Search PubMed⌕ Search

Biomedical subjects

R A Robson

Publications and source records attributed to R A Robson.

At least 73 records · Page 4Linked to original sources
PubMed1988

Activation of the food-derived mutagen 2-amino-3-methylimidazo[4, 5-f]quinoline by human-liver microsomes.

The ability of human-liver microsomes to metabolically activate the food-derived heterocyclic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), and the model mutagen, 2-aminofluorene (AF), has been investigated using Salmonella typhimurium TA98. In 6 subjects tested the number of revertants produced by 0.1 micrograms IQ per mg microsomal protein varied from 11, 830 +/- 320 to 42, 830 +/- 290 (mean +/- SD). With the same livers and a dose of 10 micrograms AF per plate the number of revertants varied from 15,770 +/- 1600 to 29,380 +/- 810 per mg microsomal protein. Metyrapone and alpha-naphthoflavone caused differential inhibition of the mutagenesis of both IQ and AF indicating the involvement of different forms of cytochrome P450 in the metabolic activation of these amines in human-liver microsomes. In presence of human-liver microsomes IQ produced no detectable increase in mutations at the hypoxanthine phosphoribosyl transferase locus in lymphocytes and caused no increase in micronuclei formation at realistic exposure levels.

Benzoflavones↗
PubMed1988

Selective inhibitory effects of nifedipine and verapamil on oxidative metabolism: effects on theophylline.

Nine healthy male volunteers were studied to assess the possibility of an interaction between theophylline and nifedipine or verapamil using a randomised, crossover design. Subjects received theophylline 125 mg 8 hourly with and without nifedipine 20 mg 12 hourly and verapamil 80 mg 8 hourly. Nifedipine treatment reduced mean total theophylline clearance by 9%, due to decreased clearances via 1- and 3-demethylation. Verapamil treatment reduced mean total theophylline clearance by 14%, due to decreased clearances via 1- and 3-demethylation and 8-hydroxylation. Verapamil and nifedipine at usual clinical doses are unlikely to cause clinically significant changes in theophylline disposition.

Adolescent↗
PubMed1988

Identification and quantitation in human liver of cytochromes P-450 analogous to rabbit cytochromes P-450 forms 4 and 6.

1. Polyclonal antibodies raised against rabbit liver cytochrome P-450 isozymes form 4 and 6 have been used to probe human liver microsomes for analogous proteins using the Western blot technique. 2. Anti-Form 4 IgG recognized a protein in human liver microsomes from six subjects of identical molecular weight to purified rabbit liver cytochrome P-450 Form 4. 3. The equivalent content of cytochrome P-450 Form 4 in the same microsomes ranged from 1.1 to 9.1 pmol per mg protein. 4. Anti-Form 6 IgG recognized a protein in human liver microsomes from the same six subjects of slightly higher molecular weight than purified rabbit cytochrome P-450 Form 6. 5. The equivalent content of cytochrome P-450 Form 6 in the above microsomes ranged from 1.6 to 3.8 pmol per mg protein. 6. No significant correlations were observed between equivalent cytochrome P-450 Forms 4 and 6 content and 2-acetylaminofluorene N-hydroxylase, aminopyrine N-demethylase, benzyprene and aniline hydroxylase activities in liver microsomes from the six subjects tested.

Adolescent↗
PubMed1987

Specificity of the inhibitory effect of dextropropoxyphene on oxidative drug metabolism in man: effects on theophylline and tolbutamide disposition.

Two groups of six healthy male volunteers were studied to assess the possibility of an interaction between dextropropoxyphene and theophylline or tolbutamide using a randomised, crossover design. Subjects received theophylline 125 mg 8 hourly or tolbutamide 500 mg i.v. with and without dextropropoxyphene hydrochloride 65 mg 8 hourly. Theophylline 8-hydroxylation was reduced by a mean of 17% but there were no changes in theophylline 1-demethylation, theophylline 3-demethylation or tolbutamide hydroxylation.

Adult↗
PubMed1987

Characterisation of theophylline metabolism in human liver microsomes.

1. A radiometric high performance liquid chromatographic method is described for the assay of theophylline metabolism in vitro by the microsomal fraction of human liver. 2. Formation of the three metabolites of theophylline (3-methylxanthine, 1-methylxanthine and 1,3-dimethyluric acid) were linear with protein concentrations to 4 mg ml-1 and with incubation times up to 180 min. 3. The coefficients of variation for the formation of 3-methylxanthine, 1-methylxanthine and 1,3-dimethyluric acid were 1.2%, 1% and 1.6%, respectively. 4. Theophylline is metabolised by microsomal enzymes with a requirement for NADPH. 5. The mean (n = 7) Km values for 1-demethylation, 3-demethylation and 8-hydroxylation were 545, 630 and 788 microM, respectively, and the mean Vmax values were 2.65, 2.84 and 11.23 pmol min-1 mg-1, respectively. 6. There was a high correlation between the Km and Vmax values for the two demethylation pathways suggesting that the demethylations are performed by the same enzyme. 7. Overall the in vitro studies are consistent with the in vivo results which suggest the involvement of two cytochrome P-450 isozymes in the metabolism of theophylline.

