Evidence of significant absorption of sodium salicylate from urinary bladder of rats

The hypothesis that weakly acidic drugs are reabsorbed from the urinary bladder was tested using adult female Fischer rats. Bladder reabsorption would have direct implications for pharmacokinetic data analysis of compounds with significant renal excretion. Sodium salicylate (SA) undergoes extensive renal excretion in the rat, and was selected as the model compound. Methodology was developed to administer an intravesical dose to a rat via a transurethral catheter. The barrier function and the integrity of the bladder urothelium were examined by light and electron microscopy, and by monitoring leakage of [14C] inulin (MW 5000) and fluorescein (MW 376). Using these methodologies, we found that urothelial integrity was maintained in about 80% of the animals. Animals that showed tissue damage were excluded from the study. In the pharmacokinetic experiments, one group of animals received an i.v. dose of SA (1.5 or 3 mg/kg), the second group received an intravesical dose of 30 mg/kg (approximately 0.3 ml) and the third group received concomitantly an i.v. tracer dose of [14C] SA and an intravesical dose of unlabeled SA (30 mg/kg). The intravesical dose was removed after 90 min. The intravesical administration of SA produced maximal blood concentrations of 10.8 +/- 5.6 micrograms/ml (mean +/- S.D., n = 10) at 90 to 100 min. The fraction of the intravesical dose recovered after 90 min was between 45 and 75%, which indicates an upper limit of 25 to 55% loss by processes including absorption. The bioavailability of the intravesical dose, calculated from the blood data and the clearance of the i.v. doses, was between 4 and 23% and averaged about 13%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical pharmacokinetics of 5-aminolevulinic acid in healthy volunteers and patients at high risk for recurrent bladder cancer

5-Aminolevulinic acid (ALA) is a precursor of protoporphyrin IX (PpIX) that is being evaluated for use in photodiagnosis and phototherapy of malignant and nonmalignant disorders. Previous clinical studies using topical, oral, and intravesical administration have been conducted in attempts to determine the optimal route of administration for ALA. The purpose of these studies was to examine the systemic pharmacokinetics and elimination of ALA, the bioavailability of ALA after oral and intravesical doses, and the factors that affect ALA concentrations in the bladder during intravesical treatment. The disposition of ALA was evaluated in six healthy volunteers receiving single intravenous and oral doses (100 mg) and eight patients at high risk for recurrent bladder cancer receiving an intravesical dose (1.328 g) of ALA. The mean (+/-S.D.) plasma area under the plasma concentration-time curve from time 0 to infinity of PpIX (0.20 +/- 0.11 microg small middle dot h/ml) after intravenous administration of ALA was not significantly different from that observed after oral administration of ALA (0.15 +/- 0.11 microg*h/ml; P = 0.49). ALA terminal half-life was approximately 45 min after intravenous or oral administration. The oral bioavailability of ALA was approximately 60%. After intravesical administration, urine production was largely responsible for decreases in ALA concentration in the bladder, with less than 1% being absorbed into the systemic circulation. In summary, oral and intravenous administration of ALA at these doses results in modest plasma levels of PpIX. Regional administration (i.e., intravesical) of ALA resulted in a significant pharmacokinetic advantage, with urinary bladder being exposed to concentrations approximately 20,000-fold higher than systemic circulation.     

Comparative evaluation of the effects of isradipine and diltiazem on antipyrine and indocyanine green clearances in elderly volunteers

Calcium antagonists have been shown to depress hepatic enzymes and accelerate hepatic blood flow. This study was designed to compare the effects of two calcium antagonists, isradipine and diltiazem, on antipyrine and indocyanine green (ICG) clearances in the elderly. Eighteen elderly subjects (aged 65 to 80 years) received either isradipine (5 mg every 12 hours), diltiazem (90 mg every 8 hours), or placebo (every 12 hours) for 4 days. On the third day after the study treatment, a 0.5 mg/kg dose of ICG was administered. Blood samples were obtained over 20 minutes for HPLC determination of ICG plasma concentrations. Ten minutes later, subjects ingested 1.2 gm antipyrine. Blood samples were obtained over 48 hours for HPLC determination of antipyrine plasma concentrations. Mean +/- SD antipyrine clearance after diltiazem (0.0258 +/- 0.0065 L/hr/kg) was significantly lower than that observed after isradipine (0.0334 +/- 0.0098 L/hr/kg) or placebo (0.0329 +/- 0.0082 L/hr/kg). Antipyrine clearance after isradipine was not significantly different from that after placebo. Mean +/- SD ICG clearances after diltiazem (9.17 +/- 1.35 ml/min/kg) or isradipine (9.57 +/- 1.82 ml/min/kg) were significantly higher than that observed after placebo (8.06 +/- 1.45 ml/min/kg). These findings suggest that diltiazem, but not isradipine, affects hepatic enzyme activity in the elderly. Both agents accelerate ICG clearance, a marker of hepatic blood flow.     

