Search PubMed⌕ Search

Biomedical subjects

S D Hall

Publications and source records attributed to S D Hall.

84 records · Page 5Linked to original sources
PubMed1986

Polymorphic metabolism of mephenytoin in man: pharmacokinetic interaction with a co-regulated substrate, mephobarbital.

The simultaneous dosing of two drugs with co-regulated genetic polymorphisms determined by a single cytochrome P-450 isozyme could result in competitive inhibition of metabolism. We investigated this hypothesis in vivo by studying the interaction of mephobarbital and mephenytoin in eight normal subjects with wide variability in S-mephenytoin 4-hydroxylation. Each received oral racemic mephenytoin (100 mg) alone and, on a separate occasion, 1 hour after oral racemic mephobarbital (200 mg). After mephenytoin dosing alone, the 8-hour urinary enantiomeric (R/S) ratio indicated one poor (PM), one intermediate (IM), and six extensive (EM) metabolizers. Total intrinsic clearance of S-mephenytoin varied more than 100-fold, whereas the range for R-mephenytoin was only twofold. The urinary R/S ratio correlated (r = 0.92) with the enantiomeric ratio of the plasma AUCs over the same period, indicating no stereoselectivity in renal clearance. When mephenytoin was taken in the presence of mephobarbital, peak levels and AUC of S-mephenytoin increased while those of the R-enantiomer remained unchanged. Accordingly, the R/S ratios in both plasma and urine were reduced, with the change rank order-related to the control value of the total intrinsic clearance of S-mephenytoin (i.e., greatest in the most extensive EM). Thus the urinary R/S ratio can be used as a measure of the enantiomeric ratio of the plasma concentrations over the same time period of collection. Moreover, this ratio may be used to detect drug interactions that involve the cytochrome P-450 isozyme(s) responsible for the polymorphic 4-hydroxylation of mephenytoin.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1986

Rapid ethanol elimination in patients with type I glycogen storage disease is an adaptive change resulting from recurrent hypoglycemia.

Patients with deficient activity of hepatic glucose-6-phosphatase (glycogen storage disease type I [GSD-I]) have fasting-induced hypoglycemia, lactic acidemia, hyperuricemia, hyperlipidemia, and a markedly increased capacity for ethanol elimination. The mechanism(s) responsible for the rapid ethanol elimination is not known but has been thought to be directly related to the enzyme defect. We postulated however, that the increased elimination of ethanol was an adaptive phenomenon that would revert toward normal with correction of other blood abnormalities by long-term maintenance of normal blood glucose concentration. Six patients were observed before treatment (group A), and four of the six were observed again 3 to 6 months after dietary treatment had normalized all blood abnormalities (group B). Patients received 16 ml/m2 absolute ethanol as a 5% solution in 0.9% sodium chloride over a 20-minute period. The rate of ethanol elimination was significantly greater (P less than 0.03) in group A than in group B (55.1 +/- 11.1 vs. 37.5 +/- 8.6 mg/dl/hr). Changes in lactate level after ethanol were also significant between the two groups (P less than 0.005). Group A showed a decrease from 9.4 +/- 0.5 to 6.4 +/- 0.4 mEq/L, whereas group B showed an increase in lactate level from 2.7 +/- 0.2 to 4.4 +/- 0.64 mEq/L. Ethanol induced no significant change in blood glucose concentration in group A, whereas there was a significant increase (P less than 0.03) in group B from 93 +/- 6 to 123 +/- 9 mg/dl.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1984

A simple system for the investigation of protein binding effects on the renal handling of drugs in an isolated perfused rat kidney preparation.

An isolated perfused rat kidney preparation was developed that allowed drug-protein binding in the perfusate to be varied while maintaining renal function. When applied to digitoxin and frusemide, two drugs highly bound to bovine serum albumin, the fraction of drug unbound could be continuously varied over approximately a 30-fold range.

Animals↗
PubMed1984

Metabolic activation of procarcinogens to genotoxic products in cultured rat liver cells.

A recently established rat liver cell line, RL-12, exhibits an unusually high sensitivity to the genotoxic effects of a number of selected procarcinogens. Significant reductions in cell survival (D37%) and induction of sister chromatid exchanges were obtained with 1 X 10(-9) M benzo[a]pyrene and 2 X 10(-8) M 7,12-dimethylbenz[a]anthracene. This rat liver epithelial cell line may serve as a useful model system to study the metabolic activation of procarcinogens to their ultimate genotoxic form.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Metabolic inversion of (R)-ibuprofen. Epimerization and hydrolysis of ibuprofenyl-coenzyme A.

