Self-inflating bags versus T-piece resuscitator to deliver sustained inflations in a preterm lamb model.

OBJECTIVE: In neonatal resuscitation, the use of a sustained inflation (SI) may facilitate lung aeration. Previous studies comparing different resuscitation devices have shown that one model of self-inflating bag (SIB) could not deliver an SI. We aimed to compare the delivery of an SI using four SIBs with that of a T-piece. STUDY DESIGN: In intubated preterm lambs, we compared four models of SIB fitted with a positive end expiratory pressure (PEEP) valve to a T-piece using a gas flow of 8 L/min. Four operators aimed to deliver three SIs of 20 cm H2O for 30 s. The study was repeated with the PEEP valve removed and again with no flow. We measured duration of SI, average inflation pressure (IP) and analysed the shape of the pressure curves. RESULTS: 204 combinations were analysed. Mean (SD) duration of SI was Ambu 6(2)s, Laerdal 14(8)s, Parker Healthcare 5(1)s, Mayo Healthcare 33(2)s and T-piece 33(1)s. Mean (SD) average IP was Ambu 17(3)cm H2O, Laerdal 17(3)cm H2O, Parker Healthcare 12(5)cm H2O, Mayo Healthcare 21(2)cm H2O and T-piece 20(0)cm H2O. Duration of SI and average IP was significantly different between SIBs (all p<0.001). The findings were substantially unchanged when PEEP valve and flow were removed (all p>0.05). Only the Mayo system delivered SIs with duration and average IP not significantly different from the T-piece (p>0.05). CONCLUSIONS: The performance of the four SIBs tested varied considerably. Some are able to deliver an SI even in the absence of gas flow. This may be useful in a resource-limited setting with no gas supply.

Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: effects of transjugular intrahepatic portosystemic shunts.

Transjugular intrahepatic portosystemic shunt (TIPS) is performed to treat some complications of cirrhosis. This study investigated the effects of cirrhosis and TIPS on intestinal and hepatic cytochrome P450 3A (CYP3A) activity. Nine volunteers were cirrhotic patients with TIPS, 9 were cirrhotic controls (matched for sex, age, etiology, and Child-Pugh class), and 9 were sex- and age-matched healthy volunteers. Simultaneous doses of midazolam were given intravenously (0.05 mg/kg) and orally (3 mg of [15N3]midazolam). Peripheral and portal venous blood samples were assayed for midazolam and [15N3]midazolam. The systemic clearance of midazolam was significantly greater (P <.05) in healthy volunteers (0.42 +/- 0.10 L x h(-1) x kg(-1)) compared with cirrhotic controls (0.20 +/- 0.05) and with cirrhotic patients with TIPS (0.21 +/- 0.09). Hepatic availability followed the same trend. The bioavailability of midazolam was significantly higher (P <.05) in cirrhotic patients with TIPS (0.76 +/- 0.20) compared with cirrhotic controls (0.27 +/- 0.14) and with healthy volunteers (0.30 +/- 0.10). The intestinal availability was significantly greater (P <.05) in cirrhotic patients with TIPS (0.83 +/- 0.17) compared with cirrhotic controls (0.32 +/- 0.16) and with healthy volunteers (0.42+/-0.15). As expected, hepatic CYP3A activity was reduced in cirrhosis. However, in cirrhotic patients with TIPS, there was a marked loss in first-pass metabolism of midazolam as a result of diminished intestinal CYP3A activity.

Histamine N-methyltransferase pharmacogenetics: association of a common functional polymorphism with asthma.

