Bioavailability and first-pass metabolism of oral pentazocine in man

The bioavailability of oral pentazocine was studied in 5 healthy volunteers. Plasma concentrations were determined from 30 min up to 6 hr following oral administration (two 50-mg tablets) and, at other occasions, after intravenous injection of 30 mg pentazocine. The average bioavailability was found to be 18.4 +/- 7.8% (SD, n = 5). It is shown that this low bioavailability depend almost entirely on the first-pass metabolism of pentazocine following oral administration by application of intravenous clearance concepts. The average beta-phase half-life was about the same following intravenous administration, 203 +/- 71 (SD, n = 5) min as following oral administration, 177 +/- 34 (SD, n = 5) min, with a total volume of distribution of 5.56 +/- 1.63 (SD, n = 5) L/kg. It is suggested that the variations in bioavailability of orally administered pentazocine have the potential to contribute to variations in pharmacologic effects in patients.     

Pharmacokinetics, oral bioavailability, and metabolism in mice and cynomolgus monkeys of (2'R,5'S-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine, an agent active against human immunodeficiency virus and human hepatitis B virus

(2'R,5'S-)-cis-5-Fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine (524W91) is a nucleoside analog with potent anti-human immunodeficiency virus and anti-human hepatitis B virus activities in vitro. The pharmacokinetics and bioavailability of 524W91 after oral dosing were studied in mice dosed with 10, 100, and 600 mg of 524W91 per kg of body weight by the oral and intravenous routes. Cynomolgus monkeys were dosed with 10 and 80 mg of 524W91 per kg. In both species, the clearance of 524W91 was rapid, via the kidney, and was independent of dose. In monkeys, the total body clearance of 10 mg of 524W91 per kg was 0.7 +/- 0.1 liter/h/kg, and the volume of distribution at steady state was 0.8 +/- 0.02 liter/kg. The terminal elimination half-life was 1.0 +/- 0.2 h. The absolute bioavailability after oral dosing was 63% +/- 4% at 10 mg/kg. Concentrations of 524W91 in the cerebrospinal fluid were 4% +/- 0.7% of the corresponding levels in plasma. In mice, the total clearance of 10 mg of 524W91 per kg was 2.3 liters/kg/h, and the volume of distribution at steady state was 0.9 liter/kg. Absolute bioavailability in mice after oral dosing was 96% at a dose of 10 mg/kg. The metabolism of orally administered [6-3H]524W91 was studied in cynomolgus monkeys at a dose of 80 mg/kg and in mice at a dose of 120 mg/kg. Monkeys excreted 41% +/- 6% of the radioactive dose in the 0- to 72-h urine, 33% +/- 10% in the feces, and 10% +/- 7% in the cage wash. Unchanged 524W91 was 64% of the total radiolabeled drug recovered in the urine. The glucuronide was a minor urinary metabolite. 5-Fluorouracil was not detected (less than 0.02% of the dose). Mice dosed orally with 120 mg of [6-3H]524W91 per kg excreted 67% +/- 7% of the radiolable in the )- to 48-h urine. Small amounts of the 3' -sulfoxide and glucuronide metabolites were observed in the urine, but 5-fluorouracil was not detected. Good bioavailability after oral dosing and resistance to metabolism recommend 524W91 for further preclinical evaluation.     

Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus

This study evaluated the safety, tolerability, and pharmacokinetics of zidovudine administered intravenously and orally to infants born to women infected with the human immunodeficiency virus. Thirty-two symptom-free infants were enrolled before 3 months of age. The pharmacokinetics of zidovudine were evaluated in each infant after single intravenously and orally administered doses of zidovudine on consecutive days, and during long-term oral administration of the drug for 4 to 6 weeks. As new patients were enrolled, doses of zidovudine were progressively increased from 2 to 4 mg/kg. Therapy was continued for up to 12 months in 7 of the infants proved to be infected with human immunodeficiency virus. Zidovudine was generally well tolerated; 20 children (62.5%) had anemia (hemoglobin level < 10.0 gm/dl) during therapy and 9 (28.1%) had neutropenia (neutrophil count < or = 750 cells/mm3); these hematologic abnormalities usually resolved spontaneously. The total body clearance of zidovudine increased significantly with age, from an average of 10.9 ml/min per kilogram in infants < or = 14 days of age to 19.0 ml/min per kilogram in older infants (p < 0.0001). Concurrently, there was a significant decrease in serum half-life from 3.12 hours in infants < or = 14 days to 1.87 hours in older infants (p = 0.0002). Oral absorption was satisfactory and bioavailability decreased significantly with age, from 89% in infants < or = 14 days to 61% in those > 14 days of age (p = 0.0002). Plasma concentrations of zidovudine were calculated to be in excess of 1 mumol/L (0.267 micrograms/ml) for 4.12 +/- 1.86 hours and 2.25 +/- 0.78 hours after oral doses of 2 mg/kg in infants younger than 2 weeks and 3 mg/kg in older infants, respectively. We conclude that zidovudine administered at oral doses of 2 mg/kg every 6 hours to infants aged less than 2 weeks and 3 mg/kg every 6 hours to infants older than 2 weeks resulted in plasma concentrations that are considered virustatic against human immunodeficiency virus. Zidovudine was well tolerated by infants at these doses.     