Lymphatic absorption is the primary contributor to the systemic availability of epoetin Alfa following subcutaneous administration to sheep

The contribution of the lymphatics to the absorption and systemic availability of recombinant human epoetin alfa (rHuEPO) following s.c. injection was examined using a cannulated sheep model. Parallel studies were conducted in sheep where a single bolus dose was administered either by i.v. (10, 100, or 1000 IU/kg) or s.c. (400 IU/kg) injection. The first s.c. group served as a control for the calculation of absolute bioavailability. In the second group, the efferent popliteal lymphatic duct was cannulated and peripheral lymph draining the injection site was continuously collected. In the third group, the thoracic duct was cannulated to allow collection of central lymph just prior to entry into the systemic circulation. Blood was periodically sampled from all animals, and concentrations in serum and lymph were determined by enzyme-linked immunosorbent assay. The cumulative amount of rHuEPO recovered in peripheral and central lymph was 83.9 +/- 6.6% and 75.3 +/- 3.9% of the administered dose, respectively, indicating almost complete absorption from the s.c. injection site and minimal clearance during transit through the lymphatic system. After i.v. administration, the systemic clearance of rHuEPO decreased with increasing dose, reflecting capacity-limited elimination kinetics. A pharmacokinetic model was developed to simultaneously fit experimental data for all treatment groups and estimate bioavailability. The direct measurement of >75% of the dose in peripheral and central lymph independently verifies the calculated bioavailability of 87% and demonstrates the major role of the lymphatic route in the overall s.c. bioavailability of rHuEPO after s.c. administration with this animal model.     

Interaction between oral hydralazine and propranolol. I. Changes in absorption, presystemic clearance and splanchnic blood flow

A study was undertaken of propranolol pharmacokinetics in dogs before and after oral coadministration of hydralazine to determine whether interactions described in humans could be reproduced in an animal model. Additionally, physiological parameters considered to be relevant to the pharmacokinetic handling (absorption rate and splanchnic hemodynamics) were studied. Coadministration of oral hydralazine and propranolol in conscious dogs caused an increase in peak plasma concentration ( Cpmax ) and area under the oral plasma concentration-time curve (AUC) of propranolol ( Cpmax = 19.2 +/- 5.8 ng/ml, control; Cpmax = 91.5 +/- 12.8 ng/ml, posthydralazine : AUC = 65.7 +/- 14.6 ng X hr/ml, control; AUC = 152.4 +/- 23.9 ng X hr/ml, posthydralazine : mean +/- S.E.M., n = 5; P less than .01 and P less than .01), without change either in the peak plasma level, time to peak or plasma AUC of [14C] propranolol and metabolites (P greater than .70, P greater than .90 and P greater than .60, respectively) or in urinary recovery (urinary recovery = 39.7 +/- 4.3% dose, control; urinary recovery = 41.8 +/- 6.2% dose, posthydralazine ). When propranolol was administered i.v., hydralazine caused a small (42.3 +/- 18%), but significant (P less than .025), increase in systemic clearance. Oral bioavailability increased from 7.3 +/- 2.1 to 23.6 +/- 5.1% (mean +/- S.E.M., n = 5, P less than .025), hepatic extraction showed correspondingly inverse changes and estimated hepatic blood flow increased from 34.9 +/- 3.8 to 63.3 +/- 10.8 ml/min/kg (P less than .025).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics, oral bioavailability, and metabolic disposition in rats of (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine, a nucleoside analog active against human immunodeficiency virus and hepatitis B virus.