Histamine is involved in the pathophysiology of asthma, and histamine N-methyltransferase (HNMT) plays the dominant role in histamine metabolism in human bronchial epithelium. Levels of HNMT activity in human tissues are controlled, in part, by inheritance. A common C314T polymorphism within the HNMT gene results in a Thr105Ile change in encoded amino acid, and the T314 allele is associated with decreased levels of both HNMT enzymatic activity and immunoreactive protein. Therefore, presence of the T314 allele would be expected to result in reduced histamine metabolism and increased bronchoconstriction. We characterized this common, functionally significant polymorphism in DNA samples from 237 randomly selected Caucasian control subjects and 192 samples from Caucasian asthmatic patients. Allele frequencies for the T314 HNMT allele were 0.08 in the control samples and 0.14 in samples from Caucasian asthmatic patients (odds ratio = 1.9, P < 0.01), indicating a significant increase in the frequency of subjects with low HNMT activity among asthmatics. The association between a common, functionally significant genetic polymorphism for HNMT and asthma suggests that individual variation in histamine metabolism might contribute to the pathophysiology and/or response to therapy of this disease.

Dose-related distribution of codeine and its metabolites into rat hair.

Drugs and endogenous compounds may be incorporated into the matrix of a growing hair shaft. However, the relationship between incorporation and dose or time course of plasma concentrations is poorly defined. The purpose of this study was to compare plasma and hair concentrations of codeine and its metabolites after various doses of codeine. Male Sprague-Dawley rats had a 1" x 1" square shaved from their backs. Codeine was administered by intraperitoneal injection (10, 20, 40, or 60 mg/kg/day) daily for 5 days. Fourteen days after beginning drug administration, the original patch was reshaved and newly grown hair was analyzed for codeine and morphine using GC/MS. The mean concentrations of codeine in hair for the 10, 20, 40, and 60 mg/kg/day groups were 0.29, 0.57, 0.96, and 1.93 ng/mg hair, respectively, and the concentrations of morphine were 0.15, 0.28, 0.49, and 0.79 ng/mg hair, respectively. The plasma concentration time courses for codeine and morphine were determined after single doses of either 20 or 40 mg/kg. Peak plasma codeine concentrations for the 20 and 40 mg/kg groups were 1,441 and 2,452 ng/ml plasma, respectively, and the areas under the plasma concentration vs. time curve were 699 and 1,581 ng-hr/ml, respectively. Morphine glucuronide, but not codeine glucuronide, was measured in the hair of rats administered codeine. Codeine was also administered to rats by constant intravenous infusion (40 mg/kg/day for 5 days). The concentration of codeine in rat hair after this route of administration was 2.92 +/- 0.72 ng/mg hair. Codeine and morphine are incorporated into rat hair in a dose-proportional fashion. Morphine glucuronide can be found in rat hair after codeine administration. The codeine concentration in hair is the same whether the drug is administered by constant intravenous infusion or daily intraperitoneal injections if the areas under the plasma concentration vs. time curve values are considered.

Effect of lipid-free total parenteral nutrition on hepatic drug conjugation in rats.

The effect of total parenteral nutrition (TPN) on drug conjugation in male Sprague-Dawley rats was examined using a nutrition solution composed of amino acids and glucose. The overall disposition of acetaminophen including the formation kinetics of the sulfate and glucuronide metabolites was used as an in vivo probe. Selected drug metabolizing enzyme activities also were examined in vitro. TPN, 200 kcal/kg/day, was administered by continuous i.v. infusion for 14 days and changes elicited were compared to control animals allowed free access to rat chow. TPN decreased the total clearance of acetaminophen by 34% and the formation clearance to acetaminophen sulfate by 47%. The formation clearance of acetaminophen to acetaminophen glucuronide was unaffected by TPN. Cytochrome P450 concentration and oxidative demethylase activity toward p-nitroanisole were decreased in parallel, 47 and 53%, respectively, and UDP-glucuronosyltransferase activity with p-nitrophenol and acetaminophen as the acceptor aglycones was decreased 44 and 25%, respectively in the animals receiving TPN. Sulfotransferase activity toward both p-nitrophenol and acetaminophen decreased 28% in animals receiving TPN vs. ad libitum rat chow. Administration of the parenteral nutrition solution as a continuous enteral infusion via a doudenal catheter slightly decreased p-nitroanisole demethylase activity (26%), but had no other significant effects on either cytochrome P450 concentration or on drug conjugating enzyme activities determined in vitro. These results show that parenteral nutrition administered i.v. depresses drug conjugation and suggest that alterations in both hepatic oxidative and conjugative biotransformation arising from total parenteral nutrition are largely attributable to bypassing the intestinal route for nutrient intake.