Ischemic injury of optic nerve axons: the nuts and bolts

The disposition of enrofloxacin was measured after intravenous and oral administration to pigs. Eight clinically healthy pigs weighing 25 to 40 kg received a dose of 5 mg/kg intravenously and 10 mg/kg orally in both a fasted and a fed condition in a three-way cross-over design. Enrofloxacin was present in plasma for up to 72 hr after both intravenous and oral administration to fasted as well as fed pigs. The steady state volume of distribution was determined to 3.9 +/- 0.5 1/kg body weight which indicates that enrofloxacin was widely distributed in the body. The bioavailability was determined to 83 +/- 13% in fed and to 101 +/- 32% in fasted pigs. Based on the bioavailability and the resulting plasma concentrations it is concluded that a therapeutically active concentration for the most common porcine microbial pathogens are maintained for at least 24 hr after oral administration of 10 mg/kg body weight to fasted as well as to fed pigs. Ciprofloxacin which is an active metabolite of enrofloxacin was observed in plasma samples from all treated pigs, but the concentration never exceeded 0.1 microgram/ml. During the first 24 hr after the administration of enrofloxacin the concentration of the metabolite made up less than 10% of the corresponding concentration of the parent compound.     

Absorption, disposition kinetics, and metabolic pathways of cyclohexene oxide in the male Fischer 344 rat and female B6C3F1 mouse

Cyclohexene oxide (CHO) is a monomer intermediate used in the synthesis of pesticides, pharmaceuticals, and perfumes. Although CHO has a variety of industrial uses where direct human exposure is possible, very little is known about its fate in the body. Therefore, the objectives of this study were to determine the absorption, distribution, metabolism, and excretion of cyclohexene oxide after oral, intravenous, and dermal exposure in male Fischer 344 rats and female B6C3F, mice. After intravenous administration of [14C]CHO (50 mg/kg), CHO was rapidly distributed, metabolized, and excreted into the urine. Plasma concentrations of CHO rapidly declined and were below the limit of detection within 60 min. Average (+/- SD) values for terminal disposition half-life, apparent volume of distribution at steady-state, and systemic body clearance were: 19.3 +/- 1.6 min; 0.44 +/- 0.08 liter/kg; and 31.3 +/- 0.5 ml/kg * min, respectively. After oral administration of [14C]CHO (10 and 100 mg/kg), it was found that 14C-equivalents were rapidly excreted in the urine of both species. At 48 hr, the majority of the dose (73-93%) was recovered in urine, whereas fecal elimination accounted for only 2-5% of the dose. At no time after oral administration was parent CHO detected in the blood. However, its primary metabolite cyclohexane-1,2-diol was present for different lengths of time depending on the dose. Four metabolites were detected and identified in mouse urine by MS: cyclohexane-1,2-diol; cyclohexane-1,2-diol-O-glucuronide; N-acetyl-S-(2-hydroxycyclohexyl)-L-cysteine; and cyclohexane-1,2-diol-O-sulfate. The sulfate conjugate was not present in rat urine. Topical application of [14C]CHO (60 mg/kg) provided poor absorption in both species. The majority of 14C-equivalents applied dermally were recovered from the charcoal skin trap (approximately 90% of the dose). Only 4% of the dose was absorbed, and the major route of elimination was via the urine. To evaluate the toxicity of CHO, animals were given daily doses of CHO orally and topically for 28 days. No statistically significant changes in final body weights or relative organ weights were noted in rats or mice treated orally with CHO up to 100 mg/kg or up to 60 mg/kg when given topically. Very few lesions were found at necropsy, and none were considered compound related. In conclusion, regardless of route, CHO is rapidly eliminated and excreted into the urine. Furthermore, after either oral or dermal administration, it is unlikely that CHO reaches the systemic circulation intact due to its rapid metabolism, and is therefore unable to cause toxicity in the whole animal under the test conditions used in this study.     

