Bioavailability of melatonin in humans after day-time administration of D(7) melatonin

Absolute bioavailability of the neurohormone melatonin (MLT) was studied in 12 young healthy volunteers (six males, six females) after administration at midday, on two separate occasions, of 23 microg by intravenous (i.v.) infusion and 250 microg by oral solution of D(7) MLT, a molecule in which seven deuterium atoms replace seven hydrogen atoms. Exogenous (D(7)) and endogenous (D(0)) MLT were quantified simultaneously but separately by a highly specific assay: gas chromatography/negative ion chemical ionization mass spectrometry, developed in our laboratory, which enabled us to go down to 0.5 pg/mL in plasma samples. After i.v. administration, the maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve (AUC) values were significantly different in male and female subjects, but there was no significant gender difference in total body clearance normalized to body weight: 1.27+/-0.20 L/h/kg and 1.18+/-0.22 L/h/kg for males and females, respectively. The apparent terminal half-life (t(1/2(z))) values were 36+/-2 and 41+/-10 min, respectively. After oral administration, pharmacokinetic parameters used to quantify bioavailability were near three-fold greater in female subjects than in males, with large inter-individual variations. The maximum plasma MLT concentration C(max)+/-S.D. was found at 243.7+/-124.6 pg/mL and 623.6+/-575.1 pg/mL for male and female subjects respectively, while the mean values for AUCs were 236+/-107 pg.h/mL and 701+/-645 pg.h/mL. The absolute bioavailability of MLT was from 1 to 37%: mean=8.6+/-3.9% and 16.8+/-12.7% for male and female subjects, respectively.     

Absolute bioavailability of moxonidine

In a randomized 2-way cross-over study with eighteen healthy male volunteers, two moxonidine preparations (tablets, treatment A vs. intravenous solution, treatment B) were tested to investigate absolute bioavailability and pharmacokinetics of moxonidine. The preparations were administered as single doses of 0.2 mg; prior to and up to 24 h after administration blood samples were collected and the plasma moxonidine concentrations determined. Urine samples were collected prior to and at scheduled intervals up to 24 h after administration for the determination of unchanged moxonidine. Moxonidine plasma and urine concentrations were determined by a validated gas chromatographic/mass spectrometric method with negative ion chemical ionization. The mean areas under the plasma concentration/time curves were calculated as [mean +/- standard deviation] 3438 +/- 962 pg.h/ml (AUC(0----Tlast)) and 3674 +/- 1009 pg.h/ml (AUC(0----infinity)) for treatment A; 3855 +/- 1157 pg.h/ml (AUC(0----Tlast)) and 4198 +/- 1205 pg.h/ml (AUC(0----infinity)) for treatment B. Mean peak plasma concentrations of 1495 +/- 646 pg/ml were attained at 0.56 +/- 0.28 h after oral treatment, mean peak plasma concentrations after intravenous treatment reached 3965 +/- 1342 pg/ml at 0.17 +/- 0.01 h (= coinciding with end of infusion). The mean terminal half-lives of moxonidine were derived as 1.98 h after administration of the tablet and as 2.18 h after infusion. The amounts of moxonidine excreted in urine during the 24 h following administration (Ae(24h)) in absolute figures and as percentage of the dose administered were 102 +/- 26 micrograms or 51 +/- 13% for the tablet and 122 +/- 33 micrograms or 61 +/- 16% for the infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relative bioavailability of a new transdermal nitroglycerin delivery system

The purpose of this study was to measure the bioavailability of nitroglycerin from a new transdermal delivery system, Nitro-Dur II, relative to that of Nitro-Dur. Twenty-four healthy male volunteers completed a two-way crossover study. Each subject randomly received Nitro-Dur (I) and Nitro-Dur II (II) for a 24-h period. Both transdermal systems had an active surface area of 20 cm2. Blood samples were collected immediately before treatment, at 0.5, 1, 2, 3, 4, 6, 8, 12, 18, and 24 h after topical application of the units, and 30 min after the units were removed. Nitroglycerin was determined with an analytical sensitivity of 50 pg/mL using gas chromatography with electron capture detection (GC-EC). Mean steady-state concentrations of nitroglycerin were 182 and 224 pg/mL for I and II, respectively. There were no statistical differences between I and II in the pharmacokinetic parameters measured (Css, AUC, Cmax, % fluctuation). Residual nitroglycerin content was measured in each transdermal unit after application to each of the 24 volunteers. The amounts of nitroglycerin delivered by I and II were 9.78 +/- 4.11 and 10.67 +/- 4.78 mg, respectively, or approximately 10 mg in 24 h. Statistical analysis of these data using an analysis of variance indicated no significant difference between these treatments (p = 0.27). Since there were also no differences in the plasma concentrations and pharmacokinetic parameters calculated after treatment with I and II, the bioequivalence of the two delivery systems was established.     