The depression of hepatic drug conjugation reactions in rats after lipid-free total parenteral nutrition administered via the portal vein.

BACKGROUND: Total parenteral nutrition provides nutrition support in patients who are unable to eat. Long-term parenteral nutrition is accompanied by alterations in gut and liver function including changes in drug metabolism. This study examined the effects of lipid-free total parenteral nutrition in rats on (1) the overall elimination pharmacokinetics of acetaminophen, (2) changes in sulfation and glucuronidation pathways during acetaminophen elimination, and (3) hepatic drug metabolizing enzyme activities determined in vitro. METHODS: Chronic indwelling catheters were implanted in the aorta, inferior vena cava, and portal vein of adult male Sprague-Dawley rats. Total parenteral nutrition, consisting of 25% dextrose, 5% amino acids, electrolytes, and vitamins, was infused via the portal vein for up to 14 days. Acetaminophen pharmacokinetics were characterized in vivo and selected drug metabolizing enzyme activities were determined in vitro. RESULTS: Parenteral nutrition for 10 days decreased the total clearance of acetaminophen by 23% (from 11.5 +/- 1.4 to 8.9 +/- 1.4 mL/min per kg; p < .05) and decreased the formation clearance to acetaminophen sulfate (from 6.2 +/- 0.4 to 3.9 +/- 0.5 mL/min per kg; p < .05). Parenteral nutrition decreased microsomal cytochrome P450 concentration (47%), p-nitroanisole demethylase activity (68%) and p-nitrophenol UDP-glucuronosyltransferase activity (58%). Cytosolic glutathione-S-transferase activity towards 1-chloro-2,4-dinitrobenzene decreased 29%. Sulfotransferase activity towards p-nitrophenol and acetaminophen was decreased 48% and 25%, respectively. CONCLUSION: Lipid-free, total parenteral nutrition depresses drug conjugative metabolism in rats. The magnitude of this effect in humans remains to be investigated.

Use of N-acetyl cysteine to increase intracellular glutathione during the induction of antitumor responses by IL-2.

IL-2 therapy can induce marked oxidative stress via reactive oxygen and nitrogen intermediates. Glutathione, the major intracellular reductant, may become rate limiting to cytotoxic lymphocyte activation and proliferation under these circumstances. N-Acetyl cysteine (NAc-cys) was used to increase intracellular glutathione levels during lymphokine-activated killer (LAK) cell activation by IL-2. Incubation of splenocytes with NAc-cys (0.6 to 1.0 mM) resulted in significant changes in intracellular reduced and total glutathione (92% and 58% increase, respectively) at 96 h. These levels correlated with markedly enhanced cell proliferation (threefold) and cytolytic effector cell generation (> fivefold increase in LU/10(6) cells) induced by the combination of NAc-cys with IL-2. IL-2 exposure by itself unexpectedly increased intracellular reduced glutathione by 43%. IL-2 and NAc-cys were synergistic in increasing glutathione levels (reduced glutathione: 292% increase; total: 251% increase). Inhibition of glutathione synthesis, using L-buthionine-(S,R)-sulfoximine reversed the effects of NAc-cys on intracellular glutathione, as well as cellular proliferation and cytotoxicity. This experiment established that the effects of NAc-cys required de novo glutathione synthesis. In conjunction with IL-2/LAK treatment, oral NAc-cys administration (260 to 900 mg/kg/day for 7 days) significantly decreased tumor progression in a refractory s.c. tumor model. A small fraction of mice (11 to 17%) had complete tumor regressions. NAc-cys may be useful as an adjunct to increase the antitumor activity of IL-2/LAK therapy.

Acute hepatic and renal toxicity from low doses of acetaminophen in the absence of alcohol abuse or malnutrition: evidence for increased susceptibility to drug toxicity due to cardiopulmonary and renal insufficiency.

