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Biomedical subjects

R A Branch

Publications and source records attributed to R A Branch.

At least 145 records · Page 8Linked to original sources
PubMed1984

Mephenytoin hydroxylation deficiency in Caucasians: frequency of a new oxidative drug metabolism polymorphism.

The ability of normal subjects to hydroxylate mephenytoin (100 mg) or debrisoquine (10 mg) after oral dosing was investigated in 156 unrelated Caucasians living in middle Tennessee. Urinary recovery of 4-hydroxymephenytoin (4-OH-M) and the urinary S:R enantiomeric ratio of mephenytoin measured in an 8-hr urine sample were investigated as phenotypic traits for mephenytoin, and the urinary metabolic ratio of debrisoquine was used to determine the debrisoquine hydroxylase phenotype. Both urinary 4-OH-M and the S:R ratio of mephenytoin discriminated between extensive (EM) and poor (PM) metabolizers of mephenytoin. The frequencies of PMs for mephenytoin and debrisoquine hydroxylation activity were 2.6% and 7.0%. These two defects in oxidative metabolism were not observed in the same subjects, which suggests that 4-hydroxylation of mephenytoin is a new polymorphism independent of that for debrisoquine.

Administration, Oral↗
PubMed1984

Mephenytoin hydroxylation deficiency: kinetics after repeated doses.

Deficient aromatic hydroxylation of S-mephenytoin was observed in an index subject during a kinetic study of stereoselective metabolism of mephenytoin. A genetic basis for this defect was suggested by decreased urinary recovery of 3-methyl-5-(4-hydroxyphenyl)-5-ethylhydantoin (4-OH-M) in the 24 hr after oral racemic mephenytoin in two brothers of the propositus. The parents and a third brother had urinary recoveries of 4-OH-M of the same order as in a group of 20 normal subjects. The kinetic implications of this defect were studied in the index subject and compared with four normal subjects after a single oral dose of differentially radiolabeled pseudoracemic mephenytoin (5 microCi of 14C-S-mephenytoin, 45 microCi of H3-R-mephenytoin, and 11.5 mumol/kg of both S- and R-mephenytoin) followed by single oral doses of 1.4 mmol of unlabeled racemic mephenytoin daily the next 4 days. In normal subjects, there was substrate stereoselective metabolism with the S-enantiomer rapidly excreted as 4-OH-M and the R-enantiomer slowly excreted as 5-phenyl-5-ethylhydantoin (PEH). Stereoselective metabolism persisted during repeated dosing. In the hydroxylation-deficient subject, there was no evidence of stereoselective metabolism, recovery of 4-OH-M was low, and both enantiomers were slowly excreted, predominantly as PEH. Plasma PEH concentrations and urinary PEH excretion rates were approximately twice that in normal subjects. Thus a genetic deficiency in ability to hydroxylate S-mephenytoin results in the S-enantiomer metabolization by the alternate route of demethylation to PEH that cumulates, thereby, in comparison to the normal, effectively doubling the dose of total hydantoin.

Adult↗
PubMed1984

Enzyme induction and beta-adrenergic receptor blocking drugs.

All beta-adrenergic receptor blockers that require metabolism prior to elimination are potentially subject to drug interactions due to enzyme induction. However, data is only available in man for propranolol, metoprolol and alprenolol. Cross-sectional population studies suggest that environmental factors, such as smoking in the young, are able to influence the oral clearance of propranolol. Long-term studies comparing within-subject clearances of metoprolol, alprenolol and propranolol before and after rifampicin and pentobarbitone, indicate that oral clearance is increased by 50%-500%. Inducing agents can influence intrinsic clearance, liver blood flow, and protein binding in addition to drug metabolising ability, indicating that changes in pharmacokinetic disposition may be complex. Enzyme induction exhibits both dose and time dependency relationships. The maximal extent of enzyme induction is similar between subjects. The range of intersubject variation in drug metabolism is similar before and after induction. The reduction in steady-state beta-adrenergic receptor drug concentration following enzyme induction is sufficiently large that an altered pharmacodynamic response would be expected if no dosage modification is made.

Adolescent↗
PubMed1984

Stereoselectivity of the arene epoxide pathway of mephenytoin hydroxylation in man.

