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J M Orr

Publications and source records attributed to J M Orr.

17 recordsLinked to original sources
PubMed1990

Pharmacokinetics and enterohepatic circulation of (E)-2-ene valproic acid in the rat.

A pharmacologically active monounsaturated metabolite of valproic acid (VPA), (E)-2-ene VPA, was administered by an intravenous bolus dose of 20 mg/kg to normal and bile-exteriorized rats. The total plasma clearance of (E)-2-ene VPA in normal rats was 4.9 ml/min/kg and in bile-exteriorized rats, 7.7 ml/min/kg. (E)-2-ene was recycled in the plasma of normal rats due to enterohepatic circulation. Approximately 32% of the dose was excreted in the urine of normal rats. Of the administered dose to bile exteriorized rats, approximately 27% was excreted in the urine and 38% in the bile. Administration of (E)-2-ene increased bile flow rate, and the induced choleresis lasted for 3-4 h. (E)-2-ene VPA was largely excreted in apparently conjugated form in the urine and bile. The pharmacokinetics of (E)-2-ene VPA were similar to that of the parent drug VPA.

Animals↗
PubMed1989

The effect of carbamazepine on valproic acid disposition in adult volunteers.

1. Pharmacokinetic parameters for valproic acid (VPA) were determined before and following 2 weeks of carbamazepine (CBZ) administration in five healthy male volunteers. Mean VPA dosage was 16.4 mg kg-1 day-1. CBZ dosage was started at 100 mg twice daily and increased after 1 week to a total daily dose of 300 mg. 2. After CBZ administration, mean VPA plasma clearance increased from 0.90 +/- 0.18 s.d. to 1.26 +/- 0.24 l h-1 (P less than 0.05) as did clearance of free VPA (20.8 +/- 7.6 to 37.0 +/- 13.6 l h-1). Mean VPA elimination rate constant increased from 0.051 +/- 0.011 to 0.067 +/- 0.011 h-1 (P less than 0.05) after CBZ administration. 3. Mean area under the serum concentration vs time curve decreased from 675.0 +/- 130.5 to 475.7 +/- 75.7 mg l-1 h (P less than 0.05) after CBZ administration. Mean serum VPA half-life decreased from 14.0 +/- 2.4 to 10.6 +/- 1.4 h (P less than 0.05). Mean serum VPA trough concentrations decreased from 44.0 +/- 16.7 to 27.0 +/- 10.4 micrograms ml-1 (P less than 0.05). 4. A significant change was not observed in the mean VPA volume of distribution after CBZ coadministration suggesting that enzyme induction rather than a competition for plasma protein binding sites was involved in this interaction. 5. Despite the increased clearance of VPA, the urinary recovery of VPA or conjugate did not increase after CBZ administration.

Adult↗
PubMed1987

Capillary GCMS assay of 2-n-propyl-4-pentenoic acid (4-ene VPA) in rat plasma and urine.

A simple, sensitive and specific capillary GCMS assay method is described for the determination of a toxic metabolite of valproic acid, 2-n-propyl-4-pentenoic acid (4-ene-VPA), in rat plasma and urine. The method involves a single extraction of a small volume of plasma or urine with ethyl acetate. Extraction efficiency is virtually 100%. Derivatization with MTBSTFA reagent is extremely rapid. Calibration curves are linear in the concentration ranges of 0.5-45 micrograms/mL and 2-80 micrograms/mL in rat plasma and urine respectively. The lowest detection limit using 80 microL of plasma is 100 ng/mL. Following I.V. administration of 20 mg/kg of 4-ene-VPA, plasma levels can be monitored for 6 hours in rats. The results indicate that pharmacokinetics of 4-ene VPA are similar to those of the parent drug valproic acid (VPA) in the rat.

Animals↗
PubMed1986

Free and total serum valproate concentrations: their relationship to seizure control, liver enzymes and plasma ammonia in children.

The relationships between total and free serum valproate (VPA) concentrations and seizure control, serum liver enzyme activity and plasma ammonia concentration were studied in 61 epileptic children. Enzyme-immunoassay (EMIT)R methods gave higher values of total VPA concentration than gas-liquid chromatography (GLC) methods. In over 80% of children with complete seizure control the ranges of total VPA concentration were 140-420 mumol/L with GLC methods and 210-560 mumol/L with EMIT methods. The range of free VPA concentrations in 78% of children with complete seizure control was 8.8-26.4 mumol/L. Increased liver enzyme activity was observed in 6 of the 61 children and raised plasma ammonia concentration in 11 of 50 children. Plasma ammonia concentration was related to total serum VPA but was not related to free serum VPA. Increased serum liver enzyme activity was related to VPA dose per kg but not to free or total serum VPA concentration. Thus free VPA concentrations do not appear to be more useful than total VPA concentrations in predicting seizure control and do not correlate with liver enzyme activity or plasma ammonia concentration.