A 67-yr-old man with chronic cardiopulmonary disease exhibited severe hepatic and moderately severe renal injury after short-term ingestion of therapeutic doses of acetaminophen (1 to 3 gm/day for 3 days). Drug metabolism and other studies, performed 5 mo after recovery from the acute insult, indicated that the patient had decreased rates of hepatic metabolism of acetaminophen to its primary, nontoxic metabolites and decreased kidney function that was compromised further by acetaminophen ingestion. He also had abnormally low concentrations of hepatic and plasma reduced glutathione. Alcohol abuse and malnutrition could not be implicated in the pathogenesis of injury; rather it appeared that advancing age with chronic renal, cardiac and pulmonary insufficiency contributed to acetaminophen toxicity in this patient.

Plasma concentrations of inorganic sulfate in Alzheimer's disease.

Recent reports have suggested that plasma concentrations of inorganic sulfate may be lower in patients with Alzheimer's disease (AD). We measured sulfate concentrations in 10 patients with AD and found an average concentration of 0.28 mM, which was not significantly different from the mean concentration in age-matched controls (0.32 mM) or young healthy controls (0.27 mM). These results indicate that plasma sulfate concentrations are not altered in AD and that previous reports suggesting altered metabolism of sulfur-containing xenobiotics in neurodegenerative diseases should be reevaluated.

Age-related changes in homeostasis of inorganic sulfate in male F-344 rats.

Advanced age is associated with a decline in renal function including decreased glomerular filtration rate, renal blood flow and renal tubular secretion. Endogenous inorganic sulfate homeostasis is maintained by concentration-dependent active renal reabsorption in the proximal tubule. The purpose of this study was to determine the effects of advanced age on: (1) the renal mechanisms for conserving endogenous inorganic sulfate and (2) the turnover of inorganic sulfate. Awake, male Fischer 344 rats age 4-5 months and 22-23 months received i.v. acetaminophen, 300 mg/kg, followed 2 h later by i.v. sodium sulfate, 2 mmol/kg, to lower and raise, respectively, plasma inorganic sulfate in order to measure the renal clearance of this anion from plasma at sub- and supraphysiologic concentration ranges. Another group of old and young male F-344 rats received a tracer injection of [35S]sodium sulfate to determine the effect of aging on the turnover of the endogenous inorganic sulfate pool. There was no statistically significant effect of advanced age on baseline plasma sulfate concentration or on the renal clearance of inorganic sulfate from plasma. The baseline excretion rate of inorganic sulfate in the senescent animals (0.38 +/- 0.25 mumol/min/kg, mean +/- S.D., n = 7) was significantly (P < 0.05) lower than that observed in the young animals (0.64 +/- 0.19 mumol/min/kg, n = 8). There was no difference in the turnover rate constant, as measured by the change in specific activity of urinary [35S]sodium sulfate, for the endogenous sulfate pool in old and young animals. Following acetaminophen administration, plasma sulfate concentrations declined similarly in young and old animals. Under the conditions of relative inorganic sulfate depletion, the renal excretion rate of inorganic sulfate decreased to zero in 7 of 8 young rats, whereas the old animals continued to excrete sulfate anion at an average rate of 23% of the baseline value. Aged animals have a defect in active tubular renal reabsorption of sulfate under conditions of sulfate depletion. Age-related changes in the total sulfate excretion rate may reflect changes in the metabolic fate of endogenous sulfate rather than changes in the endogenous production rate of this anion.

Intrathecal administration of interleukin-2 for meningeal carcinomatosis due to malignant melanoma: sequential evaluation of intracranial pressure, cerebrospinal fluid cytology, and cytokine induction.

A patient with interleukin (IL)-2 responsive metastatic melanoma developed meningeal carcinomatosis. Treatment was attempted with intrathecal (i.t.) IL-2 (5 weekly doses of 3-6 x 10(6) IU) without glucocorticosteroids. Marked increases in cerebrospinal fluid (CSF) pressure occurred 5-10 h following each IL-2 dose, resulting in reversible abnormalities of neurologic function. IL-2 clearance from the CSF ranged from 21 to 85 ml/h, with an apparent first order rate constant of 0.08-0.23 hr-1. These values were consistent with clearance by bulk flow mechanisms. Clearance also correlated directly with peak CSF pressure. Progressive increases in CSF tumor necrosis factor (TNF)-alpha and IL-6 levels, but not Il-1 alpha, were also noted over successive treatment cycles. Increasing neutrophilia (peaking at 12 h postdose) and a delayed lymphocytosis and monocytosis (at 20-30 h) were observed with each successive i.t. IL-2 dose. Activated lymphocytes were not observed in the CSF, however, suggesting that an exogenous source of activated lymphokine-activated killer (LAK) cells may be helpful in obtaining effective antitumor responses.