Single dose absorption profiles and bioavailability of two different salbutamol tablets

In a single dose cross-over experiment in twelve healthy adults a comparison of the absorption profiles and the relative bioavailability was made between a new salbutamol containing tablet (preparation A = Salbutax) and a commercially available and accepted formulation as reference (preparation B), both containing 4 mg salbutamol. Salbutamol plasma concentrations were measured frequently during a period of 16 h post dosing. Maximum salbutamol plasma concentrations after intake of product A and product B on an empty stomach were reached after 2.3 +/- 0.9 (= mean +/- S.D.) and 2.4 +/- 1.1 h, respectively, and accounted for 14.3 +/- 2.5 and 12.8 +/- 2.6 micrograms X l-1, respectively. The differences were not found to be significant (p greater than 0.05). The areas under the plasma concentration-time curves (AUC0----16), as obtained after administration of tablet A and tablet B, accounted for 73.5 +/- 14.0 and 65.0 +/- 11.8 micrograms X l-1 X h, respectively, the difference being marginally significant (p = 0.05). This results in a relative bioavailability of 114.3 +/- 15.7% for the product A 4-mg tablets. It is concluded that both products can be considered as having comparable bioavailability.     

ORTHOSTATIC AND POSTPRANDIAL BLOOD PRESSURE REDUCTION IN PATIENTS WITH ESSENTIAL HYPERTENSION

1. The role of the sympathetic nervous system in orthostatic and postprandial blood pressure reduction in patients with essential hypertension was studied in 13 hypertensive patients and 10 age-matched normotensive subjects. 2. The blood pressure (BP), pulse rate, and plasma norepinephrine (NE) were measured: (i) every minute for 20 min in the upright position after overnight recumbency (ii) every 30 min after food intake for 3 h in the supine position. 3. Orthostatic BP reduction (greater than 13 mmHg in mean BP) was observed in eight hypertensive patients with a maximum after 4 min. Seven of these patients showed postprandial hypotension (greater than 13 mmHg) with a maximum 90 min after eating, while none of the normotensives exhibited such BP reductions. Before and during the tests the plasma NE levels were higher in hypertensive patients than in the normotensives. The plasma NE level was increased from 370 +/- 80 to 790 +/- 110 pg/mL 4 min after standing (P less than 0.01) in hypertensive patients and from 220 +/- 40 to 530 +/- 90 pg/mL (P less than 0.01) in normotensive subjects. The plasma NE level was decreased 90 min after food intake from 390 +/- 90 to 260 +/- 80 pg/mL in hypertensives. Changes in plasma NE correlated with those in mean BP after standing for 4 min (r = 0.379, P less than 0.05) and also with those 90 min after food intake (r = 0.457, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Bioavailability of quinidine in slow-release form. A comparison between two preparations containing quinidine bisulphate as the active constituent.

Two different slow-release preparations of quinidine bisulphate (A and B) have been tested. The in vitro dissolution rate of preparation B was substantially lower in intestinal than in gastric juice, whereas the release rate of quinidine from preparation A was virtually unaffected by the pH of the dissolution medium. After a single dose of two tablets of each of the preparations to 6 healthy volunteers, corresponding to 386 mg (B) and 320 mg of quinidine base (A), the maximum plasma concentration was attained after about 4.5 h. The peak concentration was 5.2 +/- 0.5 mumol/l for preparation A and 4.1 +/- 0.4 mumol/l for B. A similar difference was found in the area under the plasma concentration curve (AUC), which was 68 +/- 10 mumol-h/l and 54 +/- 5 mumol-h/l, respectively. Taking into consideration that preparation B contained 20.6% more active drug per tablet these values indicate that the extent of bioavailability is about 50% higher for tablet A than for tablet B.     

