Circadian variation of tacrolimus disposition in liver allograft recipients

The aim of this study was to characterize the circadian variation of oral tacrolimus disposition in 8 stable liver allograft recipients. In the steady state, a total of 23 blood samples was taken before and after tacrolimus administration during a 24-hr period and the pharmacokinetic parameters were compared. The area under the curve (AUC) of tacrolimus after the morning dose was significantly larger than after the evening dose (211+/-43 ng x hr/ml [morning] vs. 179+/-45 ng x hr/ml [evening], P=0.02). The time to peak (Tmax) was significantly shorter after the morning dose than after the evening dose (1.6+/-0.7 hr [morning] vs. 2.9+/-0.6 hr [evening], P=0.002). The peak (Cmax) was significantly higher after the morning dose than after the evening dose (32.2+/-10.2 ng/ml [morning] vs. 19.1+/-4.3 ng/ml [evening], P=0.003). However, the trough (Cmin) was not significantly different between the morning dose and the evening dose (13.1+/-3.9 ng/ml [morning] vs. 13.3+/-4.4 ng/ml [evening], P=0.4). This study demonstrated that tacrolimus disposition in liver transplant patients was determined by administration time.     

Chronic ethanol treatment leads to increased ornithine decarboxylase activity: implications for a role of polyamines in ethanol dependence and withdrawal

STUDY OBJECTIVES: To determine intrasubject and intersubject variability in, and the effects of food and antacids on, the pharmacokinetics of pyrazinamide (PZA). DESIGN: Randomized, four-period, crossover phase I study. SUBJECTS: Fourteen healthy men and women volunteers. INTERVENTIONS: Subjects ingested single doses of PZA 30 mg/kg under fasting conditions twice, without a high-fat meal and with an aluminum-magnesium antacid. They also received standard dosages of isoniazid, rifampin, and ethambutol. MEASUREMENTS AND MAIN RESULTS: Serum was collected for 48 hours and assayed by gas chromatography with mass selective detector. Data were analyzed by noncompartmental methods and a compartmental analysis using nonparametric expectation maximization. Both fasting conditions produced similar results: mean PZA Cmax 53.4+/-10.4 microg/ml, Tmax 1.43+/-1.06 hours, and AUC(0-infinity) 673+/-79.7 microg x hr/ml. Fasting results are similar to those in previous reports. In the presence of antacids, subjects had a mean Cmax of 55.6+/-9.0 microg/ml, Tmax of 1.43+/-1.23 hours, and AUC(0-infinity) of 628+/-88.4 microg x hr/ml. In the presence of the high-fat meal, mean Cmax was 45.6+/-9.44 pg/ml, Tmax 3.09+/-1.74 hours, and AUC(0-infinity) 687+/-116 microg x hr/ml. CONCLUSIONS: These small changes in Cmax, Tmax, and AUC(0-infinity) can be avoided by giving PZA on an empty stomach whenever possible.     

Cholecystokinin-8 regulation of NGF concentrations in adult mouse brain through a mechanism involving CCK(A) and CCK(B) receptors

STUDY OBJECTIVE: To assess the potential for a drug-drug interaction between valspodar, a P-glycoprotein (mdrl) modulator used as a chemotherapy adjunct, and dexamethasone, widely included in oncology antiemetic regimens. DESIGN: Randomized, open-label, three-period crossover study. SETTING: Clinical pharmacology research center. SUBJECTS: Eighteen healthy men volunteers (age 25.8+/-3.5 yrs, weight 71.6+/-10.3 kg). INTERVENTIONS: Subjects received single fasting oral doses of valspodar 400 mg, dexamethasone 8 mg, and both drugs concomitantly with 2- to 3-week washout phases between administrations. MEASUREMENTS AND MAIN RESULTS: Lack of a pharmacokinetic drug-drug interaction with respect to valspodar was conclusively demonstrated for both Cmax,b (2.3+/-0.4 vs 2.4+/-0.5 microg/ml) and AUCb (19.8+/-4.8 vs 19.6+/-4.9 microg x hr/ml) inasmuch as bioequivalence criteria were satisfied when comparing administration alone with coadministration, respectively. Although no changes in the rate of dexamethasone absorption were noted on coadministration with valspodar (Cmax 88+/-23 vs 91+/-20 ng/ml), overall exposure was significantly increased by 24% on average (AUC 400+/-87 vs 494+/-90 ng x hr/ml). Regression analysis of valspodar Cmax,b and AUCb during coadministration versus the extent of the interaction (percentage increase in dexamethasone AUC) did not reveal a concentration-effect relationship (p=0.7299 and 0.9718, respectively). CONCLUSION: Given dexamethasone's wide therapeutic index and the short duration of coadministration foreseen for these drugs in a clinical setting (maximum 1 wk/chemotherapy cycle), the 24% increase in dexamethasone's AUC is unlikely to be relevant. Thus no alterations in valspodar or dexamethasone dosages appear warranted when the two drugs are coadministered. Multiple-dose experience in patients would be desirable to confirm these conclusions.     

