The pharmacokinetics of meprobamate following its oral and rectal administration as a series of combinations with diphenhydramine, acetylsalicylic acid, codeine and pentaerythritol tetranitrate.

Studies in human volunteers of the pharmacokinetics of the active drugs in the formulations Visano-mini (meprobamate and diphenhydramine HCl), DoloVisano (meprobamate, diphenhydramine HCl, acetylsalicylic acid and codeine phosphate) and VisanoCor (meprobamate, diphenhydramine HCl and pentaerythritol tetranitrate (PETN], have demonstrated systemic absorption of each of the drugs from all of the formulations. Bioequivalence of meprobamate is indicated despite the drug combinations involved. Some differences in diphenhydramine pharmacokinetics are, however, apparent. The bioavailability of meprobamate administered rectally to human volunteers as the marketed preparations DoloVisano Suppositories and Dolo-Visano Suppositories sine codeino, is similar to that observed following oral administration.

A study of the plasma levels of pentaerythritol mononitrate following administration of pentaerythritol tetranitrate in combination with meprobamate and diphenhydramine.

The systemic absorption of meprobamate, diphenhydramine and pentaerythritol tetranitrate (PETN) has been demonstrated following oral administration of a formulation containing all three drug substances to human volunteers. A study undertaken in dogs has also been made of the pharmacokinetics of the major nitrated metabolite of PETN when the parent drug is administered with and without meprobamate and diphenhydramine. Pentaerythritol mononitrate shows a six-fold increase in both peak plasma concentrations and area under the 0-12 hour plasma concentration-time curve when PETN is co-administered with a combination of meprobamate, diphenhydramine and nicotinic acid. No such increase is apparent when either meprobamate or diphenhydramine is excluded from the dose. Further increases in pentaerythritol mononitrate plasma levels and AUC 0-12 h are observed when all of the drugs are administered as the formulated coated tablet (VisanoCor).

The absorption, metabolism and excretion of (14C)-AR-L 115 BS in the baboon.

(14C)-Labelled 2-[(2-methoxy-4-methylsulfinyl)phenyl]-1H-imidazo[4,5-b]pyridine (AR-L 115 BS) (base) was administered to male baboons by the p.o. (10 mg . kg-1 by capsule) and i.v. (2 mg.kg-1) routes. Comparison of routes and extent of excretion suggests the importance of biliary elimination and indicates that an oral dose of (14C)-AR-L 115 BS is almost quantitatively absorbed. Thus in 5 days, after the oral dose, a mean of 42% was excreted in the urine and 38% in faeces. Similarly in 0--5 days after the i.v. dose, a mean of 49% was excreted in urine and 31% in faeces. Substantial elimination of administered radioactivity was observed in the 0--24 h period: 52% following p.o. administration and 60% following i.v. administration. Plasma levels of total radioactivity peaked at 6 micrograms equiv.ml-1 4 h following an oral dose. The concentration of unchanged AR-L 115 BS at this time was ca. 4 micrograms . ml-1. 4 h following the lower i.v. dose, plasma concentrations of ca. 0.5 micrograms equiv.ml-1 were observed and were associated with ca. 0.2 micrograms . ml-1 unchanged drug. Two phases of elimination of total radioactivity from plasma after the i.v. dose could be distinguished with t1/2 ca. 2 h and ca. 48 h. An estimated late phase t1/2 of 48 h was also observed following the oral dose. Although less polar metabolites (chromatographically identical to the synthetic compounds AR-L 114 Cl (hydrochloride) and AR-L 113 Cl) were observed in the plasma at 4 h, the urine and faeces contained some polar metabolites which appeared to be neither glucuronide nor sulphate conjugates. The lower i.v. dose was apparently more extensively metabolised than the higher oral dose.

Quantitative determination of the herbicide paraquat in human plasma by gas chromatographic and mass spectrometric methods.

The gas chromatographic (GC) determination of the herbicide paraquat, the 1,1'-dimethyl-4,4'-dipyridyl cation in human plasma is described. In poisoning cases, plasma concentrations provide a necessary index of the severity of intoxication and a means of monitoring subsequent therapy. The methods may be extended to the specific trace analysis of paraquat in body fluids of post-mortem tissue. Reduction of fully ionised paraquat salts with sodium borohydride yields a hexahydro derivative, a diene, amenable to solvent extraction and GC. Employing 1,1'-diethyl-4,4'-dipyridyl dichloride as the internal standard, plasma concentrations of 0.1 microgram/ml (+/- 6% S.D.) may be determined with flame ionisation detection and 0.025 microgram/ml with nitrogen-selective flame ionisation. Further enhancement of specificity is achieved using selected ion monitoring mass spectrometry and the value of this technique in forensic analysis is illustrated.