Adolescent↗
PubMed1986

The effect of aspirin on valproic acid metabolism.

Urinary valproic acid (VPA) and VPA metabolite profiles were determined before (day 1) and after (day 2) the administration of antipyretic doses of acetylsalicylic acid (ASA) to seven subjects with steady-state levels of VPA. Of the 13 metabolites assayed by GC/MS, levels of (E)-2-ene VPA and 3-keto VPA were significantly decreased on day 2, whereas those of the VPA conjugates (glucuronide) and 4-ene VPA were significantly increased. The beta-oxidation pathway consisting of (E)-2-ene VPA, 3-OH VPA, and 3-keto VPA was decreased from 24.5% +/- 10.3% of total metabolites excreted on day 1 to 8.3% +/- 4.2% on day 2, a decrease of 66% (P less than 0.05). VPA glucuronide content increased from 50.5% +/- 12.6% on day 1 to 65.5% +/- 14% of total excreted on day 2, an increase of 30% (P less than 0.05). The day 2/day 1 ratios of VPA glucuronide correlated significantly with the day 2/day 1 ratios of VPA mean free fraction (r = 0.9424; P = 0.005) in six of the seven subjects. Inhibition of VPA beta-oxidation by salicylate was sufficient to counterbalance the increased elimination of VPA as its conjugates and explains why total clearance of VPA after salicylate remains unchanged even though the free fraction of VPA is increased. Metabolic profiles indicate that salicylate likely inhibits VPA beta-oxidation by reducing valproyl-coenzyme A formation.

Adolescent↗
PubMed1984

Use of hexadeuterated valproic acid and gas chromatography-mass spectrometry to determine the pharmacokinetics of valproic acid.

Di-[( 3,3,3-2H3]propyl)acetic acid, a hexadeuterated analogue of valproic acid, was synthesized and its pharmacokinetic properties compared with valproic acid. Concentrations of valproic acid and [2H]valproic acid in serum and saliva were determined by GC-MS using selected-ion monitoring. Saliva drug levels were measured with good precision down to 0.1 microgram/mL. Kinetic equivalence of valproic acid and [2H]valproic acid was demonstrated in a single-dose study in a human volunteer. An isotope effect was observed for omega-oxidation, but the difference in metabolism was not sufficient to make [2H]valproic acid biologically nonequivalent. The application of [2H]valproic acid to determine the kinetics of valproic acid under steady-state concentrations was evaluated in the same volunteer. The kinetic data obtained with [2H]valproic acid was consistent with previously reported values for valproic acid including kinetic differences observed between single-dose and steady-state experiments. Saliva levels of valproic acid were found to give a good correlation (r = 0.953) with total serum valproic acid under multiple-dose conditions. A concentration dependence was found for the ratio of saliva valproic acid to free valproic acid in serum, low ratios being observed at high serum concentrations of valproic acid.

Adult↗
PubMed1983

The effects of peritoneal dialysis on the single dose and steady state pharmacokinetics of valproic acid in a uremic epileptic child.

The pharmacokinetics of valproic acid (VPA) have been studied during peritoneal dialysis in a uremic male epileptic child following a single 500 mg dose and after multiple doses over 5 months (700 mg daily) of valproic acid as the syrup. Serum level decline was biphasic in both instances with a terminal half-life of 27.2 after the single dose and 10.2 h at steady-state. Total serum clearance was 0.0236 l/h/kg after the single dose and increased to 0.0408 l/h/kg after 5 months. Free (intrinsic) serum clearances were 0.1489 and 0.1518 l/h/kg and serum free fractions were 0.224 and 0.272 respectively for the single dose and steady-state studies. Peritoneal dialysis for periods of 12 or 24 h removed an average of 4.5% of the VPA dose.

Child↗
PubMed1982

Interaction between valproic acid and aspirin in epileptic children: serum protein binding and metabolic effects.