Evaluation of gentamicin pharmacokinetics and dosing protocols in 195 neonates

Gentamicin pharmacokinetics and dosing protocols in neonates were studied. Demographic and pharmacokinetic data on 202 neonates treated with gentamicin at a 500-bed medical center were collected over a three-year period. Administered doses, gentamicin concentration measurements, and recorded times were used to calculate each patient's clearance, volume of distribution, elimination rate constant, and half-life. The performance of 15 dosing protocols, including 6 previously published ones and 9 developed on the basis of the study, was evaluated using the pharmacokinetic data. Of the 202 patients, 195 were included in the analysis. The mean +/- S.D. clearance, volume of distribution, elimination rate constant, and half-life were 0.047 +/- 0.015 L/hr/kg, 0.45 +/- 0.11 L/kg, 0.107 +/- 0.032 L/hr, and 7.19 +/- 2.64 hours, respectively. Weight, urine output, gestational age, and postconceptional age (PCA) had the highest correlation with the pharmacokinetic values. Blood urea nitrogen concentration (BUN) and Apgar score were poor predictors of the pharmacokinetic values. There were no significant differences among patient subsets based on race and BUN, but subset analysis based on PCA did indicate significant differences. In simulations, the protocols based on the study patients tended to perform better than the literature protocols, with all but three achieving therapeutic goals in 75% or more of the neonates. Of the published protocols, Murphy and Carter's produced the greatest percentage of neonates with peaks from 5 to 10 mg/L and troughs of <2 mg/L. The devised protocols tended to perform poorly in producing troughs between 1 and 2 mg/L, yet performed comparatively well in providing therapeutic peaks from 5 to 10 mg/L.     

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.     

Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children

We studied the pharmacokinetics of intravenously and orally administered lamivudine at six dose levels ranging from 0.5 to 10 mg/kg of body weight in 52 children with human immunodeficiency virus infection. A two-compartment model with first-order elimination from the central compartment was simultaneously fitted to the serum drug concentration-time data obtained after intravenous and oral administration. The maximal concentration at the end of the 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with the dose. The mean clearance of lamivudine (+/- standard deviation) in the children was 0.53 +/- 0.19 liter/kg/h (229 +/- 77 ml/min/m2 of body surface area), and the mean half-lives at the distribution and elimination phases were 0.23 +/- 0.18 and 2.2 +/- 2.1 h, respectively. Clearance was age dependent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administration, and 66% +/- 25% of the oral dose was absorbed. Serum lamivudine concentrations were maintained above 1 microM for >/=8 h of 24 h on the twice daily oral dosing schedule with doses of >/=2 mg/kg. The cerebrospinal fluid drug concentration measured 2 to 4 h after the dose was 12% (range, 0 to 46%) of the simultaneously measured serum drug concentration. A limited-sampling strategy was developed to estimate the area under the concentration-time curve for concentrations in serum at 2 and 6 h.     