Amylobarbitone hydroxylation kinetics in small samples of rat and human liver.

1. Two micro methods for determining amylobarbitone hydroxylase activity from less than 3 mg liver are described. One is based on single-ion monitoring g.l.c.-mass spectrometry and the other on t.l.c. separation of 14C-labelled product. 2. Km and Vmax have been determined with rat liver and both needle and open biopsy samples of human liver. 3. Both methods are sufficiently sensitive and reproducible for use with 20 mg needle biopsies.

Pharmacokinetics of indoramin in man.

1 The fate of oral and intravenous indoramin has been studied after single doses in man using the 14C labelled drug. Plasma concentrations of indoramin have been determined during chronic oral antihypertensive therapy employing a stable isotope dilution assay. 2 Following singleoral dosing the drug is well absorbed and extensively metabolised. Faecal excretion in 72 h accounts for 46% of the administered radioactivity of which approximately 4% is associated with indoramin. Less than 2% of the radioactivity in urine is accountable as the concentration of total metabolites. Peak plasma levels both of drug and metabolites occur 1-2 h after dosing, the maximal lowering of blood pressure occurring at this time. 3 The clearance of indoramin, determined after intravenous administration is of the same order as liver blood flow. In the isolated perfused rat liver, the extraction ratio is 0.98.

Maternal and neonatal elimination of amobarbital after treatment of the mother with barbiturates during late pregnancy.

Plasma half-lives of amobarbital were determined in newborn children of 10 mothers who had been treated with barbiturates for hypertension in pregnancy for 6 to 42 days prior to delivery. Five mothers had received amobarbital, 200 mg daily, and 5, phenobarbital, 60 to 180 mg daily. Half-lives in 7 of the babies ranged from 16.6 to 49.4 hr, comparable to those previously reported in babies of mothers who had received only a single dose of amobarbital. Thus there was no evidence of induction of amobarbital hydroxylation in these children. Two babies who had a greater than normal rise in serum bilirubin had longer half-lives (86.1 and 117.7 hr). In 1 baby whose mother had membranous glomerulonephritis, plasma amobarbital concentration did not significantly change over the period of the study.

Plasma concentration of phenylbutazone and its therapeutic effect-studies in patients with rheumatoid arthritis.

1 Phenylbutazone in doses of 50, 100, 200 and 300 mg/day has been given for four periods of 3 weeks to seven patients with rheumatoid arthritis. The trial was double-blind and the order of administration of doses was arranged to eliminate order and carry-over effects. 2 Before the trial and at the end of each period, the patient's responses were assessed by measurement of the duration of morning stiffness, the pain score, paracetamol tablet count, grip strength, digital joint size and articular index. 3 The plasma phenybutazone concentration was measured by gas-liquid chromatography and was also predicted by prior measurement of the phenazone half-life. 4. Compared with the pretreatment period, phenylbutazone had a significant therapeutic effect, as judged by morning stiffness, pain score and articular index, in a dose of 50 mg/day, but no statistically significant differences in effect were seen between the various doses of phenylbutazone. 5 There were no significant coorelations between the plasma concentration of phenylbutazone and any of the clinical assessments. 6 The plasma phenylbutazone concentration agreed closely with that predicted at doses of 50 and 100 mg, but at higher doses the plasma concentration was significantly lower than predicted (P less than 0.05). This may have been due to saturation of the protein binding sites at these doses.

Clinical pharmacology and pharmacokinetics of clonidine.

A 300-mug oral dose of clonidine was administered to 5 normal volunteers and measurements of plasma concentration and effects upon blood pressure, heart rate, circulatory reflexes, sedation, and dry mouth were made for the following 8 hr. The plasma concentration rose to a peak of 1.02 +/- 0.52 ng/ml (SD) at 90 min and fell with a mean half-life of 12.7 hr. Blood pressure of the group fell from 111.0/77.0 to 87.2/60.4 after 3 hr and was 95.2/62.2 mm Hg at 8 hr. Heart rate in recumbency was slowed. Marked sedation and a fall in salivary flow followed the same time-course as the plasma concentration. The cold pressor response was reduced but the Valsalva overshoot was little affected.