Endotoxin depresses hepatic cytochrome P450-mediated drug metabolism in women.

AIMS: In men, the inflammatory response to intravenous endotoxin depresses apparent oral clearances of antipyrine, hexobarbitone, and theophylline. The aim of this study was to investigate whether there might be gender differences in the regulation of hepatic cytochromes P450. METHODS: Experiments were carried out in seven healthy women volunteers (ages 19-51, median 22 years). Each woman received a cocktail of the three drugs on two occasions, once after a saline injection and again after endotoxin. RESULTS: Endotoxin injections, but not saline, caused the expected physiologic responses of inflammation including fever and increases in circulating tumor necrosis factor-alpha, interleukin-6, and C-reactive protein. When compared with the saline control studies, endotoxin significantly decreased clearances of all probes: antipyrine, 31% (95%CI 21%-41%); hexobarbitone, 20% (95%CI 10-31%); and theophylline, 20% (95%CI 10%-30%). The decreases were comparable with those found in the men previously studied (35%, 27%, and 22%, respectively). CONCLUSIONS: These data show that endotoxin-induced inflammation decreases hepatic cytochrome P450-mediated metabolism of selected probe drugs in women as it does in men.

Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism.

In experimental animals, injection of gram-negative endotoxin (LPS) decreases hepatic cytochrome P450-mediated drug metabolism. To evaluate this phenomenon in a human model of gram-negative sepsis, LPS was administered on two consecutive days to healthy male volunteers during which time a cocktail of antipyrine (AP-250 mg), hexobarbital (HB-500 mg), and theophylline (TH-150 mg) was ingested and the apparent oral clearance of each drug determined. Each subject had a control drug clearance study with saline injections. In the first experiment, six subjects received the drug cocktail 0.5 h after the first dose of LPS. In the second experiment, another six subjects received the drug cocktail 0.5 h after the second dose of LPS. In both experiments, LPS caused the expected physiologic responses of inflammation including fever with increases in serum concentrations of TNF alpha, IL-1 beta, IL-6, and acute phase reactants. In the first experiment, only minor decreases in clearances of the probe drugs were observed (7-12%). However in the second experiment, marked decreases in the clearances of AP (35, 95% CI 18-48%), HB (27, 95% CI 14-34%), and TH (22, 95% CI 12-32%) were seen. The decreases in AP clearance correlated with initial peak values of TNF alpha (r = 0.82) and IL-6 (r = 0.86). These data show that in humans the inflammatory response to even a very low dose of LPS significantly decreases hepatic cytochrome P450-mediated drug metabolism and this effect evolves over a 24-h period. It is likely that septic patients with much higher exposures to LPS have more profound inhibition of drug metabolism.

Effects of interferon-alpha monotherapy on hepatic drug metabolism in cancer patients.

1. The influence of interferon-alpha (IFN alpha) on the clearances of theophylline (TH), antipyrine (AP) and hexobarbitone (HB) was studied in seven cancer patients given IFN alpha as their only treatment. In addition, IFN alpha effects on drug clearance were correlated with changes in serum inflammatory cytokines and acute phase proteins. 2. A 'baseline' study was performed by administering an oral drug 'cocktail' of TH (150 mg), AP (250 mg) and HB (250 mg) with saline injected simultaneously and again 24 h later. One week later, an 'acute' study was performed at the initiation of IFN alpha therapy, 3 x 10(6) units injected with the drug cocktail and again 24 h later. After 2 weeks of IFN alpha treatment three times per week, a 'chronic' study was performed with IFN alpha injected the day prior to, simultaneously with, as well as 24 h after the drug cocktail. 3. Plasma samples were collected over 48 h and the clearances of TH, AP and HB were estimated. Serum samples were collected at various times for the measurement of tumor necrosis factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6), C-reactive protein (C-RP) and alpha 1-acid glycoprotein (AGP). 4. IFN alpha caused a 33% decrease in the oral clearance of TH during the chronic study compared with baseline (P < or = 0.05). Although IFN alpha inhibited TH clearance by 16% during the acute study and AP clearance by 20-21% during both acute and chronic studies, these changes did not reach statistical significance. IFN alpha caused minimal changes in HB clearance. There were no chronic effects of IFN alpha on serum cytokines or acute phase proteins. 5. The findings confirm that the most commonly used dose of IFN alpha inhibits the hepatic clearance in humans of some but not all drugs and that this inhibition persists during IFN alpha therapy. Because inhibition was not associated with increases in serum cytokines or acute phase proteins, the mechanism by which IFN alpha inhibits cytochrome P450 activities in vivo does not appear to involve inflammatory mediators such as TNF. IL-1 or IL-6.

Effect of the somatostatin analogue SMS-201-995 on the adrenergic response to glucose ingestion in patients with postprandial hypotension.

PURPOSE: The somatostatin analogue SMS-201-995 has recently been introduced as a new therapy for postprandial hypotension in patients with autonomic neuropathy. The present study was performed to determine the effect of SMS-201-995 on the adrenergic response to glucose ingestion in patients with this disorder. PATIENTS AND METHODS: Eleven patients with postprandial hypotension were studied: six with central autonomic dysfunction (multiple system atrophy) and five with peripheral sympathetic dysfunction (progressive autonomic failure). Patients received either a subcutaneous injection of SMS-201-995 or a placebo injection, immediately before administration of a 50-g glucose drink. Each treatment was given on separate, consecutive days in a randomized fashion. RESULTS: Glucose ingestion caused a decrease in blood pressure (from 82 +/- 6 mm Hg to 66 +/- 7 mm Hg, p less than 0.01) and an increase in plasma norepinephrine level (165 +/- 20 pg/mL to 305 +/- 85 pg/mL, p less than 0.01) in five patients with progressive autonomic failure. Administration of SMS-201-995 prevented both the decline in blood pressure and the increase in norepinephrine. By contrast, glucose ingestion elicited no increase in plasma norepinephrine levels despite profound hypotension (average postprandial mean blood pressure, 55 +/- 3 mm Hg) in six patients with multiple system atrophy. Administration of SMS-201-995 prevented postprandial hypotension in these patients, but had no effect on plasma norepinephrine. CONCLUSION: Our data indicate that the pressor effect of SMS-201-995 is independent of the sympathetic nervous system in patients with multiple system atrophy, but may suppress the adrenergic response to glucose ingestion in patients with progressive autonomic failure.