Stereoselective metabolism of mephenytoin has been investigated in four normal subjects by comparing urinary recoveries of hydroxylated metabolites after administration of racemic RS-mephenytoin (1.4 mmol/day) and R-mephenytoin (0.7 mmol/day) on separate occasions. Gas chromatography-mass spectrometry was employed to measure the urinary recovery of 3-methyl-5-(4-hydroxyphenyl)-5-ethylhydantoin (4-OH-M) and mephenytoin catechol, methylcatechol, and dihydrodiol metabolites. Following a single oral dose of racemic mephenytoin, 4-OH-M, mephenytoin catechol, and methylcatechol metabolites were identified in urine mainly as conjugates, whereas the dihydrodiol metabolite was recovered mainly in its unconjugated form. Urinary elimination of each metabolite was similar on days 1 and 10 of chronic racemic mephenytoin administration. Following R-mephenytoin administration, urinary recoveries of hydroxylated metabolites were five to 10 times smaller than after administration of the racemic drug. This implies substrate-stereoselective hydroxylation of the S-enantiomer of mephenytoin. In one subject with a genetic deficiency of aromatic mephenytoin hydroxylation deficiency, the excretion of each hydroxylated mephenytoin metabolite after RS-mephenytoin administration was decreased to 5-15% of the values found in the four extensively hydroxylating study volunteers. The impaired formation of hydroxylated mephenytoin metabolites in genetic hydroxylation deficiency, in conjunction with stereoselective hydroxylation of S-mephenytoin via an extensive NIH shift in normal man, is consistent with the hypothesis that the formation of the S-mephenytoin arene oxide is under genetic control and represents the initial enzymatic reaction of stereoselective aromatic mephenytoin hydroxylation. The formation of this potentially reactive metabolite of S-mephenytoin may have implications in mephenytoin-induced toxicity.

Ethers, Cyclic↗
PubMed1984

Endogenous prostacyclin synthesis is decreased during activation of the renin-angiotensin system in man.

Prostacyclin has been implicated as a mediator of renin release, whereas angiotensin II evokes prostaglandin I2 (PGI2) release from both vascular and nonvascular tissues in vitro. The physiological significance of these observations was assessed by measurement of an index of endogenous prostacyclin biosynthesis in human volunteers during varied activation of the renin-angiotensin system secondary to manipulation of dietary sodium. Excretion of the major urinary metabolite of prostacyclin in man, 2,3-dinor-6-keto-PGF1 alpha (PGI-M), fell from 295 +/- 51 to 176 +/- 35 (+/- SEM) ng g creatinine-1 (P less than 0.01) in 10 normal subjects when sodium intake was decreased from 150 to 10 meq/day. In five patients with primary hyperaldosteronism, PGI-M fell from 199 +/- 34 ng g creatinine-1 preoperatively to 120 +/- 26 pg/mg creatinine-1 after removal of the adenoma. In such patients, the reduction in PGI-M was associated with a significant increase in PRA. Thus, in both normal subjects and patients with hyperaldosteronism, PGI-M excretion fell rather than increased with activation of the renin-angiotensin system. This suggests that systemic biosynthesis of PGI2 is unrelated to renin release and that angiotensin II is unlikely to stimulate endogenous prostacyclin biosynthesis under these conditions in man.

Adenoma↗
PubMed1984

Stereoselective metabolism and pharmacogenetic control of 5-phenyl-5-ethylhydantoin (nirvanol) in humans.

Aromatic hydroxylation of 5-phenyl-5-ethylhydantoin (PEH) has been investigated in humans. Single oral doses of S-PEH (247 mumol) were given to seven extensive and seven poor hydroxylators of mephenytoin. Urinary recovery of PEH and 5-(4-hydroxyphenyl)-5-ethylhydantoin (4-OH-PEH) indicated that all extensive metabolizer subjects excreted appreciable quantities of 4-OH-PEH, whereas all poor metabolizer subjects had only trace amounts of 4-OH-PEH in their urine. Four extensive metabolizer subjects received dual radiolabeled (S-[14C]PEH, R-[3H]PEH) pseudoracemic (494 mumol R-PEH, 494 mumol S-PEH) PEH and had serial urine and blood samples collected over 16 days. The urinary excretion rates of S-PEH and S-4-OH-PEH had half-lives of approximately 4.5 days whereas those of R-PEH and R-4-OH-PEH were approximately 10 days. The initial S/R ratio of 4-OH-PEH in urine was 14:1 whereas that of PEH was 1:1. Stereoselective hydroxylation in these four subjects was confirmed by the negligible recovery of 4-OH-PEH after oral administration of R-PEH (494 mumol). After racemic administration, the sum of S-and R-PEH plasma concentrations declined biexponentially with half-lives of the alpha- and beta-phases being consistent with the total plasma concentration reflecting the sum of the different rates of elimination of the two enantiomers. These results are consistent with the hypothesis that the same drug metabolizing enzymes are involved in the aromatic hydroxylation of S-mephenytoin and S-PEH.