A bioavailability and pharmacokinetic study of oral and intravenous hydroxyurea

Despite the widespread usage of hydroxyurea in the treatment of both malignant and nonmalignant diseases and a recent expansion in the recognition of its potential therapeutic applications, there have been few detailed studies of hydroxyurea's pharmacokinetic (PK) behavior and oral bioavailability. Parenteral administration schedules have been evaluated because of concerns about the possibility for significant interindividual variability in the PK behavior and bioavailability of hydroxyurea after oral administration. In this PK and bioavailability study, 29 patients with advanced solid malignancies were randomized to treatment with 2, 000 mg hydroxyurea administered either orally or as a 30-minute intravenous (IV) infusion accompanied by extensive plasma and urine sampling for PK studies. After 3 weeks of treatment with hydroxyurea (80 mg/kg orally every 3 days followed by a 1-week washout period), patients were crossed over to the alternate route of administration, at which time extensive PK studies were repeated. Three days later, patients continued treatment with 80 mg/kg hydroxyurea orally every 3 days for 3 weeks, followed by a 1-week rest period. Thereafter, 80 mg/kg hydroxyurea was administered orally every 3 days. Twenty-two of 29 patients had extensive plasma and urine sampling performed after treatment with both oral and IV hydroxyurea. Oral bioavailability (F) averaged 108%. Moreover, interindividual variability in F was low, as indicated by 19 of 22 individual F values within a narrow range of 85% to 127% and a modest coefficient of variation of 17%. The time in which maximum plasma concentrations (Cmax) were achieved averaged 1.22 hours with an average lag time of 0.22 hours after oral administration. Except for Cmax, which was 19. 5% higher after IV drug administration, the PK profiles of oral and IV hydroxyurea were very similar. The plasma disposition of hydroxyurea was well described by a linear two-compartment model. The initial harmonic mean half-lives for oral and IV hydroxyurea were 1.78 and 0.63 hours, respectively, and the harmonic mean terminal half-lives were 3.32 and 3.39 hours, respectively. For IV hydroxyurea, systemic clearance averaged 76.16 mL/min/m2 and the mean volume of distribution at steady-state was 19.71 L/m2, whereas Cloral/F and Voral/F averaged 73.16 mL/min/m2 and 19.65 L/m2, respectively, after oral administration. The percentage of the administered dose of hydroxyurea that was excreted unchanged into the urine was nearly identical after oral and IV administration-36. 84% and 35.82%, respectively. Additionally, the acute toxic effects of hydroxyurea after treatment on both routes were similar. Relationships between pertinent PK parameters and the principal toxicity, neutropenia, were sought, but no pharmacodynamic relationships were evident. From PK, bioavailability, and toxicologic standpoints, these results indicate that there are no clear advantages for administering hydroxyurea by the IV route except in situations when oral administration is not possible and/or in the case of severe gastrointestinal impairment.     

A case of Buerger''s disease solitary involved in the left subclavian and axillary artery

The pharmacokinetics of ceftazidime have been investigated in eight patients with chronic renal failure undergoing continuous ambulatory peritoneal dialysis. Each subject was given ceftazidime 1 g intravenously and 1 g intraperitoneally at an interval of 1 week. Ceftazidime was assayed by high-pressure liquid chromatography. After intravenous administration, the pharmacokinetic parameters of ceftazidime were: elimination plasma half-life (t1/2 beta) = 24.6 +/- 4.6 hours; apparent volume of distribution (V(area)): 0.37 +/- 0.09 1/kg, total plasma clearance (CL): 11.9 +/- 3.3 mL/minute, peritoneal clearance (CLp): 1.7 +/- 0.3 mL/minute. Over 72 hours, only 15.6 +/- 4.7% of the dose was eliminated by the peritoneal route. After intraperitoneal administration, ceftazidime appeared in the plasma rapidly, and the peak plasma concentration of 24.5 +/- 5.2 mg/L was achieved at the fourth hour; the elimination half-life (t1/2ke) was 20.8 +/- 1.7 hours. The absorption of ceftazidime from the peritoneal space was 74.1 +/- 7.4%. These data suggest that ceftazidime has bidirectional exchange characteristics through the peritoneal membrane. A single 1-g intraperitoneal dose led to serum and dialysate concentrations of ceftazidime above the minimum concentrations for susceptible pathogen germs for 24 hours.     

Pharmacokinetics and pharmacodynamics of bumetanide in critically ill pediatric patients

This prospective, open-label, clinical trial was conducted to describe the pharmacology of bumetanide in pediatric patients with edema. Nine infants, children, and young adults with edema who were selected for diuretic therapy were studied. After a brief baseline period, each patient received parenteral bumetanide 0.2 mg/kg divided into two equal doses and administered every 12 hours. Urine excretion rate, fractional and total excretion of Na+, Cl-, and K+, creatinine clearance, and plasma and urine concentrations of bumetanide were measured at multiple intervals after drug administration. Bumetanide caused significant increases in the excretion rate of urine and each measured electrolyte. Unexpectedly, creatinine clearance increased dramatically after each dose. Adverse effects, including hypokalemia and hypochloremic metabolic alkalosis, were evident by the end of the treatment period. The plasma pharmacokinetics of bumetanide revealed mean +/- standard deviation values for total clearance and apparent volume of distribution of 3.9 +/- 2.4 mL/min/kg and 0.74 +/- 0.54 L/kg, respectively. Patients excreted an average of 34% of each dose unchanged in the urine over 12 hours. Plasma concentrations of bumetanide accurately predicted several renal effects using a link model with similar pharmacodynamic parameters in each case. Parenteral bumetanide 0.1 mg/kg administered every 12 hours produced significant beneficial and adverse effects in these critically ill pediatric patients with edema. Pharmacokinetic parameters are similar to those previously reported for infants. Plasma concentrations of bumetanide can predict effect-compartment pharmacodynamics.     