Changes in conjugative enzyme activity and acetaminophen metabolism in young and senescent male F-344 rats following prolonged exposure to buthionine sulfoximine.

This study examined how advanced age affects glucuronide and sulfate conjugation of acetaminophen after prolonged exposure to L-buthionine-S,R-sulfoximine (BSO) in male Fischer 344 rats. Young (4-5 month) and senescent (21-22 month) rats received 11 doses of BSO (2 mmol/kg) at 12-h intervals via a gastric cannula. Hepatic metabolism was assessed in vivo by measuring the products of reactions mainly responsible for acetaminophen elimination, namely the formation of the glucuronide and sulfate conjugates. Selected drug-metabolizing enzyme activities were also determined in vitro. BSO treatment increased the partial clearance to acetaminophen glucuronide by 90% and 41% in young and old rats, respectively, and similarly, induced p-nitrophenol and 1-naphthol UDP-glucuronosyl transferase activities to a greater extent in young versus senescent animals. Thus, the induction of these UDP-glucuronosyl transferase activities by BSO is preserved in senescent animals. Although the partial clearance to acetaminophen sulfate was decreased in senescent control rats compared to young controls, BSO treatment decreased the in vivo rate of sulfation in both age groups. Similar to previous findings with the Sprague-Dawley strain, BSO treatment did not induce hepatic cytochrome P-450 content or activity or cytosolic p-nitrophenol sulfotransferase activity in young and senescent Fischer 344 rats.

Dose dependence in the plasma pharmacokinetics and uptake kinetics of 2',3'-dideoxyinosine into brain and cerebrospinal fluid of rats.

Dose dependence in the plasma pharmacokinetics of 2',3'-dideoxyinosine (ddI) was examined during and after 2-hr iv infusions in rats at infusion rates of 12.4, 32.7, and 125 mg/kg/hr. After termination of the infusions, the disappearance of ddI from plasma was distinctly biphasic, suggesting that the majority of ddI is eliminated before distribution equilibrium is achieved. The mean alpha t1/2 following the infusions was 2.7 min and was independent of dose. The mean terminal half-life (beta t1/2) was approximately 24 min and also independent of dose. Nonlinear pharmacokinetic behavior in plasma after infusions was manifested in a decreased clearance with increasing dose, as determined from steady state plasma concentrations of ddI during infusions. In parallel with the decreased clearance, the apparent volume of distribution of the central compartment, Vcapp, decreased with increasing dose. Nonlinearity in clearance with increasing dose could be accounted for using a model which includes rapid, saturable tissue binding. Dose dependence in the kinetics of uptake of ddI into brain tissue and cerebrospinal fluid (CSF) was also examined during and after iv infusions. Steady state concentrations of ddI in brain tissue and CSF varied linearly with steady state plasma concentrations over a plasma concentration range of greater than 30-fold. Mean tissue to plasma concentration ratios, expressed as percentages, were 2% in CSF, 5% in brain tissue, and 1-2% in brain parenchymal tissue (corrected for the contribution of the cerebral vascular space).

Probenecid enhances central nervous system uptake of 2',3'-dideoxyinosine by inhibiting cerebrospinal fluid efflux.