Pharmacokinetics of mycophenolic acid in live donor liver transplant patients vs deceased donor liver transplant patients

The exposure of mycophenolic acid in live donor liver transplant patients (those receiving a partial hepatic volume) in comparison to deceased donor liver transplant patients (those receiving the whole hepatic volume) after administration of mycophenolate mofetil has not been reported earlier. The aim of the present study is to compare the pharmacokinetics parameters of mycophenolic acid and mycophenolic acid glucuronide in live donor liver transplant patients versus deceased donor liver transplant patients. Twelve live donor liver transplant and 12 deceased donor liver transplant recipients were studied over a dosing interval after intravenous administration of mycophenolate mofetil. The maximum concentration (Cmax) and the area under the plasma concentration versus time curve (AUC) for mycophenolic acid in live donor liver transplant patients were significantly higher than in deceased donor liver transplant patients (Cmax/AUC: live donor liver transplant patients: 16.1 +/- 6.6 microg/mL/43.9 +/- 12.6 microg/mL.h vs deceased donor liver transplant patients: 10.7 +/- 2.0 microg/mL/28.9 +/- 7.1 microg/mL.h; P = .046/.002). The volume of distribution was higher in the deceased donor liver transplant patients compared with live donor liver transplant patients. However, the mean plasma concentration at 12 hours (Clast), drug disposition rate constant, half-life (t 1/2), and mean residence time were similar in both groups. The mean plasma concentration of mycophenolic acid glucuronide was 1.4 to 2.0 times higher in deceased donor liver transplant patients compared with live donor liver transplant patients. These observations point to the need to use a lower dosage (approximately 30%) of mycophenolate mofetil in live donor liver transplant patients compared with deceased donor liver transplant patients.     

Pharmacokinetics of betamethasone and betamethasone 17-monopropionate in Chinese healthy volunteers after intramuscular injection of betamethasone phosphate/betamethasone dipropionate

The aim of this study was to evaluate the pharmacokinetic profiles of betamethasone (BOH, CAS 378-44-9) and betamethasone 17-monopropionate (B17P), the active metabolites of betamethasone phosphate (BSP) and betamethasone dipropionate (BDP), respectively, after administration of betamethasone i.m. (BSP 2 mg and BDP 5 mg). After ten healthy volunteers had received a single-dose intramuscular adminitration of betamethasone i.m., blood samples were collected pre-dose and for 336 h postdose. The plasma levels of B17P and BOH were measured by liquid chromatography-tandem mass spectrometry (LC-MS/ MS). When compared to BOH, B17P exhibited a longer time to maximum concentration (15.0 +/- 9.0 h vs. 2.8 +/- 1.7 h), a lower Cmax (0.6 +/- 0.2 ng/mL vs. 14.5 +/- 3.7 ng/mL), and a much longer half-life (80.8 +/- 22.7 h vs. 9.6 +/- 3.6 h). Betamethasone i.m. produced rapid onset and sustained action through an initial rapid-increased plasma concentration of BOH and a sustained plasma concentration of B17P, respectively.     

In vitro protein binding of diclofenac sodium in plasma and synovial fluid

The in vitro protein binding behavior of diclofenac sodium (sodium[o-(2,6-dichloroanilino)phenyl]acetate) in plasma and synovial fluid was investigated by equilibrium dialysis. The drug was highly protein bound (approximately 99.5%) and the extent of binding remained constant for drug concentrations of 2-10 micrograms/mL. Comparable results were obtained with human serum albumin solution (45 g/L) indicating that albumin is probably the responsible protein. The extent of binding remained relatively constant for drug concentrations of 0.25-10 micrograms/mL when albumin concentrations were greater than 25 g/L. For albumin concentrations less than 10 g/L, the extent of binding tended to decrease with increased drug concentration. This concentration (10 g/L) is substantially lower than that usually observed in plasma or synovial fluid of arthritic patients. Curvature of the Scatchard plot indicated the existence of two classes of sites. Excellent results were obtained from fitting of the data according to two classes of sites (r2 greater than 0.999). Parameter estimates (SEM) of the number of binding sites, n1 and n2, and the corresponding association constants, k1 and k2, were 2.26 (0.55), 10.20 (0.69), and 1.32 (0.54) X 10(5) M-1, and 3.71 (1.11) X 10(3) M-1, respectively. Simultaneous samples obtained from arthritic patients indicate considerably higher total protein and albumin concentrations in plasma compared with synovial fluid, but the albumin:total protein ratios were essentially the same. There was very little difference in plasma binding in arthritic patients compared with normal subjects. The extent of binding in synovial fluid samples was consistently lower than that for plasma samples (mean +/- SD of 99.5 +/- 0.2% versus 99.7 +/- 0.1%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Bioavailability of three oral dosage forms of cisapride, a gastrointestinal stimulant agent