Adolescent↗
PubMed1986

Paracetamol metabolism in pregnancy.

Paracetamol disposition was studied in groups of pregnant and non-pregnant women of comparable age. Paracetamol apparent oral clearance was 58% higher and elimination half-life was 28% lower in the pregnant women compared to the control group. The higher clearance in the pregnant women was due to increased activity of the glucuronidation (75% higher) and oxidative (88% higher) pathways of paracetamol metabolism. There was no difference between the two groups in paracetamol sulphation or renal clearance of unchanged drug.

Acetaminophen↗
PubMed1986

Influence of gender and oral contraceptive steroids on the metabolism of salicylic acid and acetylsalicylic acid.

Salicylic acid and acetylsalicylic acid (aspirin) disposition after an oral dose of aspirin, 900 mg (equivalent to 689.7 mg of salicylic acid) was studied in eight males, eight females and eight females receiving oral contraceptive steroids (OCS). Salicylic acid clearance was 61% higher in males compared to the control female group, an effect due largely to enhanced activity of the glycine conjugation pathway (salicyluric acid formation) in males. Salicylic acid clearance was 41% higher in OCS-users compared to the control female group due to increases in both the glycine and glucuronic acid conjugation pathways in the pill users. There was no difference in any salicylic acid disposition parameter between males and OCS-users. Area under the plasma concentration-time curve (AUC) and elimination half-life of aspirin was significantly greater and aspirin plasma hydrolysis rate was significantly lower in both female groups compared to males. There was no difference between OCS-users and the control female group in any of these parameters. Aspirin AUC and elimination half-life were significantly correlated with aspirin plasma hydrolysis rate. These data confirm the importance of hormonal factors in the regulation of drug conjugation reactions in humans and suggest that sex-related differences in salicylic acid and aspirin disposition may be of clinical importance.

Adult↗
PubMed1986

Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man.

The pharmacokinetics of caffeine (CA), paraxanthine (PX), theobromine (TB) and theophylline (TP) were studied in six healthy male volunteers after oral administration of each compound on separate occasions. The total plasma clearances of CA and PX were similar in value (2.07 and 2.20 ml min-1 kg-1, respectively) as were those for TP and TB (0.93 and 1.20 ml min-1 kg-1, respectively). The unbound plasma clearances of CA and PX were also similar in magnitude (3.11 and 4.14 ml min-1 kg-1, respectively) as were those of TP and TB (1.61 and 1.39 ml min-1 kg-1, respectively). The half-lives of TP and TB (6.2 and 7.2 h, respectively) were significantly longer than those of CA and PX (4.1 and 3.1 h, respectively). The volume of distribution at steady state of TP (0.44 l kg-1) was lower than that of the other methylxanthines (0.63-0.72 l kg-1). The unbound volume of distribution of TP (0.77 l kg-1) was however the same as that of TB (0.79 l kg-1) whereas the unbound volume of distribution of PX (1.18 l kg-1) was similar to that of CA (1.06 l kg-1).

Adult↗
PubMed1986

Quantitative assessment of caffeine partial clearances in man.

Five subjects who participated in an earlier study (Lelo et al., 1986b) of the comparative pharmacokinetics of caffeine (CA) and its primary monodemethylated metabolites paraxanthine (PX), theobromine (TB) and theophylline (TP) were administered CA to steady-state. Using areas under the plasma concentration-time curves for each of the dimethylxanthines derived from CA in the steady-state study and individual plasma clearances of PX, TB and TP determined in the previous study, the fractional conversion of CA to PX, TB and TP and the individual partial clearances of CA have been defined. The mean (+/- s.d.) fractional conversion of CA to PX, TB and TP was 79.6 +/- 21.0%, 10.8 +/- 2.4% and 3.7 +/- 1.3%, respectively. When only demethylation pathways are considered PX, TB and TP accounted for 83.9 +/- 5.4%, 12.1 +/- 4.1% and 4.0 +/- 1.4%, respectively of the CA demethylations. The mean partial clearance of CA to PX was approximately 8-fold and 23-fold greater than those to TB and TP respectively. These data confirm earlier reports that PX is the major metabolite of CA in humans but suggest that PX formation is quantitatively more important than previously believed.