Pharmacokinetics of single intravenous and oral doses of dolasetron mesylate in healthy elderly volunteers

Dolasetron mesylate (MDL 73,147EF, Anzemet; Hoechst Marion Roussel, Laval, Canada) is a 5-HT3 receptor antagonist undergoing clinical evaluation for use as an antiemetic agent. The pharmacokinetics of dolasetron and its reduced metabolite (MDL 74,156) were studied after administration of single intravenous and oral doses of dolasetron mesylate 2.4 mg/kg in 18 healthy elderly subjects. Expressed as the dolasetron base, this dose was 1.8 mg/kg. Dolasetron was rapidly metabolized to the reduced metabolite, which appeared in plasma within 10 minutes after intravenous or oral administration. The mean half-life (t1/2) of dolasetron was 0.24 hours after intravenous administration and 0.50 hours after oral administration. The pharmacokinetic parameters of the reduced metabolite were similar after intravenous and oral administration. The apparent absolute bioavailability of the reduced metabolite was 89%, and it had an elimination t1/2 of approximately 7 hours and an apparent volume of distribution (Vd beta) of 4.69 L/kg. Dolasetron was not detected in urine. Metabolites were excreted in urine almost completely within 24 hours of administration. The primary metabolite detected in urine was the (+)-enantiomer of the reduced metabolite, which accounted for 25.35% (+/- 7.79%) and 18.88% (+/- 7.65%) of the intravenous and oral doses, respectively. Hydroxylated metabolites accounted for 5% or less of the total dose via either route. The pharmacokinetics of the reduced metabolite after single intravenous or oral doses in elderly volunteers were consistent with pharmacokinetics observed in both young healthy men and cancer patients receiving high-dose cisplatin chemotherapy. Dosage adjustments of dolasetron mesylate on the basis of age do not appear to be necessary.     

Methylprednisolone pharmacokinetics, cortisol response, and adverse effects in black and white renal transplant recipients

It is generally assumed that chronic glucocorticoid therapy is similar pharmacologically when administered to either black or white renal transplant recipients, resulting in adrenal suppression, low circulating plasma cortisol concentrations, and a similar degree of drug exposure and toxicity. To examine this theory and to investigate the relationship of glucocorticoid metabolism to steroid-induced adverse effects among specific ethnic groups of renal transplant recipients, 9 black and 9 white male patients chronically receiving methylprednisolone were enrolled. All patients had stable renal function and were matched for age, weight, and time since transplant. Standard pharmacokinetic parameters for methylprednisolone were determined and cortisol responses were characterized by total cortisol area under the concentration curve (AUC), return cortisol AUC, and cortisol suppression half-life. All patients received their daily oral dose of methylprednisolone (mean daily dose = 11 mg for blacks and 11 mg for whites) as an intravenous infusion with serial plasma samples obtained over 24 h. The patients were assessed for the presence of specific cushingoid manifestations (buffalo hump, moon facies) and steroid-associated diabetes. Methylprednisolone and cortisol were analyzed via HPLC. In the black patients, the mean clearance of methylprednisolone (206 +/- 70 ml/hr/kg) was significantly slower with a smaller volume of distribution (0.95 +/- 0.32 L/kg) when compared with the white group (327 +/- 129 ml/hr/kg, P = 0.03; volume of distribution = 1.33 +/- 0.27 L/kg, P = 0.015). Despite chronic methylprednisolone therapy, a definite 24-hr cortisol response pattern was noted in 15 of the 18 patients with a mean total cortisol AUC of 732 +/- 443 ng.hr/ml in blacks and 539 +/- 361 ng.hr/ml in whites (P = 0.17, black vs. white). The mean cortisol suppression half-life was 4.31 +/- 1.54 hr in black recipients and 4.11 +/- 1.49 hr in whites (P = 0.48). The mean return cortisol AUC for the black patients was 327 +/- 279 ng.hr/ml and 370 +/- 207 ng.hr/ml for white patients (P = 0.28). The serum cortisol nadir for black patients was 12.3 +/- 7.2 ng/ml, which was significantly higher than the cortisol nadir in white patients (6.4 +/- 4.4 ng/ml; P = 0.03). A majority (94%) of patients (9 black, 8 white) had moon facies and 27% of patients (3 black, 1 white) had a buffalo hump. While 5 of 9 black patients had steroid-associated diabetes, no white patients manifested this adverse effect. The black patients with diabetes had higher cortisol AUCs with lower methylprednisolone clearances than the white group.(ABSTRACT TRUNCATED AT 400 WORDS)     