Treatment of orthostatic hypotension with octreotide.

The purpose of this study was to evaluate the therapeutic potential of the somatostatin analog octreotide in patients with orthostatic hypotension. Octreotide was administered sc, and its pressor effect was assessed while the patients were semirecumbent and on the tilt table. We also studied the effect of octreotide on blood pressure while patients walked. The efficacy of therapy was assessed by measuring the duration of walking (walking time) before the onset of hypotension. Low doses of octreotide (0.2-0.4 micrograms/kg) had a pressor effect in all patients with progressive autonomic failure (n = 7), multiple system atrophy (n = 7), and diabetic autonomic neuropathy (n = 8), but not in patients with sympathotonic orthostatic hypotension (n = 6). Larger doses (0.4-1.6 micrograms/kg) resulted in a sustained (greater than or equal to 50 min) increase in blood pressure during walking in four of six patients with progressive autonomic failure and in one of six patients with multiple system atrophy. Some patients in whom octreotide failed to stabilize upright blood pressure had a satisfactory response to the drug after pretreatment with dihydroergotamine (10 micrograms/kg, sc). Patients with diabetic autonomic neuropathy, although sensitive to the pressor effect of octreotide, often developed nausea or abdominal cramps after moderate doses (greater than 1.0 micrograms/kg). These results indicate that the pressor effect of octreotide is sufficiently potent to prevent orthostatic hypotension in some patients with autonomic neuropathy. Others require treatment with both dihydroergotamine and octreotide to achieve a stable upright blood pressure.

Sympathotonic orthostatic hypotension: a report of four cases.

We describe four patients with sympathotonic orthostatic hypotension, a syndrome in which the decrease in blood pressure associated with standing is accompanied by tachycardia. The patients in this series had experienced either a viral infection or rapid weight loss prior to the onset of their orthostatic intolerance. Vasomotor reflexes and norepinephrine production were normal, and analysis of palmar autonomic surface potentials indicated that the sympathetic innervation of the upper extremities was intact. The amplitudes of the plantar autonomic surface potentials, however, were decreased although still within the normal range. The latencies of plantar autonomic surface potentials were slightly prolonged. Although most autonomic function tests are normal in sympathotonic orthostatic hypotension, mild abnormalities in the plantar autonomic surface potentials may indicate a neuropathy that primarily affects low thoracic or lumbar sympathetic neurons.

Effects of acute and chronic ethanol ingestion on pantothenate and CoA status of rats.

Total coenzyme A (CoA) and pantothenate levels in tissues were compared in three studies in which rats were fed Lieber-DeCarli formula diet with either 5% ethanol or maltose-dextrin (controls) for 19-36 d. The heart pantothenate levels of ethanol-fed rats were 51-78% of that in controls. The heart total CoA levels of ethanol-fed rats were 78-90% of that in controls. Liver total CoA and pantothenate levels were lower in ethanol-fed rats than in controls in one and two studies, respectively. Differences were diminished in rats fasted for 24 h. Control and chronic ethanol-treated rats given no ethanol for 24 h were intubated with [1-14C]pantothenate. Accumulation of radioactive pantothenate in hearts of ethanol-treated rats was 58% and accumulation in livers was 75% of that in controls. An acute effect of ethanol on pantothenate conversion to CoA in liver was found in naive rats intubated with 0.5-2.5 g ethanol/kg body weight and given [1-14C]pantothenate by intubation or intraperitoneal injection. In ethanol-treated rats, conversion of [1-14C]pantothenate to CoA was 4-28% of that in controls. These studies demonstrated an effect of chronic ethanol ingestion on pantothenate and total CoA contents of heart and possibly other tissues and an acute effect of ethanol ingestion on [1-14C]pantothenate conversion to CoA in liver.

Possible role of acetyl-CoA in the inhibition of CoA biosynthesis by ethanol in rats.

Ethanol, both administered to rats in vivo and added to cultured hepatocyte incubations, inhibits the conversion of [14C]pantothenate to coenzyme A (CoA). Data suggesting that the inhibition by ethanol involves its oxidation to acetate were obtained with rat hepatocytes maintained in primary culture. Ethanol, acetaldehyde and acetate were approximately equally effective inhibitors of [14C]pantothenate conversion to CoA (46-71%) and had no effect on uptake of [14C]pantothenate by hepatocytes. In the presence of saturating levels of acetate, acetaldehyde had no additional inhibitory effect. Cyanamide and diethyldithiocarbamate decreased the inhibition by acetaldehyde at the same concentration (10 microM), which saturated their ability to inhibit acetaldehyde oxidation. Studies with an isolated pantothenate kinase preparation showed that, of the ethanol metabolites, only acetyl-CoA was an effective inhibitor. Acetate and butyrate, which were both inhibitors of [14C]pantothenate conversion to CoA, increased the acetyl-CoA and decreased the free, unacylated CoA (CoASH) content of the cultured hepatocytes. The data were consistent with a mechanism for the inhibitory effect of ethanol that involves inhibition of pantothenate kinase by acetyl-CoA, but did not exclude a possible role of additional regulatory factors.