The effects of probenecid on the pharmacokinetics of 2',3'-dideoxyinosine (ddl) and on the distribution of ddl to cerebrospinal fluid (CSF) and brain tissue were determined in rats during and after a 2-hr i.v. infusion of ddl, 125 mg/kg/hr. Probenecid-treated rats received a loading dose of probenecid followed by an i.v. infusion of probenecid initiated 1 hr before and continued during and for 2 hr after termination of the ddl infusion. Plasma concentrations of probenecid averaged 221 +/- 34 micrograms/ml upon termination of the ddl infusion and 258 +/- 34 micrograms/ml (mean +/- S.D., n = 4) 1 hr later. In the probenecid-treated animals, ddl concentrations were higher in plasma (1.5-fold), brain (1.5-fold) and CSF (5.4-fold) at the termination of the ddl infusion and postinfusion concentrations declined more slowly compared to controls. Postinfusion, the CSF/plasma and brain/plasma ratios steadily increased to a greater extent in the probenecid-treated rats compared to control animals. The time course of plasma, CSF and brain tissue concentrations were analyzed by nonlinear least-squares regression using two different compartmental models, one which neglected the direct exchange of drug between the CSF and brain parenchyma, whereas the other allowed for such exchange to occur and neglected direct vascular transfer of drug to brain tissue. Allowing exchange between the CSF and brain tissue gave slightly improved fitting of the data from both probenecid-treated and control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacists and the mandate of pharmaceutical care.

Implementing the mandate for delivery of drug therapy to achieve definite outcomes that improve a patient's quality of life is discussed from the perspective of the changes currently needed in both practice and education. Specifically, changes in practice should include: (1) a managerial framework that continuously supports clinical activities in everyday practice, (2) recognition of competence in clinical practice, and (3) documentation of and reimbursement for clinical service. Changes in education should include: (1) teaching of problem-solving skills to students by faculty/practitioners, and (2) redirecting the curricular content to provide the minimum knowledge base required for competent clinical practice. Pharmacists will begin to accept the mandate of pharmaceutical care when there is widespread training and use of technicians, implementation of problem-based education in the schools, and adequate problem-solving support for pharmacists in practice.

Drug metabolizing enzyme changes after chronic buthionine sulfoximine exposure modify acetaminophen disposition in rats.

This study examined the effects of prolonged exposure to buthionine sulfoximine (BSO) on 1) the overall elimination pharmacokinetics of acetaminophen; 2) the sulfate and glucuronide conjugation processes primarily responsible for acetaminophen elimination; and 3) in vitro microsomal and cytoplasmic enzyme activities in rats. Rats imbibed drinking water containing 30 mM BSO for 6 days and then received an iv injection of acetaminophen, 150 mg/kg in a propylene glycol vehicle. Exposure to BSO, a specific inhibitor of gamma-glutamylcysteine synthetase, produced marked depletion of glutathione (GSH) and resulted in induction of hepatic UDP-glucuronosyltransferase and GSH-S-transferase enzyme activities, but not cytochrome P-450. BSO pretreatment had no effect on the total or renal clearance of acetaminophen in rats. However, BSO exposure increased the partial clearance of acetaminophen to acetaminophen glucuronide by 47% (1.29 +/- 0.08 vs. 1.90 +/- 0.23 ml/min/kg; p less than 0.01) and significantly (p less than 0.02) increased the percentage of the dose recovered as the glucuronide conjugate from 17.6 +/- 2.5 to 26.5 +/- 0.6 The partial clearance of acetaminophen to acetaminophen sulfate was decreased, although not significantly, from 4.46 +/- 0.62 to 3.39 +/- 0.82 ml/min/kg. BSO treatment increased microsomal UDP-glucuronosyltransferase activity toward three xenobiotic aglycones, p-nitrophenol, 1-naphthol, and morphine by 308, 61, and 66%, respectively (p less than 0.05), but not toward testosterone or estrone. Cytosolic GSH-S-transferase activity toward 1-chloro-2,4-dinitrobenzene was increased 52% by BSO, whereas p-nitrophenol sulfotransferase activity was not altered. Cytochrome P-450 concentration and monooxygenase activity were unchanged by BSO exposure.

Effect of advanced age on p-aminohippurate-induced inhibition of renal tubular secretion in male Fischer 344 rats.