In five of six epileptic children who were taking 18 to 49 mg/kg/day valproic acid (VPA), the steady-state serum free fractions of VPA rose from 12% to 43% when antipyretic doses of aspirin were also taken. Mean total VPA half-life (t1/2) rose from 10.4 +/- 2.7 to 12.9 +/- 1.8 hr and mean free VPA t1/2 rose from 6.7 +/- to 2.1 to 8.9 +2- 3.0 hr when salicylate was present in the serum. The in vitro albumin binding association constant (ka) for VPA was decreased by salicylate, but the in vivo ka value was not affected. The 12-hr (trough) concentrations of both free and total VPA were higher in the presence of serum salicylate in five of six patients. Renal excretion of unchanged VPA decreased in five of six patients, but the VPA carboxyl conjugate metabolite-excretion patterns were not consistently affected. Salicylate appeared to displace VPA from serum albumin in vivo, but the increased VPA t1/2 and changes in VPA elimination patterns suggest that serum salicylate also altered VPA metabolism.

Aspirin↗
PubMed1980

Oligoclonal bands and quantitation of IgG in cerebrospinal fluid as indicators of multiple sclerosis.

The authors evaluated two laboratory procedures in respect to usefulness in evaluating patients suspected of having multiple sclerosis (MS). They classified 185 patients as having MS (MS-positive) or as not having MS (MS-negative). Agarose electrophoretic patterns of cerebrospinal fluid (CSF) samples were inspected for the presence of oligoclonal bands. CSF immunoglobulin G (IgG) was quantitated and compared with total CSF protein for 175 patients. Oligoclonal bands were present in specimens from 77% of the MS-positive group; elevated percentages of IgG (18% or more of total CSF protein) were present in specimens from 20%. Oligoclonal bands were present in specimens from 0.6% of the MS-negative group; elevated percentages of IgG were found for 1.4% of the MS-negative group. The presence or absence of oligoclonal bands in agarose electrophoretic patterns is sensitive (77%) and very specific (99%) in respect to MS. CSF IgG quantitation using the authors' criteria does not add useful information.

Demyelinating Diseases↗
PubMed1975

The effect of fasting on the rate of intestinal drug absorption in rats: preliminary studies.

The absorption rates of two model drugs, salicylate and antipyrine, from the small intestines of rats deprived of food for various periods of time were compared with rats fed ad libitum. Fasting reduced the absorption rate constants for both drugs with the salicylate rates being depressed more severely than the rates for antipyrine. Intestinal mass studies showed that the weight/length ratio of the rat intestine is progressively decreased as fasting is prolonged up to 96 hr. The intestinal weight loss was much more pronounced than the total body weight loss. The loss in intestinal weight and the observed decrease in drug absorption rate are believed to be related to the inhibition of intestinal cell proliferation due to fasting, resulting in a decreased absorptive surface and reduced mucosal cell viability.

Animals↗
PubMedDate not supplied

Pharmacokinetics and enterohepatic circulation of 2-n-propyl-4-pentenoic acid in the rat.

The pharmacokinetics of 4-ene-valproic acid (4-ene-VPA), a putative hepatotoxic metabolite of the anticonvulsant valproic acid (VPA), were studied in normal and bile-exteriorized rats. A single iv bolus dose of 20 or 100 mg/kg of 4-ene-VPA was administered to each rat. Plasma decline of 4-ene-VPA was apparently monoexponential at the low dose and nonlinear at the high dose. In normal rats, 4-ene-VPA was recycled in the plasma due to enterohepatic circulation (EHC). A time lag pharmacokinetic model was used to describe the plasma profile, including the appearance of a secondary plasma peak, in normal animals receiving the low dose of 4-ene-VPA. Total apparent plasma clearance was 8.67 ml/min.kg at the low dose and 5.89 ml/min.kg at the high dose. EHC was abolished in bile-exteriorized animals. In these rats, the apparent plasma elimination half-life increased from 12.7 to 18.8 min and plasma clearance decreased from 11.4 to 7.41 ml/min.kg with a 5-fold increase in the dose. 4-ene-VPA was largely eliminated in urine and bile as conjugates. In normal rats, 22% and 28% of the low and high dose, respectively, were eliminated in urine. Approximately 29% of the low dose and 21% of the high dose were recovered in bile of the rat. Like the parent drug VPA, 4-ene VPA induced dose-dependent choleresis in the rat. The pharmacokinetics of 4-ene-VPA in the rat were similar to those reported for VPA.

Animals↗