Relative bioavailability of the investigational gastrointestinal stimulant agent cisapride after oral administration was determined in healthy men. Treatments administered were (A) two 5-mg tablets; (B) one 10-mg tablet; (C) 10 mL of a 1-mg/mL suspension; and (D) 10 mL of a 1-mg/mL aqueous reference solution. The study had a randomized four-way, crossover design; drug administration was followed by a standard breakfast. Plasma cisapride concentrations in blood samples drawn over 48 hours were measured by high-performance liquid chromatography. Individual and mean values for bioavailability parameters were subjected to analysis of variance followed by multiple comparison testing. Time to maximum concentration was shortest after administration of the solution. There was a significant difference in mean peak plasma concentrations between treatment A (48.8 +/- 12.8 ng/mL) and treatment D (41.6 +/- 10.6 ng/mL), with treatment A producing a 17.3% higher peak concentration. No significant differences between treatments were found for area under the plasma concentration-time curve. The overall mean elimination half-life was 7.01 hours. The results of the study indicate that the tablet and suspension dosage forms of cisapride are bioequivalent to the reference solution.     

Pharmacokinetics and safety of recombinant human parathyroid hormone (1-34) (teriparatide) after single ascending doses in Chinese healthy volunteers

The pharmacokinetics and safety of recombinant human parathyroid hormone (1-34) [rhPTH (1-34)] after single ascending doses were evaluated in Chinese healthy volunteers. Nine healthy volunteers (five male and four female) were recruited for an open label, randomized, three multiply three crossover, single ascending dose (10, 20, and 40 microg) study. Using a validated radioimmunoassay, we determined the plasma concentrations of rhPTH (1-34). The mean peak plasma concentration (Cmax) were 123.6, 195.6, and 318.2 pg x mL(-1) respectively, and were reached from 25.6 to 36.1 min after subcutaneous administration. After Cmax was reached, the plasma drug level decreased quickly, with elimination halflife (t(1/2)) of 53.9 to 64.1 min. The mean AUC(0-infinity) (the area under the plasma concentration versus time curve from time zero to infinite) of rhPTH (1-34) were 11794.2 +/- 974.8, 21606.7 +/- 4753.9, 33877.0 +/- 8374.4 pg x min x mL(-1), respectively. The mean AUC(0-t) (the area under the plasma concentration versus time curve from time zero to the last quantifiable concentration) of rhPTH (1-34) were 9034.4 +/- 1073.9, 17883.3 +/- 4597.1, 31693.5 +/- 6574.8 pg x min x mL(-1), respectively. Dose-related linear trend were observed for AUC(o-t) and Cmax of rhPTH (1-34). t(1/2) and Tmax (time to Cmax) of rhPTH (1-34) were independent of administered dose. rhPTH (1-34) was safe and well tolerated by all volunteers.     

Bioavailability of glycerol trinitrate (nitroglycerin) from an ointment preparation

After application of an ointment of glycerol trinitrate (nitroglycerin, Nitrofortin; in the following briefly called GTN) the bioavailability of the unchanged GTN was evaluated. For that purpose a gas chromatographic/mass spectrometric method was employed, the only method which guarantees the selectivity and sensitivity necessary for this kind of studies. In this respect selectivity means that only the unchanged drug is determined and degradation and/or biotransformation products are measured only if needed. Considering the well-known tremendous inter-individual variations, which are quite common in studies with this compound, and the associated problems of getting statistically relevant data the study was performed on 12 volunteers. Detectable GTN-levels were obtained up to 48 h after application, maximum plasma levels (836.1 +/- 124.2 pg/ml) were reached after 1.37 +/- 1.55 h. 12 h after application plasma concentrations of 154 +/- 20 pg/ml were observed which decreased to 65 +/- 13 pg/ml after 24 h.     