The effect of aging on glomerular filtration, effective renal plasma flow and on the responsiveness of the renal tubular anion secretory system to inhibition by 4-aminobenzoylglycine (p-aminohippurate, PAH) was examined in young (5-month) and old (22-month) Fischer 344 male rats. Plasma clearance, protein binding and renal extraction of [131I]o-iodohippurate, [125I]iothalamate and HPLC-purified [99mTc]mercaptoacetyltriglycine (MAG3), were used as in vivo probes of renal function. The effect of advanced age, without concomitant PAH, on the disposition of these markers was initially determined in ketamine anesthetized, temperature-maintained male rats, ages 5, 14 and 22 months by means of constant infusion clearance studies. Aging per se decreased (P less than 0.05) the kidney-weight normalized or body weight-normalized GFR and effective renal plasma flow rates. GFR values averaged 1.67, 1.43 and 1.32 ml/min per g kidney for the 5-, 14- and 22-month-old rats, respectively. Kidney- or body weight-normalized clearances of MAG3 and o-iodohippurate showed similar (25-27%) decreases, whereas the absolute values (ml/min) for GFR, o-iodohippurate and MAG3 clearance rates were not altered by aging. The effective filtration fraction, extraction ratio and plasma protein binding were also unchanged by advanced age. Overall, the age-related decreases in renal function were minimal in Fischer-344 rats, compared to other species. Differences in data normalization, species and gender account, in part, for discrepancies observed when comparing results in different studies on the effects of advanced age on renal function. Subsequently, we examined the effect of aging on the renal responsiveness to inhibition of tubular anion secretion using constant rate PAH infusion studies, adjusted for age-related changes in renal function. Aging did not alter PAH-induced inhibition of iodohippurate secretion. Inhibition of MAG3 elimination was more pronounced in the old rats compared to the young controls.

Effect of aging on hepatic biotransformation in female Fischer 344 rats: changes in sulfotransferase activities are consistent with known gender-related changes in pituitary growth hormone secretion in aging animals.

The effect of aging on hepatic drug conjugation in 5- to 6-, 12- to 13- and 22- to 23-month-old female Fischer 344 rats was examined. The overall disposition of acetaminophen including the formation and elimination kinetics of its sulfate and glucuronide metabolites were used as in vivo probes. The effects of aging on selected in vitro drug metabolizing enzyme activities and on the pattern of phenol and bile salt sulfotransferase isoenzymes were also determined. Aging decreased the total clearance of acetaminophen and the partial clearance of acetaminophen to acetaminophen sulfate by 36 and 47%, respectively. Increasing age also resulted in a reduced partial clearance of acetaminophen to the glucuronide- (24%) and to the glutathione-derived conjugates (29%). UDP glucuronosyltransferase activity toward 1-naphthol, morphine and testosterone was unaffected by advanced age, whereas there was a significant correlation between increased age and increased UDP glucuronosyltransferase activity toward estrone. Cytochrome P-450 concentration and glutathione-S-transferase activity toward 1-chloro-2,4-dinitrobenzene were unchanged by aging. Oxidative demethylase activity toward p-nitroanisole was decreased 18% and sulfotransferase activities toward p-nitrophenol, acetaminophen and glycolithocholate were decreased 27, 12 and 12%, respectively, in the 22- to 23-month-old rats, compared to the 5- to 6-month-old animals. In contrast to the age-related feminization in the pattern of sulfotransferase isoenzyme activities that occurs in male rats, there was no effect of aging on the pattern of phenol and bile salt sulfotransferase isoenzyme activities in female rats.(ABSTRACT TRUNCATED AT 250 WORDS)

New chronic gastric cannula for feeding ethanol liquid diet to young and old rats.

Fifty-eight male Fischer-344 rats ages 5 and 23 mo were fed a liquid diet containing ethanol for 6 wk by means of a newly designed chronic gastric cannula that permitted maximum allowable freedom with minimum stress. Rats were weaned onto the Lieber-DeCarli diet and fed 10 mL three times daily by bolus injection. With or without ethanol, the minimum daily intake of calories necessary to maintain body weight was determined to be approximately 150-160 kcal/kg/day for the young adult rats and 120-125 kcal/kg/day for the aged animals.