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Biomedical subjects

M L Orme

Publications and source records attributed to M L Orme.

At least 73 records · Page 4Linked to original sources
PubMed1984

An investigation of the effects of phenobarbitone on the pharmacokinetics of norethindrone in the rat using liver perfusion and everted gut sacs.

Previous in vivo studies have suggested that phenobarbitone increases the first pass clearance of norethindrone in the rat by induction of enzymes both in the gut wall and liver. In the present study phenobarbitone caused an increase in both the production of highly polar ether-extractable metabolites and the conjugation of the steroid as it crossed the wall of the everted gut sac preparation. In addition, there was a marked increase in the uptake of norethindrone into the liver followed by increased phase I metabolism in the isolated perfused liver. As expected for a highly cleared drug, enzyme induction had no measurable effect on the terminal half-life of norethindrone in the perfused liver preparation.

Animals↗
PubMed1984

Pharmacokinetics of oral contraceptive steroids following the administration of the antimalarial drugs primaquine and chloroquine.

The effects of a single dose of two antimalarial drugs chloroquine (CQ) and primaquine (PQ) on the pharmacokinetics of a combined oral contraceptive (O.C.) have been studied in volunteers. Each woman was studied on 3 separate occasions over 3 cycles and plasma concentrations of ethinyloestradiol (EE2) and levonorgestrel were measured by radioimmunoassay following administration of a single dose of O.C. (30 micrograms EE2 + 150 micrograms levonorgestrel) in the absence and presence of the antimalarial drugs (PQ, 45 mg; CQ, 300 mg). Neither CQ or PQ given 1 h before the O.C. had any significant effect on plasma concentrations of EE2 or levonorgestrel or on any pharmacokinetic parameter determined. There is therefore, no evidence that CQ or PQ interfere with the hepatic handling of O.C.'s. This is in contrast to previously reported inhibitory effects of PQ on the metabolism of antipyrine.

Adult↗
PubMed1984

Pharmacokinetics of primaquine in man: identification of the carboxylic acid derivative as a major plasma metabolite.

A method is described for the simultaneous determination of the carboxylic acid and N-acetyl-derivatives of primaquine, in plasma and urine. After oral administration of 45 mg primaquine, to five healthy volunteers, absorption was rapid, with peak primaquine levels of 153.3 +/- 23.5 ng/ml at 3 +/- 1 h, followed by an elimination half-life of 7.1 +/- 1.6 h, systemic clearance of 21.1 +/- 7.1 l/h, volume of distribution of 205 +/- 371 and cumulative urinary excretion of 1.3 +/- 0.9% of the dose. Primaquine underwent rapid conversion to the carboxylic acid metabolite of primaquine, which achieved peak levels of 1427 +/- 307 ng/ml at 7 +/- 4 h. Levels of this metabolite were sustained in excess of 1000 ng/ml for the 24 h study period, and no carboxyprimaquine was recovered in urine. N-acetyl primaquine was not detected in plasma or urine. Following [14C]-primaquine administration to one subject, plasma radioactivity levels rapidly exceeded primaquine concentrations. Plasma radioactivity was accounted for mainly as carboxyprimaquine . Though 64% of the dose was recovered over 143 h, as [14C]-radioactivity in urine, only 3.6% was due to primaquine. As neither carboxyprimaquine nor N- acetylprimaquine were detected in urine, the remaining radioactivity was due to unidentified metabolites.

Adult↗
PubMed1983

The pharmacodynamics and pharmacokinetics of conventional and long-acting propranolol in patients with moderate hypertension.

1 The effects on heart rate and blood pressure after single and multiple dosing (1 month) of a long acting formulation of propranolol 160 mg daily, and conventional propranolol, 80 mg twice daily, or 160 mg daily were compared in 11 moderately hypertensive subjects previously shown to respond to propranolol. 2 After acute dosing all three treatments produced significant reduction in blood pressure. After multiple dosing all three treatments maintained significant reductions in lying, standing and exercise heart rate and blood pressure throughout the 24 h. At 24 h, after multiple dosing, the fall in resting and standing systolic BP was significantly greater with LA propranolol than with conventional propranolol 80 mg twice daily or conventional propranolol 160 mg once daily (P at least less than 0.05). 3 The plasma propranolol concentration time curve after LA propranolol showed slowed absorption, and the area under the curve was significantly lower than after conventional propranolol (acute dosing; LA propranolol 160 mg 560 mg ml-1 h, conventional propranolol 80 mg twice daily 1135 mg ml-1 h, conventional propranolol 160 mg daily 1414 mg ml-1 h).

Adult↗
PubMed1983

Effect of chloroquine and primaquine on antipyrine metabolism.

