Biomedical subjects

D G May

Publications and source records attributed to D G May.

At least 19 recordsLinked to original sources

PubMed1994

Genetic differences in drug disposition.

Genetic polymorphisms of drug metabolizing enzymes are well recognized. This review presents molecular mechanisms, ontogeny and clinical implications of genetically determined intersubject variation in some of these enzymes. Included are the polymorphic enzymes N-acetyl transferase, cytochromes P4502D6 and 2C, which have been well described in humans. Information regarding other Phase I and Phase II polymorphic pathways, such as glutathione and methyl conjugation and alcohol and acetaldehyde oxidation continues to increase and are also discussed. Genetic factors effecting enzyme activity are frequently important determinants of the disposition of drugs and their efficacy and toxicity. In addition, associations between genetic differences in these enzymes and susceptibility to carcinogens and teratogens have been reported. Ultimately, the application of knowledge regarding these genetic factors of enzyme activity may guide medical therapy and minimize xenobiotic-induced disease.

Acetylation↗

PubMed1994

Frequency distribution of dapsone N-hydroxylase, a putative probe for P4503A4 activity, in a white population.

Phenotypic trait values in 166 healthy white subjects (age range, 18 to 88 years) were determined for dapsone N-hydroxylation, dapsone N-acetylation, debrisoquin 4-hydroxylation, and S-mephenytoin 4'-hydroxylation after single oral dose administration of the probe drugs dapsone (100 mg), debrisoquin (10 mg), and mephenytoin (100 mg). No associations or evidence of cosegregation were found between the individual routes of metabolism. Dapsone N-hydroxylation exhibited a unimodal distribution, with marked (tenfold) intersubject variability, and aging was associated with reduced N-oxidation. However, the other measured routes of metabolism were age independent, but intersubject variability in all of the trait measurements increased with age. In subjects younger than 50 years, S-mephenytoin 4'-hydroxylation was modestly (34%) less in men than in women. In contrast, dapsone N-acetylation, dapsone N-hydroxylation, and debrisoquin 4-hydroxylation were not influenced by gender. Previous smoking habit and alcohol consumption were not associated with a difference in any of the four routes of metabolism. Accordingly, the measured phenotypic traits of drug oxidation and N-acetylation appear to be quite robust in regard to some common demographic variabilities present in population studies, with the exception of dapsone N-hydroxylase, which is affected by aging.

Acetylation↗

PubMed1992

The disposition of dapsone in cirrhosis.

Acetylation and N-hydroxylation of dapsone were evaluated in drug-free, non-smoking, normal subjects and subjects with cirrhosis (n = 7 for each group) after oral administration of 100 mg dapsone. Acetylation was not correlated with oral dapsone clearance or reduced in cirrhosis (0.37 +/- 0.43 versus 0.52 +/- 0.32). Fractional metabolic clearance of dapsone to its hydroxylamine was associated with dapsone oral clearance (r = 0.96, p less than 0.001, n = 14). In patients with cirrhosis, liver disease was associated with a trend to reduction in oral clearance (22%) and metabolic clearance of dapsone (48%). Protein binding was minimally reduced by cirrhosis (73% +/- 1% versus 69% +/- 3% in patients with cirrhosis (p less than 0.02). The dapsone recovery ratio was validated as a phenotypic index of the metabolic clearance of dapsone (r = 0.74, p less than 0.05). In an extended comparison of 14 patients with cirrhosis to 70 control subjects, cirrhosis was associated with reductions of 28% in dapsone recovery ratio (p less than 0.001), and 37% in acetylation ratio (p less than 0.01). Neither dapsone recovery ratio nor acetylation ratio correlated with Pugh Score, conventional liver function tests, indocyanine green clearance, or phenotypic measures of S-mephenytoin hydroxylase or debrisoquin hydroxylase activity. We conclude that cirrhosis is associated with minor changes in dapsone disposition and that dosage modification is not required. In addition, there is evidence that cirrhosis has a selective influence on activity of individual isozymes of cytochrome P450.

Acetylation↗

PubMed1992

Cimetidine-carbaryl interaction in humans: evidence for an active metabolite of carbaryl.

The influence of cimetidine on the pharmacokinetic and pharmacodynamic response to the insecticide carbaryl has been investigated in isolated human erythrocytes (red blood cells; RBC) and after oral administration of 1 mg/kg carbaryl to four normal subjects in the absence or presence of cimetidine (300 mg, 8/hr for 3 days). Carbaryl induced a concentration-dependent reduction of isolated RBC acetylcholinesterase activity requiring 1 microgram/ml to achieve 20% inhibition. Cimetidine also induced a dose-dependent inhibition of RBC acetylcholinesterase activity, but at 40-fold higher concentrations. At high concentrations, cimetidine was additive to carbaryl-induced inhibition of RBC acetylcholinesterase, but exhibited no effect at the therapeutically relevant concentrations (10 micrograms/ml). After oral carbaryl administration to normal subjects, plasma concentrations rapidly rose to a peak, then declined with a half-life of 0.79 +/- 0.47 hr. Oral carbaryl clearance was 5.4 +/- 2.0 l/min. Peak plasma carbaryl concentrations were associated with 27% inhibition of RBC acetylcholinesterase activity, and the concentration associated with a reduction of RBC acetylcholinesterase activity of 20% was 0.02 microgram/ml. The terminal half-life for the dynamic response was 2.6 +/- 1.5 hr. After pretreatment with cimetidine, peak plasma carbaryl concentrations doubled and clearance was reduced (to 2.5 +/- 1.5 l/min) (P less than .05). However, half-life remained unchanged. Despite increased carbaryl levels, the maximum inhibition of RBC acetylcholinesterase activity was significantly reduced, and the concentration of carbaryl required to achieve 20% inhibition of RBC acetylcholinesterase activity was increased to approximately 0.5 microgram/ml. These results are consistent with the hypothesis that carbaryl is metabolized by drug-metabolizing enzymes that can be inhibited by cimetidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗

PubMed1990

Scleroderma is associated with differences in individual routes of drug metabolism: a study with dapsone, debrisoquin, and mephenytoin.