Adult↗
PubMed1985

Compensatory renal hypertrophy after donor nephrectomy.

Renal length was measured radiographically in 65 living kidney donors, aged 27-69 years, who had undergone unilateral nephrectomy during the past 20 years. In 34 of these subjects, pre- and post-operative kidney length, glomerular filtration rate (GFR) and blood pressure were available for analysis. Male donors developed greater compensatory hypertrophy than female donors. The extent of renal enlargement correlated negatively with the age of the subject at the time of nephrectomy and with the current mean arterial blood pressure. However, no correlation was found between the percentage change in renal length and either GFR or time since nephrectomy.

Adult↗
PubMed1985

The effect of ranitidine on the disposition of lignocaine.

The effect of pretreatment with ranitidine (150 mg twice daily for 5 days) on the disposition of lignocaine was examined in 10 healthy volunteers (five male, five female). Each subject received separate oral (250 mg) and intravenous (1.5 mg/kg) doses of lignocaine hydrochloride before and after ranitidine. Lignocaine systemic clearance was reduced by 9% (1.11 to 0.99 1 h-1 kg-1; P less than 0.01) following ranitidine pretreatment. The volume of distribution at steady-state was reduced by 15% (3.34 to 2.85 1 kg-1; P less than 0.005). Lignocaine oral clearance, elimination half-life and oral bioavailability were unchanged after ranitidine pretreatment. There was no sex difference in the effects of ranitidine pretreatment on lignocaine disposition. These results are consistent with small reductions in blood flow to the splanchnic and other vascular beds due to ranitidine.

Adolescent↗
PubMed1985

Selectivity and dose-dependency of the inhibitory effect of propranolol on theophylline metabolism in man.

The effects of separate 5 day pretreatments of propranolol 120 mg day-1 and 720 mg day-1 on theophylline clearance and metabolism at steady-state were determined in seven healthy males. Propranolol 120 mg day-1 decreased theophylline plasma clearance (CL) by 30%. Clearance of theophylline to each metabolite was reduced by this treatment, clearances to the two demethylated products by 42-43% and clearance to the 8-hydroxylation product by 27%. Propranolol 720 mg day-1 decreased theophylline CL by 52%. Again, clearance of theophylline to each metabolite was reduced by this treatment, clearances to the two demethylation products by 73-77% and clearance to the 8-hydroxylation product by 44%. These data are consistent with a dose-dependent and selective inhibitory effect of propranolol on the separate forms of cytochrome P-450 involved in theophylline demethylation and 8-hydroxylation.

Adult↗
PubMed1985

Cortisol does not inhibit prednisolone clearance.

The disposition of prednisolone has been studied in eight male subjects with and without the concomitant administration of cortisol which produced plasma cortisol concentrations 10-fold higher than endogenous levels. The clearance and steady-state distribution volume of total prednisolone were increased as was the prednisolone free fraction but the clearance of unbound prednisolone was unaltered by cortisol co-administration.

Adult↗
PubMed1984

Gender and oral contraceptive steroids as determinants of drug glucuronidation: effects on clofibric acid elimination.

The disposition of clofibric acid, a drug metabolised largely by glucuronidation, was studied in eight males, eight females and eight females receiving oral contraceptive steroids (OCS). Clofibric acid plasma clearance was not significantly different in males compared to the control female group but was 48% greater (P less than 0.01) in women receiving OCS compared to non-pill using females. This difference was due to an alteration in clofibric acid metabolic clearance as there were no differences between the groups in clofibric acid free fraction. Along with previous data the results suggest that induction of drug glucuronidation by OCS may be of clinical importance, although any sex-related differences are unlikely to be of clinical significance.

Adult↗
PubMed1984

Theophylline-rifampicin interaction: non-selective induction of theophylline metabolic pathways.

The effect of rifampicin pre-treatment (600 mg daily for 6 days) on theophylline disposition at steady state was investigated in six healthy males. Following rifampicin treatment total plasma clearance of theophylline increased by 82%. Theophylline clearance through each metabolic pathway was increased, 1-demethylation by (116 +/- 34%) (mean +/- s.e. mean), 3-demethylation by (91 +/- 16%) and 8-oxidation by (81 +/- 17%). Renal clearance of unchanged drug was not altered. Previous studies have suggested that two forms of cytochrome P-450 are involved in theophylline metabolism, one mediating the N-demethylations and the other 8-oxidation. Thus, unlike the selective inductive effect of rifampicin on antipyrine metabolic pathways, rifampicin does not differentially affect those forms of cytochrome P-450 involved in theophylline metabolism. The extent to which theophylline metabolism is induced by rifampicin is likely to have important clinical consequences.

Adult↗