The pharmacokinetics and metabolism of the potent anti-human immunodeficiency virus and anti-hepatitis B virus compound, (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine (FTC), were investigated in male CD rats. Plasma clearance of 10 mg of FTC per kg of body weight was biexponential in rats, with a half-life at alpha phase of 4.7 +/- 1.1 min (mean +/- standard deviation) and a half-life at beta phase of 44 +/- 8.8 min (n = 5). The total body clearance of FTC was 1.8 +/- 0.1 liters/h/kg, and the oral bioavailability was 90% +/- 8%. The volume of distribution at steady state (Vss) was 1.5 +/- 0.1 liters/kg. Increasing the dose to 100 mg/kg slowed clearance to 1.5 +/- 0.2 liters/kg/h, lowered the Vss to 1.2 +/- 0.2 liters/kg, and reduced the oral bioavailability to 65% +/- 15%. FTC in the brains of rats was initially less than 2% of the plasma concentration but increased to 6% by 2 h postdose. Probenecid elevated levels of FTC in plasma as well as in brains but did not alter the brain-to-plasma ratio. The urinary and fecal recoveries of unchanged FTC after a 10-mg/kg intravenous dose were 87% +/- 3% and 5% +/- 1.6%, respectively. After a 10-mg/kg oral dose, respective urinary and fecal recoveries were 70% +/- 2.5% and 25% +/- 1.6%. Two sulfoxides of FTC were observed in the urine, accounting for 0.4% +/- 0.03% and 2.7% +/- 0.2% of the intravenous dose and 0.4% +/- 0.06% and 2.5% +/- 0.3% of the oral dose. Also observed were 5-fluorocytosine, representing 0.4% +/- 0.06% of the intravenous dose and 0.4% +/- 0.07% of the oral dose, and FTC glucuronide, representing 0.7% +/- 0.2% of the oral dose and 0.4% +/- 0.2% of the intravenous dose. Neither deaminated FTC nor 5-fluorouracil was observed in the urine (less than 0.2% of dose). The high oral availability and minimal metabolism of FTC encourage its further preclinical development.     

Ranitidine bioavailability and kinetics in normal male subjects

Ranitidine is a potent histamine H2-receptor blocker that inhibits histamine- and pentagastrin-induced gastric acid secretion. After doses of 100 mg both intravenously and orally ranitidine kinetics and bioavailability were investigated in a single dose two-way crossover study in 12 normal men. Serum concentrations of ranitidine were determined by radioimmunoassay and urine concentrations by an ion-pair HPLC method. Intravenous data were fitted to exponential equations with the computer program NONLIN; model-independent kinetic parameters were calculated. Elimination t 1/2, plasma clearance, renal clearance, hepatic clearance, and volume of distribution for ranitidine after intravenous injection were 2 hr, 10.4 ml/(min X kg), 7.2 ml/(min X kg), 3.1 ml/(min X kg), and 1.82 l/kg, respectively; after oral doses mean t 1/2 was 2.7 hr and mean bioavailability was 52%. The average cumulative urinary excretion of ranitidine as percent of dose was 69.4 +/- 6.1% and 26.7 +/- 7.2% after intravenous and oral doses.     

Kinetics of fenoximone, a new cardiotonic, in healthy subjects

Fenoximone, a new cardiotonic, was given to six healthy men as a single intravenous dose of 1 mg/kg and a single oral dose of 3 mg/kg as solution in a crossover study. Plasma concentrations were monitored for 8 hr and urine was collected for 24 hr. Peak plasma concentrations (Cmax) were reached 30 min after the oral dose. Decay of plasma concentrations was fitted to a mean (+/- SD) elimination t1/2 (t1/2 beta) of 60 +/- 14 min after intravenous injection and 78 +/- 26 min after oral dosing. Mean total body clearance for intravenous dosing was 2062 +/- 846 ml/min, renal clearance (ClR) was 5.3 +/- 2.4 ml/min, and extrapolated volume of distribution was 0.37 +/- 0.26 l/kg. The sulfoxide derivative was detected as the main metabolite. Cmax of the sulfoxide metabolite occurred 10 min after the end of the intravenous infusion and 20 to 60 min after oral dosing. From the decay of the plasma concentrations of the sulfoxide, the t1/2 beta s were calculated as 132 +/- 15 min after intravenous injection and 140 +/- 27 min after oral dosing of fenoximone. ClR of the sulfoxide was 499 +/- 106 ml/min after intravenous injection; 24-hr urinary recovery of the sulfoxide was 75.7% +/- 5.7% after intravenous injection and 64.3% +/- 10.4% after oral dosing. Mean oral bioavailability of fenoximone was 53% (range 44% to 69%).     