Adolescent↗
PubMed1983

Systemic prostaglandin I2 synthesis is normal in patients with Bartter's syndrome.

Urinary excretion of 2, 3 dinor-6-keto-PGF1 alpha, a metabolite of prostacyclin (PGI2), was measured in 9 patients with Bartter's syndrome. The rate of excretion of this metabolite was normal in these patients during ingestion of both a normal and high dietary intake of potassium. This suggests that in Bartter's syndrome the rate of entry of PGI2 into the circulation is normal. Excessive systemic synthesis of PGI2 is therefore unlikely to be an explanation for either the vascular insensitivity to angiotensin II or the defect in platelet aggregation characteristic of the syndrome.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Effect of aminophylline on renal vasoconstriction produced by amphotericin B in the rat.

Administration of the antifungal agent amphotericin B causes a pronounced reduction in renal blood flow (RBF). Since amphotericin B induced renal vasoconstriction may contribute to the clinical nephrotoxicity of this drug, the purpose of these studies was to investigate the mechanism of amphotericin B induced renal vasoconstriction. To determine if the vascular response to amphotericin B is linked to the intrarenal release of either adenosine or angiotensin II, the effects of aminophylline (5 mumol/kg/min for 10 min followed by 0.5 mumol/kg/min) and saralasin (6 micrograms/min) on the renal vascular response produced by two 10 min intravenous amphotericin B (0.35 mg/kg) infusions were examined. In the control group, amphotericin B decreased RBF 1.7 ml/min (22%, P less than 0.01) and 3.5 ml/min (44%, P less than 0.001) during the 1st and 2nd amphotericin B infusions, respectively. In animals pretreated with aminophylline the decrease in RBF produced by amphotericin B was only 0.4 ml/min (5.5%; N.S.) and 1.3 ml/min (15%, P less than 0.05) during the 1st and 2nd amphotericin B infusions, respectively. In contrast, neither saralasin nor the direct vasodilator sodium nitroprusside (0.4-2 micrograms/min) influenced the renal vascular response to amphotericin B. These data suggest that the renal vascular response to amphotericin B is not linked to the formation of angiotensin II, but rather might be mediated by increases in renal adenosine levels.

Aminophylline↗
PubMed1983

Amphotericin B nephrotoxicity in humans decreased by salt repletion.

A major limitation in the use of amphotericin B is its potential to cause nephrotoxicity. In animals, increased dietary sodium reduces renal toxicity. Experience with five patients in whom impaired renal function developed early during amphotericin B therapy is reported. In four of the patients, there was evidence of sodium depletion due to low sodium intake, diuretic administration, or vomiting. In all five patients, sodium loading was associated with improved renal function, which permitted amphotericin B therapy to be continued in fully effective doses to the completion of elective courses of treatment without evidence of residual impaired renal function. These observations are consistent with the hypothesis that intrarenal regulatory mechanisms contribute to changes in renal function due to amphotericin B therapy.

Aged↗
PubMed1983

Effect of aminophylline on amphotericin B nephrotoxicity in the dog.