Exposure to certain environmental agents may induce a scleroderma-like syndrome in a small proportion of individuals. Differences in susceptibility could involve metabolic activation of a protoxin, with affected patients having a greater converting ability. This possibility was investigated in 84 patients with scleroderma and 108 control subjects with in vivo probes of specific pathways of metabolism. Scleroderma was associated with reduced hydroxylating activity for dapsone and S-mephenytoin, whereas the ability to hydroxylate debrisoquin and N-acetyl dapsone was similar in both groups. Logistic regression confirmed these associations based on the shift in frequency distribution. Individuals who were poor metabolizers for mephenytoin and only modest N-hydroxylators of dapsone had a tenfold increased risk of scleroderma (p = 0.008). Thus this combined metabolic impairment may be causally involved in the development of scleroderma or, alternatively, the disease may produce inhibition of selected metabolizing enzymes in a subset of patients.

Acetylation↗

PubMed1990

The contribution of N-hydroxylation and acetylation to dapsone pharmacokinetics in normal subjects.

The relative importance of N-hydroxylation and acetylation of dapsone to the oral clearance of dapsone (100 mg) was investigated in seven healthy volunteers. Plasma dapsone and monoacetyldapsone concentrations rose rapidly with subsequent similar monoexponential elimination. The oral clearance of dapsone was low (33 +/- 14 ml/min), with a threefold variability. Four subjects were identified as fast acetylators; however, differences in acetylation did not explain the variability in oral clearance. The cumulative urinary recoveries of dapsone and its hydroxylamine were approximately 20% of the dose. The formation clearance of hydroxylamine, which exhibited a tenfold intersubject variability, was closely associated with the oral clearance of dapsone (r = 0.96). Thus, the formation of the hydroxylamine is more important than acetylation in determining dapsone's intersubject variability in oral clearance. Variation in N-hydroxylation may have clinical consequences, because the hydroxylamine is considered to be important in dapsone-mediated toxicity.

Acetylation↗

PubMed1988

Carbaryl metabolism is inhibited by cimetidine in the isolated perfused rat liver and in man.

The potential for cimetidine to alter the metabolism of carbaryl has been investigated in the isolated perfused rat liver and in man. In the isolated perfused rat liver, carbaryl was removed by a high intrinsic clearance process, which was inhibited in a dose dependent fashion by cimetidine in the concentration range of 60-240 micrograms/ml. The pharmacokinetic profile in one subject for orally administered carbaryl was altered following administration of cimetidine (200 mg every eight hours for three days). The peak carbaryl level occurred 25 minutes later and was increased by twofold, due to a 46% reduction in apparent oral clearance. The observations indicate that cimetidine can inhibit the metabolism of carbaryl in both rat and man. These data suggest that administration of cimetidine to individuals exposed to carbaryl could result in enhanced toxicity.

Adult↗

PubMed1987

Vancomycin entry into lung lymph in sheep.

The distribution of antibiotics into target tissues is a crucial factor in therapeutic efficacy. To estimate the availability of systemically administered vancomycin to the interstitial fluid in the lung, we have used a sheep model with a chronic pulmonary lymph fistula to collect simultaneously series of plasma and pulmonary lymph specimens during a 6-h period after an intravenous dose of vancomycin (7 mg/kg). After a minor delay in transit from blood to lymph, vancomycin was completely distributed to pulmonary lymph with a ratio of free drug in lymph to free drug in plasma of 0.9. This suggests that vancomycin is an excellent choice for treating pulmonary infections by susceptible organisms.

Animals↗

PubMed1975

Renal mechanisms for the excretion of nicotinic acid.

Nicotinic acid, an essential endogenous organic acid, was studied in free-flow clearance experiments in the dog at plasma concentrations ranging from 1.2 to 600 mug/ml. At all concentrations, net reabsorption was observed. At concentrations of 1.2 mug/ml, the clearance of nicotinic acid as compared to the clearance of insulin was approximately 0.50. As nicotinic acid plasma concentrations were increased to 90 mug/ml, the clearance ratio declined to 0.22. The clearance ratio then steadily increased to 0.75 as plasma concentrations reached 600 mug/ml. Plasma levels of nicotinic acid in excess of 600 mug/ml resulted in renal toxicity as indicated by a marked decrease in the glomerular filtration rate. The decline in the clearance ratio in the presence of 90 mug/ml of nicotinic acid suggested saturation of a secretory system and hence cyanine 863 and probenecid were used to observe their effects on the clearance ratio. The base transport inhibitor was without effect; probenecid decreased the clearance. Alkalinization of the urine had no noticeable effect on nicotinic acid clearance. Protein binding did not occur. The data indicate two important points. First, nicotinic acid is secreted to a limited degree by the organic anion secretory system and is simultaneously reabsorbed. Second, a homeostatic mechanism for conservation of nicotinic acid at low plasma levels does not seem to exist.

Animals↗

PubMed1972