Suprapubic bladder drainage versus a transurethral catheter in patients following anterior colporrhaphy

Gynaecological operations for urinary stress incontinence necessitate long-term drainage of the bladder. In this retrospective study 100 patients receiving a conventional indwelling urethral catheter system were compared with 90 patients receiving a transabdominal suprapubic catheter for postoperative bladder drainage. The transurethral catheter was removed 5 days after the operation while the suprapubic catheter was left in place until no residual urine was detected. Patients with suprapubic bladder drainage showed no residual urine two days earlier (8.8 +/- 4.3 versus 10.9 +/- 5.0 days), left the hospital two days earlier (12.3 +/- 3.9 versus 13.9 +/- 4.4 days), and had a lower incidence of urinary tract infections (17% versus 30%) than patients with urethral catheters. In five cases suprapubic catheters had to be removed prematurely because of complications such as pain, persistent haematuria or obstruction of the catheter. Rates of haematuria were similar in both groups. Catheter-related pain was less frequent with suprapubic drainage. The acceptance of the suprapubic system by patients and nursing staff was good, particularly since measurement of the residual urine did not necessitate repeated urethral catheterization. The additional time required for placing the suprapubic catheter postoperatively is by far outweighed by the advantages of this system, such as shorter hospitalization and a lower incidence of urinary tract infections.     

Clinical pharmacokinetics of adefovir in human immunodeficiency virus type 1-infected patients.

The pharmacokinetics and bioavailability of adefovir [9-[2-(phosphonomethoxy)ethyl]adenine] were examined at two dose levels in three phase I/II studies in 28 human immunodeficiency type 1-infected patients. The concentrations of adefovir in serum following the intravenous infusion of 1.0 or 3.0 mg/kg of body weight were dose proportional and declined biexponentially, with an overall mean +/- standard deviation terminal half-life of 1.6 +/- 0.5 h (n = 28). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 12 h, and more than 98% was recovered by 24 h postdosing. The overall mean +/- standard deviation total serum clearance of the drug (223 +/- 53 ml/h/kg; n = 25) approximated the renal clearance (205 +/- 78 ml/h/kg; n = 20), which was significantly higher (P < 0.01) than the baseline creatinine clearance in the same patients (88 +/- 18 ml/h/kg; n = 25). Since adefovir is essentially completely unbound in plasma or serum, these data indicate that active tubular secretion accounted for approximately 60% of the clearance of adefovir. The steady-state volume of distribution of adefovir (418 +/- 76 ml/kg; n = 28) suggests that the drug was distributed in total body water. Repeated daily dosing with adefovir at 1.0 mg/kg/day (n = 8) and 3.0 mg/kg/day (n = 4) for 22 days did not significantly alter the pharmacokinetics of the drug; there was no evidence of accumulation. The oral bioavailability of adefovir at a 3.0-mg/kg dose was < 12% (n = 5) on the basis of the concentrations in serum or 16.4% +/- 16.0% on the basis of urinary recovery. The subcutaneous bioavailability of adefovir at a 3.0-mg/kg dose was 102% +/- 8.3% (n = 5) on the basis of concentrations in serum or 84.8% +/- 28.5% on the basis of urinary recovery. These data are consistent with preclinical observations in various species.     