Absolute bioavailability of mianserin tablets and solution in healthy humans

A pharmacokinetic study with mianserin . HCl was performed in six healthy male subjects. The subjects were treated on different occasions intravenously with a constant-rate infusion of 5 mg mianserin. HCl in 1 h, orally with a single dose of 60 mg as two tablets of 30 mg each and with 60 mg as an oral solution. The wash-out period between treatments was 1 month. Blood samples were taken at predetermined times over a period of 120 h following dosing. The mianserin concentration in the plasma samples was determined and the results were pharmacokinetically analyzed. The intravenous data could be adequately described by a 3-compartment model and the oral data by a 2-compartment model, both with first-order transfer and elimination rate constants. The mean plasma clearance of mianserin was found to be 19 +/- 2 l h-1 (mean +/- SEM), the kinetic volume of distribution 444 +/- 250 l, the steady-state volume of distribution 242 +/- 171 l and the elimination half-life 33 +/- 5 h. The absolute bioavailability in terms of extent of absorption was 22 +/- 3% for the solution and 20 +/- 3% for the tablets. The mean peak level for the solution was 79 +/- 11 ng X ml-1 and for the tablets 54 +/- 5 ng X ml-1; mean peak time for the solution was 1.1 +/- 0.2 h and for the tablets 1.4 +/- 0.2 h. The mean absorption half-life for the solution was 0.43 +/- 0.13 h and for the tablets 0.39 +/- 0.11 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic profiles of controlled-release hydrogel polymer vaginal inserts containing misoprostol

Misoprostol, a prostaglandin E1 analogue, is commonly administered intravaginally for cervical ripening and induction of labor. There is uncertainty regarding the correct dose because of the need to divide the tablets, and there is difficulty in removing the product when there is an adverse event. A proprietary hydrogel polymer containing a removable controlled-release reservoir dose of misoprostol is being developed for vaginal administration (misoprostol vaginal insert) to address these drawbacks while maintaining efficacy. This study investigated the pharmacokinetic profiles of these vaginal inserts and orally administered misoprostol. Twelve nonpregnant women received 100-, 200-, and 400-microg misoprostol vaginal inserts and separately received an oral dose of 200 microg of misoprostol. Values for area under the plasma concentration versus time curve, from time 0 to the last measurable concentration, were dose proportional with 481, 1026, and 2191 pg.h/mL for the 100-, 200-, and 400-microg misoprostol vaginal inserts, respectively. Maximum plasma concentrations were 33.1, 73.4, and 144 pg/mL for the 100-, 200-, and 400-microg misoprostol vaginal inserts, compared with 609 pg/mL for the 200 microg of oral misoprostol. After administration of the insert, plasma misoprostol acid levels increased gradually with time of the maximum measured plasma concentration at 5 to 9 hours. Following removal of the insert, misoprostol acid was eliminated rapidly from the systemic circulation with a mean half-life <1 hour.     

Clinical pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in patients with B-lineage lymphoid malignancies

The authors examined the pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in 17 patients (4 children, 13 adults) with B-lineage lymphoid malignancies, including 12 patients with acute lymphoblastic leukemia (ALL) and 5 patients with non-Hodgkin's lymphoma (NHL). The immunoconjugate was administered intravenously as a 1-hour continuous infusion at a dose level of either 0.1 mg/kg (N = 12) or 0.18 mg/kg (N = 5), and the plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameters. Pharmacokinetic analyses revealed a plasma half-life of 19 +/- 4 hours, mean residence time of 22 +/- 4 hours, and a systemic clearance of 18 +/- 2 mL/h/kg. The average (mean +/- SEM) values for the maximum plasma concentration Cmax, volume of distribution at steady state (Vss), and area under curve (AUC) were 1092 +/- 225 ng/ml, 291 +/- 37 mL/kg, and 9987 +/- 2021 micrograms x h/L, respectively. The AUC values were higher at the 0.18 mg/kg dose level than at the 0.1 mg/kg dose level (16,848 +/- 5118 micrograms x h/L vs. 7128 +/- 1156 micrograms x h/L, p = 0.009). Patients with ALL had a significantly larger volume of distribution at steady state (332 +/- 47 mL/kg vs. 191 +/- 12 mL/kg, p = 0.04), faster clearance (21 +/- 3 mL/h/kg vs. 11 +/- 2 mL/h/kg, p = 0.03), and lower dose-corrected AUC than patients with NHL (6010 +/- 836 micrograms x h/L vs. 12,044 +/- 2707 micrograms x h/L, p = 0.006). There was a trend toward faster clearance rates (23 +/- 4 mL/h/kg vs. 16 +/- 3 mL/h/kg, p = 0.1), shorter elimination half-lives (5.7 +/- 3.6 hours vs. 13 +/- 8.8 hours, p = 0.1), and shorter mean residence times (11 +/- 3 hours vs. 25 +/- 5 hours, p = 0.08) for non-Caucasian patients as compared to Caucasian patients. When compared to adult patients, pediatric patients showed a significantly larger volume of distribution at steady state (418 +/- 82 mL/kg vs. 252 +/- 34 mL/kg, p = 0.02) and a longer elimination half-lives (18.4 +/- 13.6 hours vs. 8.7 +/- 6.7 hours, p = 0.04). The pharmacokinetics of B43-Genistein was not affected by the gender of the patients or by bone marrow transplantation in past medical history. Overall, B43-Genistein showed favorable pharmacokinetics in this heavily pretreated leukemia/lymphoma patient population, which is reminiscent of its recently reported favorable pharmacokinetics in cynomolgus monkeys. To our knowledge, this is the first clinical pharmacokinetics study of a tyrosine kinase inhibitor containing immunoconjugate.     