Ibuprofen [(racemic)2-(4-isobutylphenyl)propionic acid] has been proposed but not directly demonstrated to undergo unidirectional inversion from the (R)- to the (S)-configuration via a coenzyme A (CoA) thioester intermediate. Chemically synthesized (R)- and (S)-ibuprofenyl-CoA, and rat and human liver homogenates were used to investigate the relative rates of ibuprofenyl-CoA epimerization and hydrolysis. Rat whole liver homogenate completely epimerized (R)- or (S)-ibuprofenyl-CoA, whereas hydrolysis of this intermediate occurred at a much slower rate. Rat liver mitochondria was the most efficient at both epimerizing and hydrolyzing ibuprofenyl-CoA, whereas rat liver microsomes hydrolyzed ibuprofenyl-CoA at a rate similar to whole liver homogenate but had very little epimerization activity. Rat liver cytosol was the poorest at hydrolyzing ibuprofenyl-CoA but had substantial epimerization capability. Whole liver homogenate from human tissue was less efficient at epimerizing but as efficient at hydrolyzing ibuprofenyl-CoA as rat whole liver homogenate. No stereoselectivity of either epimerization or hydrolysis was noted for any of the enzyme preparations studied. This study demonstrates that the inversion of (R)-ibuprofen occurs, at least in part, via the epimerization of the metabolic intermediate, ibuprofenyl-CoA, in both rat and human liver tissues.

Animals↗
PubMedDate not supplied

Metabolic inversion of (R)-ibuprofen. Formation of ibuprofenyl-coenzyme A.

Ibuprofen [(racemic)2-(4-isobutylphenyl)propionic acid] undergoes metabolic inversion via formation, epimerization, and hydrolysis of the coenzyme A (CoA) thioester, ibuprofenyl-CoA. In this study, (R)-ibuprofen was incubated with either rat whole liver homogenate, human whole liver homogenate, rat liver mitochondria, or rat liver microsomes, and the formation of ibuprofenyl-CoA measured. Rat whole liver homogenate (Vmax/KM = 0.022 +/- 0.005 ml/min/mg protein) was approximately 4-fold more efficient at forming ibuprofenyl-CoA than human whole liver homogenate (Vmax/KM, = 0.005 +/- 0.004 ml/min/mg protein). Rat liver microsomes (Vmax/KM = 0.047 +/- 0.019 ml/min/mg protein) were approximately 2-fold more efficient than rat whole liver homogenate at forming ibuprofenyl-CoA, whereas rat liver mitochondria (Vmax/KM = 0.027 +/- 0.017 ml/min/mg protein) did not differ from whole liver homogenate. Palmitic (Ki = 0.005 mM) and octanoic acids (Ki = 0.19 mM) were capable of inhibiting ibuprofenyl-CoA formation, whereas propionic acid had no effect, suggesting the possible involvement of both long- and medium-chain fatty acyl-CoA synthetases. Of the xenobiotics tested, only bezafibrate (Ki = 0.85 mM) and (S)-ibuprofen (Ki = 0.095 mM in rats, 0.32 mM in human tissue) were capable of substantially inhibiting ibuprofenyl-CoA formation. Thus, it appears that the metabolic inversion of ibuprofen involves lipid-metabolizing pathways and may be affected by fatty acids or xenobiotics.

Animals↗
PubMedDate not supplied

Variable furosemide absorption and poor predictability of response in elderly patients.

STUDY OBJECTIVES: To determine the between- and within-patient variability of furosemide bioavailability and natriuretic response, and whether four marketed products differ in bioavailability and response. DESIGN: Open-label, crossover study. SETTING: General clinical research center at an academic medical center. PATIENTS: Convenience sample of 17 patients age 65 +/- 6 years receiving diuretics for the treatment of hypertension or congestive heart failure. INTERVENTION: Each patient received each of five furosemide products (one intravenous and four oral tablet formulations) twice in random order for a total of 10 treatments. MEASUREMENTS AND MAIN RESULTS: Measurements included absolute bioavailability using cumulative amounts of urinary furosemide collected over 8 hours after oral versus intravenous dosing, and cumulative amounts of urinary sodium. Extensive between- and within-patient variability in all measured values rendered any differences among the products neither clinically nor statistically significant. Mean (+/-SD) bioavailability was 49 +/- 17% (range 12-112%) and coefficients of variation with different products were from 25-43%. Coefficients of variation for urinary furosemide excretion and urinary sodium excretion were also large, 25-42% and 23-51%, respectively. Multivariate analyses that incorporated between- and within-patient effects failed to reveal differences among the products for bioavailability (F = 1.04, p = 0.403), urinary furosemide excretion (F = 1.09, p = 0.371), or urinary sodium excretion (F = 0.97, p = 0.448). Correlation coefficients were 0.81-0.85 for the rates of sodium and furosemide excretion, and half-maximum response using a sigmoid Emax model did not differ among products. CONCLUSION: Although furosemide concentration in urinary and natriuretic responses showed good correlation, variability in bioavailability considerably affects the drug's excretion into urine. Variability in absorption both among patients and within an individual patient is great and overwhelms any differences in bioavailability among approved furosemide products. Switching from one formulation to another will not likely result in any predictable change in patient response.

Administration, Oral↗