Renal secretion of phenolsulfonphthalein: analysis of its vectorial transport in normal and mutant analbuminemic rats

Transtubular transport of many organic anions, such as p-aminohippuric acid and phenolsulfonphthalein (PSP), from plasma into urine is an important renal function. Most of these nephrophilic ligands strongly bind to albumin in the circulation. To investigate a possible function of plasma albumin in vectorial transport of these organic anions, plasma clearance and urinary excretion of PSP, on one hand, and its interaction with serum proteins, on the other, were studied in normal and mutant Nagase analbuminemic rats (NAR). Intravenously administered PSP rapidly disappeared from the circulation, followed by its urinary excretion in both NAR and normal rats. However, its plasma clearance was significantly larger in NAR (53.9 ml/min/kg body weight) than in normal animals (4.7 ml/min/kg body weight). Gel exclusion Sephadex G-100 chromatography and ultrafiltration analysis revealed that the PSP binding capacity of serum proteins was considerably lower in NAR than in normal rats; 32.0% and 12.5% of the ligand bound to NAR serum protein and 94.4% and 84.2% to normal rat serum protein (predominantly albumin) at 0.1 and 0.5 mmol/L ligand concentrations, respectively. Despite the greater PSP clearance in NAR, its urinary excretion was lower in NAR than in the normal animals; 20.9% +/- 2.5% and 46.0% +/- 12.6% of the administered dose appeared in NAR and normal rat urine, respectively, within 3 hours of administration. Injection of PSP with equimolar albumin resulted in a decrease in plasma clearance and an increase in urinary excretion of PSP in NAR; more than 31.4% +/- 3.3% of the injected dose appeared in the urine within 3 hours of administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phencyclidine (PCP) disposition kinetics in dogs as a function of dose and route of administration

Phencyclidine (PCP) disposition kinetics has been examined in dogs as a function of dose and after i.v. and p.o. administration. Intravenous doses ranged from a tracer quantity of [3H]PCP to 5 mg/kg of unlabeled PCP. The elimination half-life of intact PCP was relatively short with harmonic mean values of 2.7, 5.4 and 3.9 hr for the tracer, 1- and 5-mg/kg doses, respectively. In contrast, measurement of total radioactivity gave a much longer half-life (35-52 hr) suggesting slower metabolite elimination. The drug has a large apparent volume of distribution (weighted mean of 20 liters/kg) and a systemic clearance (which is primarily metabolic) that approaches estimates of liver blood flow in the dog. Renal clearance of intact PCP represents a small fraction of total clearance. Percentage of the [3H]PCP dose recovered as total radioactivity was 49% in urine and 12% in feces. Several metabolites of PCP were determined in urine and they account for about 30% of the dose with the aminopentanoic acid derivative being present in the greatest amount. One of the hydroxylated metabolites is present in cis- and trans-forms, with the latter predominating. Three animals received an i.v. dose of [3H] PCP and a p.o. dose of unlabeled PCP at the same time to determine absolute bioavailability. Approximately 25% of the dose is absorbed intact. The p.o. (intrinsic) clearance of PCP is about four times greater than systemic clearance suggesting a blood flow-dependence in clearance and substantial first-pass hepatic metabolism.     

Transplacental pharmacokinetics of dideoxyinosine in pigtailed macaques.

To determine whether dideoxyinosine is actively transported across the placenta, four pregnant macques (Macaca nemestrina) near term and their fetuses were infused intravenously in random order with simultaneous doses of dideoxyinosine (42.5 micrograms/min/kg of body weight) and antipyrine (41.7 micrograms/min/kg) for 30 h. The infusions took place after the dams had been chronically catheterized at 128 +/- 0.8 days of gestation. In a third infusion, the dams alone received a higher dosage of dideoxyinosine (425 micrograms/min/kg) and the same dosage of antipyrine (41.7 micrograms/min/kg). Samples of maternal and fetal blood and amniotic fluid were collected at intervals for up to 30 h. The concentrations of dideoxyinosine and antipyrine were determined by high-performance liquid chromatography. The transplacental maternal-fetal drug clearances were compared by the paired Student's t test. The ratio (mean +/- standard deviation) of the steady-state plasma dideoxyinosine concentration in the fetus to that in the dam was 0.49 +/- 0.10 at the low dideoxyinosine infusion rate and 0.51 +/- 0.00 at the high dideoxyinosine infusion rate. The clearance associated with maternal-fetal transfer of the drug, CLdf (0.38 +/- 0.21 ml/min/kg), was not significantly different (P > 0.05) from the clearance associated with fetal-maternal transfer of the drug, CLfd (0.56 +/- 0.27 ml/min/kg). Also, CLdf was not significantly different (P > 0.05) from CLfd when normalized with respect to the corresponding transplacental clearance of antipyrine (0.07 +/- 0.04 CLdf versus 0.09 +/- 0.04 CLfd). ur data indicate that passage of dideoxyinosine across the placenta in pregnant M. nemestrina near term is passive and constant over the dosage range studied.     