The effects of two antimalarial drugs, chloroquine and primaquine on antipyrine kinetics and metabolism have been studied in volunteers. Chloroquine (250 mg) given 2 h before antipyrine (600 mg orally) had no effect on salivary kinetics of antipyrine or on the urinary recovery of metabolites. Primaquine (45 mg) given 2 h before antipyrine (300 mg orally), increased antipyrine half-life (calculated from 0-24 h) from 12.7 +/- 3.2 (mean +/- s.d.) to 25.3 +/- 3.9 h and decreased clearance from 3.01 +/- 0.67 to 1.32 +/- 0.32 1 h-1. There was no change in the apparent volume of distribution. Antipyrine half life changed with time in the presence of primaquine and when calculated between 24 and 48 h had returned to control. After primaquine, the metabolic clearance (calculated from 0-24 h) of antipyrine to its three main metabolites, 3-hydroxymethylantipyrine, 4-hydroxyantipyrine and norantipyrine was significantly reduced. There was no selective effect on a particular metabolic pathway. There was no change in 6 beta-hydroxycortisol excretion (expressed as a ratio of total 17-hydroxy-corticosteroids) in the period 0-48 h following primaquine administration. The inhibition of hepatic metabolism by primaquine but not the structurally related chloroquine may be an example of a structure activity phenomenon and could be of clinical significance.

Adult↗
PubMed1983

The biliary and urinary metabolites of [3H]17 alpha-ethynylestradiol in women.

The metabolism of 17 alpha-ethynyl[6,7-3H]estradiol (3H-EE2) (50 micrograms) given orally was studied in two groups of women: (a) six subjects from whom duodenal bile samples were obtained after 4 h by endoscopic aspiration; (b) two subjects with bile-duct (T-tube) drainage. The first group eliminated 16.6 +/- 7.8% (mean +/- S.D.) of the dose in urine over 72 h, the second group 28.6% and 27.5%. Biliary excretion by the latter was 41.9% and 28.3% of the dose, respectively, during the first 24 h after dosing. The metabolites excreted in bile and urine were largely polar conjugates: 1-12% of the 3H was ether extractable. Approx. 70-90% of urinary and biliary 3H was extractable following beta-glucuronidase-arylsulphohydrolase hydrolysis. Both beta-glucuronides and arylsulphates were excreted. Unchanged 3H-EE2 was the principal 3H-labelled component of the glucuronide and arylsulphate fractions of bile, and it was a major component of urinary fractions. 2-Hydroxy-EE2 and 2-methoxy-EE2 were identified as conjugated biliary metabolites.

Aged↗
PubMed1982

The effect of renal disease on the pharmacokinetics of diethylcarbamazine in man.

1 The pharmacokinetics of diethylcarbamazine (DEC) were studied in twelve patients with chronic renal function impairment. 2 Selected pharmacokinetic parameters, plasma half-life (T1/2), area under the plasma concentration-time curve (AUC), elimination rate constant (Kel) and 24 h urinary excretion were regressed versus parameters indicative of renal function. 3 Significant negative correlations were observed between creatinine clearance and both plasma T1/2 and log10 T1/2. 4 Significant positive correlations were obtained between (a) creatinine clearance and elimination rate constant of DEC and (b) reciprocal serum creatinine and l/T1/2. Creatinine clearance was significantly and positively correlated with 24 h urinary excretion of DEC. 5 No significant correlations were observed between age, sex or weight and renal function but DEC excretion did appear to decrease with increasing urinary pH. 6 Plasma half-life, and area under the plasma concentration-time curve were increased and 24 h urinary excretion of DEC was significantly reduced in patients with chronic renal function impairment, compared with normal volunteer subjects receiving an identical dosage of DEC at acidic urinary pH.

Adult↗
PubMed1982

A clinical and pharmacokinetic study of indomethacin in standard and slow release formulations.

Fifteen patients with rheumatoid arthritis received indomethacin in three treatment schedules; indomethacin retard 75 mg twice daily; indomethacin capsules 50 mg three times daily; and indomethacin 100 mg suppository at night with 50 mg by mouth each morning. The study was a double-blind, double-dummy one with each treatment being given for 2 weeks after a washout period of 3 days. After the washout period, and at the end of each 2 week active treatment period, blood samples were taken during a dosage interval for assay of indomethacin concentrations in plasma. Clinical assessments were also performed. All three treatment period produced significant clinical improvements in the assessments compared with the placebo washout period. However, no differences were seen between the treatments. Side effects occurred with equal frequency in all three periods, and the anticipated reduction in central nervous system side effects during the indomethacin retard period was not seen. Plasma concentrations of indomethacin were significantly higher during indomethacin retard therapy with a peak concentration of 2500 +/- 25 ng ml-1 during indomethacin retard therapy (mean +/- s.d.) and 1900 +/- 200 ng ml during conventional oral therapy. Indomethacin retard is as effective as the other formulations of indomethacin but appears to offer no significant advantages.

Aged↗