The polyene antibiotic, amphotericin B, causes an acute reduction in renal blood flow and glomerular filtration rate. The purpose of this study was to evaluate the hypothesis that the renal vascular response to amphotericin B can be blocked by aminophylline. Toward this end, the effect of aminophylline on the renal response to amphotericin B in sodium-depleted dogs was examined. In dogs not treated with aminophylline, amphotericin B (0.5 mg/kg infused i.v. over 20 min) significantly reduced renal blood flow and glomerular filtration by 49.9 +/- 12.6 ml/min (mean +/- S.E.M.) and 23.4 +/- 2.4 ml/min, respectively at 140 min after the amphotericin B infusion. In dogs treated with an intrarenal aminophylline infusion (5 mg/min), the renal blood flow and glomerular filtration rate response to amphotericin B did not differ from that of amphotericin B vehicle. We conclude that aminophylline inhibits the renal response to amphotericin B. The possible clinical relevance of these observations are discussed.

Aminophylline↗
PubMed1983

Prostaglandin biosynthesis does not participate in hypercapnia-induced cerebral vasodilatation in the dog.

The participation of cerebral prostaglandin biosynthesis in hypercapnia-induced cerebral vasodilation was assessed in pentobarbital-anesthetized dogs using the radioactive microsphere technique. In five dogs, administration of 5% CO2 increased pCO2 from 31.0 +/- 0.8 to 53.4 +/- 2.4 mm Hg (P less than .001) and decreased total cerebral vascular resistance from 11.2 +/- 3.0 to 2.6 +/- 0.6 mm Hg . min . 100 g . ml-1 (P less than .001). The observed increases in pCO2 and the decreases in cerebral vascular resistance during 5% CO2 inhalation were unchanged 1 hr after administration of an i.v. bolus of 0.1 M Na2CO3 (vehicle). In another group of five dogs, 5% CO2 increased pCO2 from 30.4 +/- 0.58 to 55.2 +/- 4.2 mm Hg (P less than .01) and decreased total cerebral vascular resistance from 5.7 +/- 0.6 to 1.8 +/- 0.4 mm Hg . min . 100g . ml-1 (P less than .001). In these dogs, the CO2-induced decrease in cerebral vascular resistance 1 hr after a bolus dose of indomethacin (10 mg/kg i.v.) dissolved in 0.1 M Na2CO3 was also unchanged. In both groups of dogs the patterns described for total cerebral vascular resistance were also observed in the cerebrum, cerebellum and brainstem. The dose of indomethacin used in this study abolished the vasodepressor responses to i.v. arachidonic acid and suppressed the total brain secretion rate of immunoreactive 6-keto-prostaglandin F1 alpha. Furthermore, the administration of 5% CO2 did not increase the total brain secretion rate of immunoreactive 6-keto-prostaglandin F1 alpha. We conclude that cerebral prostaglandin biosynthesis does not mediate or modulate hypercapnia-induced cerebral vasodilation in the dog.

Animals↗
PubMed1983

Periportal localization of lorazepam glucuronidation in the isolated perfused rat liver.

The relative effects of pretreatment with allyl alcohol and carbon tetrachloride on oxidative and glucuronide metabolism of lorazepam have been compared in the isolated perfused rat liver. Livers from rats pretreated for 24 hr with allyl alcohol (1.8 ml/kg, 1:50 solution, to induce pericentral hepatic necrosis), carbon tetrachloride (0.8 mg/kg in corn oil, to induce perivenular hepatic necrosis), or vehicle were perfused with 20% rat blood, 80% Krebs bicarbonate buffer at 20 ml/min. After 300 micrograms of lorazepam had been added to the reservoir, perfusate concentrations of lorazepam were measured in the perfusate at timed intervals. After 180 min, lorazepam and lorazepam glucuronide were measured in perfusate, bile, and liver homogenate. Allyl alcohol and carbon tetrachloride lowered lorazepam clearance by 47% and 77%, respectively. Recovery of lorazepam glucuronide after 180 min was lowered by 35% by treatment with allyl alcohol and increased 73% by treatment with carbon tetrachloride. Glucuronide recovery permitted estimation of fractional glucuronide vs. nonglucuronide clearance. In control rats, glucuronide clearance accounted for 25% of total clearance. Allyl alcohol caused a 64% reduction in glucuronide clearance but only a 39% reduction in nonglucuronide clearance. In contrast, carbon tetrachloride caused a 60% reduction in glucuronide clearance but an 83% reduction in nonglucuronide clearance. The differences in ratios of the changes in glucuronide and nonglucuronide clearance provide further circumstantial evidence that is consistent with the hypothesis of predominant periportal localization of glucuronidation and pericentral localization of oxidative metabolism of lorazepam.