Pharmacokinetics of intramuscular amopyroquin in healthy subjects and determination of a therapeutic regimen for Plasmodium falciparum malaria.

The disposition of amopyroquin was investigated in 10 healthy volunteers after a single 2-mg/kg (body weight) intramuscular dose of amopyroquin base. The major form of the drug in plasma and in whole blood was nonmetabolized amopyroquin, and only very low levels of its primary amine derivative were detected. After a rapid absorption phase (15 min), levels in plasma declined, following a tri-exponential model with a terminal elimination half-life of 129.6 +/- 92.5 h. The apparent volume of distribution (V/F) and the systemic clearance (CL/F) were 238 +/- 75 liters/kg and 2,063 +/- 1,159 ml/min, respectively. The renal clearance, calculated by using urine excreted during the first 48 h, was 119 +/- 99 ml/min and represented about 6% of the systemic clearance. About 1.2 and 0.2% of the amopyroquin dose was excreted in the urine during the first 48 h as nonmetabolized amopyroquin and its primary amine metabolite, respectively. Twenty-two Plasmodium falciparum malaria patients were studied after treatment with one of the following regimens of intramuscularly injected amopyroquin base: 3 mg/kg (body weight), 6 mg/kg, or 6 mg/kg followed by 3 mg/kg 24 h later. Parasitemia was cleared at day 7 in one of six, four of seven, and seven of nine patients, respectively. On the basis of this study, a regimen of 12 mg/kg (body weight) administered in two or three injections is suggested.     

In vivo maternal-fetal pharmacokinetics of stavudine (2',3'-didehydro-3'-deoxythymidine) in pigtailed macaques (Macaca nemestrina).

To determine whether stavudine (2',3'-didehydro-3'-deoxythymidine) is actively transported in vivo across the placenta and to determine the extent of its transfer, stavudine was administered as an intravenous bolus to four near-term macaques (Macaca nemestrina) (5 mg/kg of body weight via the femoral vein) or to their fetuses (10 mg/kg via the carorid artery) at gestational age 134 +/- 5 days, with the administrations about 1 week apart. Antipyrine (a passive diffusion marker) was always coadministered (20 mg/kg) with stavudine. Samples of maternal and fetal plasma and amniotic fluid were collected at frequent intervals up to 240 min after the dose. In a separate experiment, three animals received stavudine for 30 h at a low rate of infusion (22 micrograms/min/kg via the femoral vein) to the dam or at a 10-fold-higher rate of infusion (220 micrograms/min/kg), separated by at least one week, in order to determine if the transplacental transfer of stavudine is saturable. Antipyrine (41.7 micrograms/min/kg) was coinfused with stavudine. Samples of maternal and fetal plasma and amniotic fluid were collected at regular intervals for up to 30 h. The concentrations of stavudine and antipyrine were determined by high-performance liquid chromatography. The transplacental maternal-fetal drug clearances were compared by the paired Student t test. The clearance associated with maternal-fetal transfer of the drug (CLdf) (0.54 +/- 0.08 ml/min/kg) was not significantly different (P > 0.05) from the clearance associated with fetal-maternal transfer of the drug, CLfd (0.66 +/- 0.11 ml/min/kg). Also, CLdf was not significantly different (P > 0.05) from CLfd when normalized with respect to the corresponding transplacental clearance of antipyrine (0.23 +/- 0.04 versus 0.36 +/- 0.25). The ratios of the steady-state plasma stavudine concentration in the fetus to that in the dam were 0.77 +/- 0.06 at the low stavudine infusion rate and 0.81 +/- 0.09 at the high stavudine infusion rate. The obtained data indicate that transfer of stavudine across the placenta is passive and constant over the dose range studied.     