Circulatory, respiratory and acid-base balance changes produced by anesthetics in the rat

14C-D,L-verapamil was administered intravenously (10 mg) and orally (80 mg) to five volunteer patients. Plasma concentrations of verapamil, which were determined by mass fragmentography, declined bi-exponentially with half-lives of the chi-phase ranging from 18 to 35 min and of the beta-phase from 170 to 440 min. The apparent volume of distribution ranged from 270 to 460 litre and plasma clearance from 730 to 1980 ml/min. Following oral administration absorption was almost complete as judged from the area under the curve (AUC) of 14C-activity and cumulative urinary excretion of 14C. After intravenous infusion of verapamil about 80% of the radioactivity administered could be recovered in urine and faeces within 5 d. Despite its almost complete absorption after oral administration verapamil was shown to undergo extensive first pass metabolism as the bioavailability was only 10 to 22%. Rapid biotransformation had occurred as only a small percentage of AUC of 14C was seen to correspond to unchanged verapamil after both intravenous and oral administration.     

Inhibition of Salmonella enteritidis by oleuropein in broth and in a model food system

OBJECTIVE: To compare the pharmacokinetics of methylprednisolone in renal transplant recipients on 2 occasions separated by at least 1 month during chronic immunosuppression. DESIGN: A prospective unblinded trial. PATIENTS: Ten renal transplant recipients (aged 25-62 years) evaluated in a public university-affiliated hospital clinic. INTERVENTIONS: All patients received their chronic oral dose of methylprednisolone as a 10-20-minute intravenous infusion during the 2 study periods. MAIN OUTCOME MEASURES: Serum methylprednisolone concentrations were determined by HPLC and were used to generate the pharmacokinetic parameters of the drug. RESULTS: During study 1, which ranged from 1.2 to 24 months posttransplant, the mean +/- SD methylprednisolone dose was 13.2 +/- 6.4 mg. In study 2 (2.5-38.5 mo posttransplant), the mean dose was 10.6 +/- 3 mg. During both study periods, methylprednisolone concentrations exhibited a monoexponential decline. Considerable variability in methylprednisolone clearance was observed between periods in certain patients. Four of the 10 patients demonstrated a reduction in clearance from study 1 to study 2, which ranged from a 28% to a 53% decrease. Two patients exhibited an increase in clearance of 40% and 49%. The mean +/- SD total body clearance in study 1 was 363 +/- 330 mL/min/kg, whereas the mean volume of distribution was 1.18 +/- 0.53 L/kg. The mean elimination rate constant was 0.29 +/- 0.14 h-1, with a mean serum half-life of 2.87 +/- 1.15 h during the first phase. In study 2, the mean methylprednisolone clearance was 261 +/- 150 mL/min/kg (p > 0.05) and the mean volume of distribution was 0.89 +/- 0.31 L/kg (p > 0.05). The mean serum half-life of methylprednisolone was 2.91 +/- 0.60 h (p > 0.05), with the mean elimination rate constant of 0.25 +/- 0.06 h-1 (p > 0.05). CONCLUSIONS: These data demonstrate that intrapatient variability in methylprednisolone clearance exists among certain renal allograft recipients. As a result of the observed variability, patients who are continued on the same dose of methylprednisolone during the posttransplant period of chronic immunosuppression will be subjected to a changing pattern of exogenous glucocorticoid exposure. The impact of these changing patterns requires further prospective evaluation.     