Allyl Compounds↗
PubMed1983

Role of binding in distribution of furosemide: where is nonrenal clearance?

Furosemide is an acidic drug that binds tightly to anionic binding sites on albumin, but has negligible binding to tissue proteins. As a consequence, it has a low volume of distribution of total drug at steady state (Vdss total), which is less than extracellular fluid volume. With decreases in serum albumin concentration, plasma protein binding decreases, total Vdss increases, and Vdss of free drug decreases in a manner that is quantitatively consistent with no change in tissue binding. The elimination of furosemide is partly by renal clearance of unchanged drug (predominantly because of renal tubule secretion) and partly by nonrenal routes. Glucuronidation appears to occur in extrahepatic sites in dogs and, possibly, humans. Residual nonrenal elimination is not influenced by liver disease but is reduced by probenecid pretreatment and uremia. Furthermore, there is appreciable recovery of 35S-labeled furosemide in feces after i.v. administration without the appearance of 35S in the bile. These observations are consistent with the hypothesis of active secretion of furosemide into the gut. The independent variables of distribution and elimination contribute to determine intersubject variability of plasma concentration-time profiles in health and disease and, therefore, are important in determining the extent and duration of diuretic response.

Furosemide↗
PubMed1983

Aminophylline inhibits renal vasoconstriction produced by intrarenal hypertonic saline.

An intrarenal infusion of hypertonic saline to sodium-depleted dogs causes an acute reduction in renal blood flow (RBF) which has been postulated to be due to tubuloglomerular feedback (TGF). Adenosine has been suggested as a mediator of TGF, as adenosine receptor blockade with methylxanthines inhibits TGF. In order to test further the hypothesis that the renal response to hypertonic saline is mediated by TGF, the RBF response to intrarenal hypertonic saline infusions have been investigated in sodium-depleted dogs before and after either an infusion of vehicle or an intrarenal infusion of aminophylline. Aminophylline (2.5 mg/min), at a dose which did not change basal RBF or responses to bolus doses of angiotensin II, inhibited the responses to intrarenal bolus doses of adenosine. In control dogs (n = 5), a 10-min intrarenal infusion of hypertonic saline significantly (P less than .05) reduced RBF both before (-27 +/- 4%) and during (-16 +/- 9%) an infusion with aminophylline vehicle. In a second group of animals (n = 5), an intrarenal hypertonic saline infusion reduced RBF before (-33 +/- 8%; P less than .05), but not during an intrarenal aminophylline infusion (2.5 mg/min). We conclude that aminophylline inhibits the renal vascular response to hypertonic saline and that the renal response to hypertonic saline might be mediated by intrarenal adenosine release.

Adenosine↗
PubMed1982

Prostacyclin production during pregnancy: comparison of production during normal pregnancy and pregnancy complicated by hypertension.

We investigated prostacyclin (PGI2) biosynthesis during pregnancy by measuring urinary excretion of 2,3-dinor-6-keto-prostaglandin F1 alpha (dinor) and 15-keto-13,14-dihydro-2,3-dinor-6-keto-prostaglandin F1 alpha (15 kd dinor) with the use of specific gas chromatography-mass spectrometry assays. Nine normotensive nonpregnant women, five normotensive women in the mid-trimester of pregnancy, eight normotensive women in the third trimester of pregnancy, and six women who developed hypertension during the third trimester provided 24-hour samples of urine. Normal pregnant women had a fivefold increase in urinary excretion of dinor in comparison to nonpregnant women (253 +/- 21 ng dinor/gm creatinine for controls vs. 1,224 +/- 110 and 1,127 +/- 152 for second and third trimesters) (mean +/- SEM). Pregnant subjects with hypertension had a significant (50%) reduction in urinary dinor excretion in comparison to normotensive pregnant subjects (561 +/- 105 ng dinor/gm creatinine). In subjects selected from each group, the ratio of dinor to 15 kd dinor remained constant. We conclude that PGI2 biosynthesis is increased during normal pregnancy, and that this increase is less in pregnancy-induced hypertension. This raises the possibility that PGI2 helps mediate hemodynamic changes during normal pregnancy, and that a relative decrease in production might be related to the pathogenesis of pregnancy-induced hypertension.

Adult↗