Absence of an interaction between ibuprofen and zaleplon.

The potential interaction between zaleplon and ibuprofen was studied. Healthy adult volunteers were given a dose of zaleplon 10 mg alone, a dose of ibuprofen 600 mg alone, or a dose of zaleplon 10 mg and a dose of ibuprofen 600 mg concomitantly in an open-label, randomized, three-period crossover study. There was a seven-day washout period between treatments. Venous blood samples were collected for pharmacokinetic analysis at various intervals up to 14 hours after drug administration. A total of 17 subjects (11 men and 6 women) completed the study. There were no significant differences between zaleplon monotherapy and combination therapy in mean +/- SD, of zaleplon clearance (CL) (2.80 +/- 0.72 versus 2.72 +/- 0.89 L/hr/kg, respectively), maximum plasma concentration (Cmax) (37.1 +/- 17.9 versus 39.8 +/- 20.0 ng/mL), or area under the concentration-versus-time curve (AUC) (56.7 +/- 22.8 versus 59.2 +/- 22.0 ng.hr/mL). There were no significant differences between ibuprofen monotherapy and combination therapy in ibuprofen CL (71.6 +/- 17.0 versus 71.7 +/- 14.9 L/hr/kg), Cmax (40.8 +/- 10.2 versus 40.4 +/- 10.0 micrograms/mL), or AUC (127.6 +/- 29.6 versus 126.4 +/- 29.7 micrograms.hr/mL). Three subjects had one or more adverse effects with zaleplon alone, one subject had one or more with ibuprofen alone, and one subject had one or more with combination therapy. The adverse effects were mild and resolved without intervention. There was no evidence of a significant interaction between zaleplon and ibuprofen.     

Effects of food on the bioavailability of sustained-release pinacidil in humans

The effects of a standard breakfast meal on the bioavailability of a sustained-release tablet formulation of pinacidil [(+/-)-2-cyano-1- (4-pyridyl)-3-(1,2,2-trimethylpropyl)guanidine monohydrate) were investigated in eight healthy volunteers. Concomitant food intake resulted in significantly increased maximum measured serum pinacidil concentrations, Cmax, (172 +/- 21 versus 102 +/- 49 ng/mL, p less than 0.05), and relative bioavailability, measured as AUCo-infinity (904 +/- 189 versus 697 +/- 279 ng.h/mL, p less than 0.05). The time to maximum serum concentration (tmax) was not affected by food (2.3 +/- 1.3 versus 3.3 +/- 1.2 h, p greater than 0.05), and the terminal elimination half-life, (t1/2z) was significantly decreased (4.7 +/- 2.2 versus 2.3 +/- 0.4 h, p less than 0.05).     