Diltiazem treatment impairs hepatic drug oxidation: studies of antipyrine

To evaluate the effect of diltiazem on antipyrine disposition and metabolism, 10 healthy subjects received 1.2 gm antipyrine on two occasions, once while taking no other medications and once during long-term oral diltiazem, 120 mg three times daily. Antipyrine oral clearance was markedly reduced from (mean +/- SEM) 41.7 +/- 4.1 to 29.9 +/- 2.8 ml/min (P less than 0.01) during diltiazem treatment, resulting in prolongation of antipyrine elimination t1/2 from 12.2 +/- 1.0 to 16.7 +/- 1.3 hours (P less than 0.01), with no change in apparent volume of distribution (42.1 +/- 4.0 vs. 41.3 +/- 3.1 L; not significant). Measurement of urinary antipyrine and metabolites excreted in the urine during 24 hours after the antipyrine dose (percent of total 24-hour excretion) showed increased antipyrine (4.4% +/- 1.0% vs. 7.8% +/- 1.6%; P less than 0.01) during diltiazem treatment with no significant change in proportion of 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine excretion between trials. Chronic oral diltiazem in therapeutic doses markedly impairs antipyrine oxidation. Diltiazem may therefore impair the clearance of other coadministered drugs that undergo hepatic oxidation.     

早期系统护理干预对宫颈癌术后留置尿管时间的研究

目的 通过对宫颈癌患者进行早期系统护理干预,促进膀胱功能的恢复,从而提前拔除留置的尿管,减少膀胱功能障碍的发生.方法 将80例宫颈癌行子宫广泛切除术患者随机分成治疗组和对照组各40例,治疗组采用系统护理干预(心理护理、盆底肌肉训练、排尿中断训练、腹肌训练、Valsalva屏气法及Crede手压法、定时开放结合个体化放尿、热滚动按摩疗法),对照组采用常规护理加上一些简单的膀胱功能训练.比较2组术后留置尿管的时间.结果 治疗组留置尿管的时间为(9.65±1.49)d.对照组的时间为(15.88±4.03)d,有显著差异,术后残余尿、尿潴留及泌尿系统感染发生均低于对照组.结论 早期系统的护理干预能有效缩短宫颈癌术后留置尿管的时间,减少膀胱功能障碍的发生,提高宫颈癌患者的手术效果及生活质量.     

Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone

BACKGROUND: The disposition of the long-acting opioid methadone, used to prevent opiate withdrawal and treat short- and long-lasting pain, is highly variable. Methadone undergoes N -demethylation to the primary metabolite 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium (EDDP), catalyzed in vitro by intestinal, hepatic, and expressed cytochrome P450 (CYP) 3A4. However, the role of CYP3A4 in human methadone disposition in vivo is unclear.This investigation tested the hypothesis that CYP3A induction (or inhibition) would increase (or decrease) methadone metabolism and clearance in humans. METHODS: Healthy volunteers were studied in a randomized, balanced, 4-way crossover study. They received intravenous (IV) midazolam (to assess CYP3A4 activity) and then simultaneous oral deuterium-labeled and IV unlabeled methadone after pretreatment with rifampin (INN, rifampicin) (hepatic/intestinal CYP3A induction), troleandomycin (hepatic/intestinal CYP3A inhibition), grapefruit juice (selective intestinal CYP3A inhibition), or nothing. Methadone effects were measured by dark-adapted pupil diameter. CYP isoforms catalyzing methadone metabolism by human liver microsomes and expressed CYPs in vitro were also evaluated. RESULTS: Methadone had high oral bioavailability (70%) and low intestinal (22%) and hepatic (9%) extraction, and there was a significant correlation ( r = 0.94, P <.001) between oral bioavailability and intestinal (but not hepatic) availability. Rifampin decreased bioavailability and oral and IV methadone plasma concentrations and increased IV clearance (4.42 +/- 1.00 mL. kg -1. min -1 versus 1.61 +/- 0.67 mL. kg -1. min -1, P <.05) and oral clearance (8.50 +/- 3.68 mL. kg -1. min -1 versus 2.05 +/- 0.92 mL. kg -1. min -1, P <.05), EDDP/methadone area under the curve (AUC) ratios, EDDP formation clearances, and hepatic extraction (0.27 +/- 0.06 versus 0.09 +/- 0.04, P <.05). Troleandomycin and grapefruit juice decreased the EDDP/methadone AUC ratio after oral methadone (0.17 +/- 0.10 and 0.14 +/- 0.06 versus 0.27 +/- 0.20, P <.05) but not IV methadone and had no effect on methadone plasma concentrations, IV clearance (1.29 +/- 0.41 mL. kg -1. min -1 and 1.48 +/- 0.55 mL. kg -1. min -1 ) or oral clearance (2.05 +/- 1.52 mL. kg -1. min -1 and 1.89 +/- 1.07 mL. kg -1. min -1 ), or other kinetic parameters. There was no correlation between methadone clearance and hepatic CYP3A4 activity. Pupil diameter changes reflected plasma methadone concentrations. In vitro experiments showed a predominant role for both CYP3A4 and CYP2B6 in liver microsomal methadone N -demethylation. CONCLUSION: First-pass intestinal metabolism is a determinant of methadone bioavailability. Intestinal and hepatic CYP3A activity only slightly affects human methadone N -demethylation but has no significant effect on methadone concentrations, clearance, or clinical effects. Greater rifampin effects, compared with troleandomycin and grapefruit juice, on methadone disposition suggest a major role for intestinal transporters and for other CYPs, such as CYP2B6. Interindividual variability and drug interactions affecting intestinal transporter and hepatic CYP3A and CYP2B6 activity may alter methadone disposition.     