A multiplex RT-PCR assay for analysis of relative transcript levels of different members of multigene families: application to Arabidopsis calmodulin gene family

In systemic amyloidosis, widespread amyloid deposition interferes with organ function, frequently with fatal consequences. Diagnosis rests on demonstrating amyloid deposits in the tissues, traditionally with histology although scintigraphic imaging with radiolabeled serum amyloid P component (SAP) has lately been developed as a specific noninvasive alternative. We report a detailed analysis of the abnormal turnover of SAP in patients with systemic amyloidosis and an assessment of its clinical value. METHODS: Iodine-123-labeled human SAP (200 MBq) SAP was injected intravenously into 49 patients with histologically proven systemic AA- or AL- amyloidosis and in 7 control subjects. Plasma clearance and whole-body retention of labeled SAP were analyzed over 48 hr using plasma sampling, whole-body gamma camera imaging and measurement of radioactivity in the urine. The rate of SAP synthesis and interstitial exchange were determined, and the size of the amyloid compartment was compared with clinical estimates of whole-body amyloid load and patient survival. RESULTS: All plasma time-activity curves were biphasic. In comparison with control subjects, patients with amyloidosis showed significantly faster plasma disappearance [4-hr value: AA 48% +/- 18%, AL 45% +/- 15% versus 65% +/- 8% (p < 0.05)], higher total-body retention 48 hr p.i. [AA 74% +/- 14%, AL 73% +/- 17% versus 46% +/- 15% (p < 0.01)] and especially higher extravascular retention 48 hr p.i. [AA 59% +/- 16%, AL 58% +/- 19% versus 30% +/- 14% (p < 0.01)]. Extravascular retention correlated with clinical estimation of the amyloid load. If extravascular retention values in patients with AL amyloidosis were over 60%, survival was decreased (median 4 versus 23 mo, p < 0.001). Markedly increased interstitial exchange rates were present in amyloidosis (AA 64 +/- 61, AL 50 +/- 37 versus 18 +/- 8 mg/hr), whereas the SAP synthesis rate did not differ from the control values (AA 5.0 +/- 3.0, AL 5.5 +/- 3.2 versus 4.5 +/- 1.4 mg/hr). CONCLUSION: The presence of systemic amyloidosis is characterized by accelerated initial clearance of 123I-SAP from the plasma and increased interstitial exchange rate and extravascular retention. These findings reflect reversible binding of radiolabeled SAP to amyloid deposits and provide clinically useful information for diagnosis, monitoring of therapy and prognosis in patients with systemic amyloidosis.     

The pharmacokinetics of a new antiglaucoma drug, latanoprost, in the rabbit

Latanoprost (13,14-dihydro-17-phenyl-18,19,20-trinor-prostaglandin F2alpha-1-isopropyl ester) is a unique prostaglandin analogue developed for the treatment of glaucoma. To investigate the pharmacokinetics, tritium-labeled latanoprost was administered topically on the eyes of rabbits and intravenously. About 7.7% of the applied dose was found in the cornea at 15 min after the drug administration. The following Cmax and elimination half-life (interval 1-6 hr) values of the total radioactivity in the eye tissues were found: aqueous humor, 0.09 ng eq/ml and 3.0 hr; anterior sclera, 1.49 ng eq/mg and 1.8 hr; cornea, 1.59 ng eq/mg and 1.8 hr; ciliary body, 0.39 ng eq/mg and 2.8 hr; conjunctiva, 1.41 ng eq/mg and 1.4 hr; and iris, 0.39 ng eq/mg and 2.1 hr. Latanoprost was rapidly hydrolyzed, and most of the radioactivity found in the aqueous humor, anterior eye tissues, and plasma corresponded to the pharmacologically active acid of latanoprost. The initial plasma elimination half-life of the acid of latanoprost was 9.2 +/- 3.2 min after iv and 2.3 +/- 1.9 min after topical administration on the eyes. The plasma clearance of the acid of latanoprost was 1.8 +/- 0.3 liters/hr.kg, and the volume of distribution was 0.4 +/- 0.1 liter/kg after iv administration. Based on the retention times on HPLC and GC-MS, the main metabolite in urine and feces was identified as the 1,2,3,4-tetranor metabolite of acid of latanoprost. This acid existed in equilibration with the corresponding delta-lactone. The AUC of radioactivity in the eye tissues was approximately 1000 times higher than in plasma AUC. The recovery of radioactivity was complete.     