Effect of food on the bioavailability of lisinopril, a nonsulfhydryl angiotensin-converting enzyme inhibitor

A randomized, two-way, crossover study was performed on 18 normal volunteers to assess the influence of food on the bioavailability of lisinopril, (1-[N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline), a long-acting nonsulfhydryl angiotensin converting enzyme inhibitor. A single, 20-mg oral dose of lisinopril was administered to volunteers in the fasting state or following a standardized breakfast. Treatment periods were separated by 2-week intervals. No significant differences existed between fasting and fed regimens in the mean +/- SD area under the serum concentration-time curve (AUC0-120h; 1231 +/- 620 versus 1029 +/- 254 ng X h X ml-1), peak lisinopril serum concentration (86 +/- 48 versus 69 +/- 19 ng/mL), or time to peak lisinopril serum concentration (6.2 +/- 1.1 versus 6.8 +/- 1.0 h). Five-day urinary excretion of lisinopril was not altered by food (5.3 +/- 3.0 versus 5.1 +/- 2.0 mg). Based on the urinary data, the mean +/- SD bioavailability of lisinopril was not different following fasting or fed regimens (27 +/- 15 versus 26 +/- 10%). Unlike with captopril, food did not affect the bioavailability of lisinopril.     

Comparison of pentoxifylline pharmacokinetics between smokers and nonsmokers.

Pentoxifylline is a synthetic xanthine derivative and is hepatically cleared. The natural dimethylxanthines theobromine and theophylline have been shown to have enhanced metabolism in smokers when compared with nonsmokers. Subsequently, the effect of smoking on pentoxifylline plasma concentrations was investigated. Twenty healthy volunteers (10 smokers and 10 nonsmokers) received pentoxifylline 400 mg as a controlled-release tablet every 8 hours for 17 doses. Several blood samples were collected for 8 hours after the final dose. These samples were assayed for pentoxifylline and its metabolites. The mean values of the smokers were compared with those of the nonsmokers. With respect to pentoxifylline, no statistically significant differences in maximum concentration and time of maximum concentration were observed between the two groups. Although no statistical differences in plasma concentrations and area-under-the-curve at steady state (AUCss) were observed, the oral clearance of pentoxifylline among the smokers (.22 +/- .08 L/minute/kg) was significantly greater (P < .05) than that among the nonsmokers (0.15 +/- 0.06 L/minute/kg) when corrected for body weight. With respect to the pentoxifylline metabolite 1-(5-hydroxy-hexyl)-3,7-dimethylxanthine (MI), the maximum concentration and AUCss of the smokers were significantly decreased when compared with the nonsmokers. The AUCss of the smokers was 1438 +/- 819 ng.hour/mL and of the nonsmokers was 2864 +/- 1375 ng.hour/mL (P < .02). The results of this trial suggest that smoking tends to reduce pentoxifylline plasma concentrations and significantly reduces MI plasma concentrations.     

Absolute bioavailability and noncompartmental analysis of intravenous and intramuscular Cefotan (cefotetan) in normal volunteers

Cefotetan (1 g) was administered to 12 normal volunteers as a 30 minute intravenous infusion and as an intramuscular injection. The pharmacokinetic parameters were estimated using noncompartmental analysis. The mean +/- SD maximum plasma concentration, terminal half-life, and systemic clearance after intravenous infusion were 158 +/- 21 micrograms/mL, 4.54 +/- 1.05 hours, and 29.1 +/- 3.8 mL/min/1.73 m2, respectively. Renal clearance and nonrenal clearance accounted for 63.1% and 36.9% of the systemic clearance, respectively. The mean +/- SD maximum plasma concentration, time to maximum concentration, terminal half-life, and absolute bioavailability after intramuscular injection were 75.5 +/- 8.7 micrograms/mL, 1.33 +/- 0.48 hours, 4.32 +/- 0.77 hours, and 0.931 +/- 0.193, respectively. Moment analysis gave average +/- SD mean residence times (MRT) of 4.98 +/- 0.75 and 5.86 +/- 0.77 hours after intravenous and intramuscular administration, respectively. The average +/- SD mean absorption time (MAT) after intramuscular injection was 1.11 +/- 0.57 hours. The mean +/- SD steady-state volume of distribution after intravenous infusion was 0.129 +/- 0.024 L/kg. The mean +/- SD cumulative percentage of the dose excreted in the urine in 24 hours were 61.1 +/- 11.4% and 50.4 +/- 13.5% after intravenous and intramuscular dosing, respectively. The maximum urinary cefotetan concentrations occurred during the first 2 hours after dosing by both routes of administration. Cefotetan tautomer was detected in the plasma and urine of all subjects after both routes of administration, but the mean concentrations were only minimal compared to those for cefotetan. In conclusion, intramuscular cefotetan (1 g) is rapidly and almost completely absorbed.(ABSTRACT TRUNCATED AT 250 WORDS)