Decreased Antipyrine Clearance following Endotoxin Administration: In Vivo Evidence of the Role of Nitric Oxide

Klebsiella pneumoniae endotoxin has been found to decrease hepatic P450-mediated drug-metabolizing enzyme activity in a time-dependent manner. In this study, we investigated the role of nitric oxide (NO) in the decrease in hepatic drug-metabolizing enzyme activity caused by endotoxin in vivo. We measured in vivo pharmacokinetic parameters of antipyrine in rats treated with endotoxin and/or a selective inhibitor of inducible NO synthase (iNOS), S-methylisothiourea. Intraperitoneal injection of endotoxin (1 mg/kg of body weight) dramatically decreased the systemic clearance of antipyrine, reflecting reduced hepatic drug-metabolizing enzyme activity, and significantly increased the level of nitrite and nitrate (NOx) in the plasma. S-Methylisothiourea (10 mg/kg) reversed this decreasing antipyrine clearance and reduced the level of NOx in plasma. Repeated injections of an NO donor, (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK-409; 10 mg/kg), at a dose which maintained plasma NOx at the same levels as those caused by endotoxin injection, also decreased the systemic clearance of antipyrine. These findings suggest that the overproduction of NO observed in this animal model is at least partially responsible for the significant reduction in the hepatic drug-metabolizing enzyme activity that may happen in a gram-negative bacterial infection.     

Nonlinear pharmacokinetics of aspirin in rats

Rats are frequently used as an animal model for studies of the antithrombotic action of aspirin. The purpose of this investigation was to explore factors that influence the systemic exposure to unhydrolyzed aspirin after oral and systemic administration of the drug to adult male Sprague-Dawley rats. The experiments were performed according to a crossover design, and drug concentration measurements were made on whole blood. Intravenous injection and oral administration of aspirin (200 mg/kg) showed that the drug is eliminated rapidly (total clearance approximately 45 ml/min/kg; half-life approximately 8 min), that only about one-fourth of the dose is absorbed intact, and that the systemic availability of the oral dose is highly variable (coefficient of variation approximately 60%). A 40 mg/kg i.v. dose was cleared almost twice as rapidly as a 200 mg/kg i.v. dose. Injection of salicylic acid to yield concentrations similar to those obtained after injection of the large dose of aspirin (approximately 400 mg/l) reduced the total clearance of a 40 mg/kg i.v. dose of aspirin by about one-third, suggesting product inhibition of ester hydrolysis. The systemic availability of aspirin infused into the portal circulation was about 80% over a wide range of infusion rates, showing that presystemic hydrolysis of the drug occurs mainly in the gut. As in humans, absorption of orally administered aspirin affects the exponential decline of aspirin concentrations in blood, resulting in an apparent half-life substantially longer than the actual biologic half-life of the drug after i.v. injection.(ABSTRACT TRUNCATED AT 250 WORDS)