Ratio of pulmonary venous to mitral A velocity is a useful marker for predicting mean pulmonary capillary wedge pressure in patients with left ventricular systolic dysfunction

OBJECTIVE: To determine the effect of oral magnesium hydroxide [Mg(OH)2] on iron absorption after simulated iron overdose in human subjects. METHODS: A randomized, controlled crossover study was conducted in healthy adult male human volunteers taking no medications. Subjects received an average of 5.0 mg/kg elemental iron orally followed 1 hour later by either oral administration of 4.5 g of Mg(OH)2 per g ingested elemental iron or no treatment. Serial serum specimens were obtained over the 12 hours following iron ingestion and stored at -60 degrees C until standard serum iron assay was performed. After a 2-week washout period, the subjects were enrolled in the alternative trial arm. Individual baseline diurnal variation in serum iron levels was determined over a 12-hour period on the day prior to each trial. Area under time-concentration curves (AUCs) were calculated, and the AUC due to experimental iron ingestion (deltaAUC) was determined by subtracting the baseline diurnal AUC from the experimental AUC for each subject. RESULTS: Thirteen healthy adult male subjects were enrolled. Mean +/- SEM for deltaAUC due to experimental iron ingestion followed by treatment with Mg(OH)2, 78 +/- 23 micromol(hr)/L, was significantly less than that followed by no treatment, 144 +/- 33 micromol(hr)/L (p = 0.03 by signed rank test). CONCLUSIONS: Magnesium hydroxide, administered 1 hour post-iron ingestion at an oral dose of 4.5 g per g elemental iron ingested, significantly reduced iron absorption during a 12-hour period following simulated mild iron overdose in healthy adult human volunteers.     

Guidelines for the pre-hospital care of patients with severe head injuries. Working Group for Neurosurgical Intensive Care of the European Society of Intensive Care Medicine

OBJECTIVE: To evaluate the absorption of oral ciprofloxacin within 24 hours of laparotomy for major elective surgery or peritonitis. DESIGN: In this prospective trial, patients were given a 750-mg oral close the morning after major elective surgery (n=15) or surgery for peritonitis (n=7). Healthy volunteers served as controls (n=9). Serial urine and blood samples were drawn during the subsequent 12 hours, and pharmacokinetic measures were determined by standard high-performance liquid chromatography assay procedures. SETTING: Multicenter, university-affiliated hospitals. MAIN OUTCOME MEASURES: Drug absorption as determined by area under the concentration time curve, maximum concentration, and time to maximum concentration. RESULTS: Oral bioavailability was reduced in elective surgery and peritonitis patients compared with controls. Among the 15 elective surgery patients, 27% (4/15) showed no absorption. The remaining 73% (11/15) had an area under the curve comparable with that of controls (8.3+/-1.6 (mg/[L x h]). Among all patients, those who showed drug absorption vs those who showed no absorption did not differ with respect to malignant neoplasm, case type, age, or biochemistry. However, patients showing no absorption were significantly heavier than patients showing absorption (patients showing absorption, 15%+/-3% over ideal body weight vs patients showing no absorption, 29%+/-6% over ideal body weight; P<.05). When elective surgery patients were stratified by presence or absence of obesity (25% above ideal body weight), mean area under the curve in nonobese patients was 9.80+/-2.37 vs 0.91+/-0.56 (mg/(L x h) in obese patients (P<.05). CONCLUSIONS: Oral bioavailability was reduced for peritonitis surgery patients on the first day postoperatively, and for obese elective surgery patients. To achieve adequate serum levels requires continuation of intravenous antibiotics in patients with peritonitis, and adjustment of oral dosage in obese patients in the early period after elective surgery.     

Effect of furosemide on the renal excretion of digoxin

Digoxin serum and urine levels were determined by radioimmunoassay in 6 subjects (4 patients with heart disease and 2 volunteers without heart disease) who had been maintained on oral digoxin (0.25 or 0.5 mg daily). Observations were made during a 3-day control period and then during 8 days of concomitant digoxin and oral furosemide (40 mg daily) therapy. Serum digoxin levels determined 10 and 24 hr after each dose of digoxin averaged 1.2+/-0.1 ng/ml (M+/-SE) during control and 1.3+/-0.1 during the last 3 days on digoxin and furosemide. The daily urinary excretion of digoxine averaged 51+/-6% of the oral dose during control and 52+/-6 during the entire period of furosemide administration. The renal clearance of digoxin and creatinine averaged 94+/-7 and 87+/-11 ml/min, respectively, during control; corresponding values were 88+/-8 and 85+/-9 for urine collections demonstrating a distinct diuretic effect of furosemide and 87+/-8 and 75+/-10 for urine collections not demonstrating such an effect during diuretic therapy. The results suggest that the diuretic effect of furosemide does not significantly affect the excretion of digoxin