetics, diuretic response and hemodynamics of furosemide in the dog.

Indomethacin has the potential to interact with furosemide in a number of different fashions. We have investigated some of these possibilities in seven mongrel dogs that received furosemide (2 mg/kg i.v.). Plasma and urinary concentration of furosemide were measured by high performance liquid chromatography, diuretic response was assessed by urinary sodium excretion and renal blood flow and its distribution were estimated using the radioactive microsphere technique. Furosemide induced a prompt diuresis associated with a 50% increase in total renal blood flow. Intrarenal blood flow was preferentially increased in the inner cortical zones. Furosemide was rapidly eliminated with a renal clearance that was 35% of the total systemic clearance. Maximal sodium excretion was attained at plasma furosemide concentrations greater than 0.8 microgram/ml; below this concentration there was a linear relationship between plasma concentration and rate of sodium excretion. The ratio of sodium/furosemide concentration in urine rose to a plateau, then remained constant. Indomethacin pretreatment inhibited the hemodynamic response to furosemide. In addition, indomethacin reduced the renal and extrarenal clearance of furosemide by approximately 30%, but did not change the proportion of unchanged drug excreted in the urine. Although the diuretic response for any given plasma concentration of furosemide was reduced, the ratio of urinary sodium/furosemide concentration was not changed by indomethacin. Since the amount of furosemide reaching the urine was not altered, the total diuretic response was not significantly affected by indomethacin. From these observations we conclude that indomethacin alters the pharmacokinetics of the disposition of furosemide and furosemide-induced renal hemodynamic changes. However, our data indicate that the response of the renal tubule to furosemide secreted into tubular fluid is not changed by indomethacin.

Animals↗
PubMed1977

Plasma concentrations of 5-(4-hydroxyphenyl)-5-phenylhydantoin in phenytoin-treated patients.

A mass fragmentographic method was used to determine unconjugated and conjugated 5-(4-hydroxyphenyl)-5-phenylhydantonin (4-OH-DPH) in plasma of patients being treated with phenytoin (DPH). The plasma concentration of unconjugated 4-OH-DPH is stable at steady-state for DPH and the level does not change during the dose interval. Most patients (82.5%) have plasma concentrations of unconjugated 4-OH-DPH between 0.04 and 0.2 mug/ml at concentrations of DPH between 5 and 30 mug/ml. Interindividual differences in the ratio between plasma concentration of unconjugated 4-OH-DPH and DPH were noted in a wide range of doses. Dosage adjustments of DPH in patients were not associated with major changes in the plasma level of unconjugated 4-OH-DPH. The plasma concentration of conjugated 4-OH-DPH also showed interindividual differences and varied between 1.2 and 4.5 mug/ml in patients with DPH concentrations between 5 and 30 mug/ml. The data are consistent with the concept of Michaelis-Menten kinetics for DPH metabolism.

Dose-Response Relationship, Drug↗
PubMed1977

Prediction of hepatic extraction ratio from in vitro measurement of intrinsic clearance.

Under first-order conditions the activity of the hepatic drug-metabolizing enzymes may be closely approximated by the ratio of the in vitro kinetic constants Vmax and Km, which in turn is equivalent to the intrinsic clearance of the drug. In theory, after appropriate consideration for liver weight, blood flow and rug binding in the blood, the intrinsic clearance may be used to predict the extraction ratio for the total organ. This hypothesis was tested by comparing the predicted ratio based on a perfusion-limited model of hepatic elimination with that determined directly in the isolated perfused rat liver. Good agreement was obtained between the predicted and observed hepatic extraction ratios for antipyrine, carbamazepine, hexobarbital, phenytoin, propranolol, alprenolol and lidocaine, which span the extraction ratio from less than 0.1 to greater than 0.9.

Animals↗
PubMed1977

Biphasic kinetic profile for carbamazepine epoxide formation.

The formation of the stable 10,11-epoxide from carbamazepine by rat liver microsomes was studied. A biphasic activity-substrate profile was consistently found with microsomes from both control and phenobarbital pretreated rats. These data could either indicate epoxide formation by multiple catalytic sites with differential substrate affinity or a solvent effect on the enzyme or its environment.

Animals↗
PubMed1976

Kinetics of carbamazepine and its 10,11-epoxide metabolite in children.

The plasma steady-state concentration of carbamazepine (CBZ) and its metabolite (carbamazepine-10,11-epoxide, CBZ-epoxide) was assessed in 43 children (2-15 yr) on CBZ (Tegretol) treatment. Twenty of the children received combined treatment with other anticonvulsant drugs simultaneously. The plasma concentrations were in the same range as had been found in adult patients on corresponding doses. Only a weak correlation was noted between dose and plasma CBZ concentration in the group of children on single-drug treatment, and there was no correlation in the group of children on combined drug regimen. Plasma levels of CBZ correlated with those of the metabolite. Children on combined treatment had lower CBZ concentration and, expressed as percent of the parent drug, the metabolite concentration was significantly higher than in children treated only with CBZ. In 2 children the plasma half-life of CBZ was estimated and found to be slightly shorter than has previously been reported in adults. In evaluating the plasma level-effect relationship of CBZ, the plasma concentration of the CBZ-epoxide should be measured simultaneously because of its anticonvulsant effect and interindividual variability.

Adolescent↗