Flexor hallucis longus tendon injury in dancers and nondancers

A sandwich transfer enzyme immunoassay for elcatonin (ECT) and its usability for the pharmacokinetic study are described. The anti-salmon calcitonin (SCT) antibody was used for the present assay. The assay procedure consisted of the reaction of ECT with 2,4-dinitrophenylbiotinyl anti-SCT IgG and anti-SCT Fab'-beta-D-galactosidase conjugate, trapping onto (anti-2,4-dinitrophenyl bovine serum albumin) IgG-coated polystyrene balls, eluting with epsilonN-2,4-dinitrophenyl-L-lysine and transferring to streptavidin-coated polystyrene balls and fluorometric detection of beta-D-galactosidase activity. The practical detection limit of ECT was 0.15 pg (44 amol)/50 microl of sample and 3 pg/ml as the concentration. The application of this method has enabled us to directly estimate the bioavailability of ECT dosed intranasaly at a therapeutic level (100 IU, 17 microg) for its anti-osteoporotic effect as compared to an intramuscular dose (40 IU, 6.7 microg). The pharmacokinetic parameters of the intranasal ECT (n = 6) thus estimated were as follows: the area underthe serum concentration-time curve (AUC) = 2,570 +/- 1,650 (SD) pg x min/ml, and the maximal concentration (Cmax) = 60 +/- 25 (SD) pg/ml with the maximal time (Tmax) = 17.5 +/- 6.9 (SD) min, when the AUC for the intramuscular ECT (n = 9) = 9,460 +/- 5,870 (SD) pg x min/ml and the Cmax = 165 +/- 79 (SD) pg/ml with the Tmax = 16.1 +/- 4.2 (SD) min.     

Double-blind evaluation of the safety and pharmacokinetics of multiple oral once-daily 750-milligram and 1-gram doses of levofloxacin in healthy volunteers

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (Cmax) values were generally attained within 2 h postdose. The mean values of Cmax and area under the concentration-time curve from 0 to 24 h (AUC0-24) following a single 750-mg dose were 7.1 microg/ml and 71.3 microg x h/ml, respectively, compared to 8.6 microg/ml and 90.7 microg x h/ml, respectively, at steady state. Following the single 1-g dose, mean Cmax and AUC0-24 values were 8.9 microg/ml and 95.4 microg x h/ml, respectively; corresponding values at steady state were 11.8 microg/ml and 118 microg x h/ml. These Cmax and AUC0-24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (Vss/F), half-life (t1/2), and renal clearance (CL[R]) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, Vss/F, t1/2, and CL(R) following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache.     

Intermittent intraperitoneal ceftazidime dosing in end-stage renal disease

Infections are a common problem in dialysis patients. As hospital stay shortens, many require outpatient antibiotic therapy. Parenteral administration may pose considerable logistic and financial burdens, whereas daily intraperitoneal dosing increases the risk of contamination. Ceftazidime, with its long half-life, may provide adequate dosing when administered intraperitoneally thrice weekly. The authors therefore studied the kinetics of a 2 g loading dose followed by a 1.5 g dose every 48 hr in seven stable chronic peritoneal dialysis patients. In vitro stability at 4 degrees C (measured by high performance liquid chromatography) was 91% at 120 hr. Peak serum concentration (60 +/- 22 microg/ml) was reached at 4.9 +/- 2.2 hr. Serum values were 25 +/- 9 and 8 +/- 3 microg/ml at 24 and 48 hr, respectively. However, median trough levels at 48 hr in dialysate were significantly lower than in serum (2.8 vs 8.5 microg/ml, respectively; p = 0.0425). Pharmacokinetic parameters were as follows: bioavailability (F), 88% +/- 8%; volume of distribution at steady state (VDss), 20 +/- 8 L; absorption half-life (T1/2(abs)), 1.8 +/- 1.3 hr; elimination half-life (T1/2(el)), 11.4 +/- 4.5 hr; and clearance (CL), 22 +/- 10 ml/min. Intraperitoneal ceftazidime every 48 hr is a practical alternative to parenteral therapy of nonperitoneal infections. In peritonitis, whether increased permeability results in improved dialysate levels remains to be defined.     

Kainate/AMPA receptors expressed on human fetal astrocytes in long-term culture

OBJECTIVES: To study pravastatin and lovastatin pharmacokinetic and pharmacodynamic effects and their interactions with cydosporine (INN, ciclosporin) in kidney transplant patients after single and multiple doses. SUBJECTS AND METHODS: The pharmacokinetic and pharmacodynamic effects of administration of 20 mg/day oral pravastatin and lovastatin for 28 days and their interactions with cyclosporine (2 to 6 mg/kg/day) were studied in a double-blind, double-dummy, randomized, parallel-group multicenter trial in 44 stable kidney graft recipients. RESULTS: The median area under the curve [AUC(0-24)] of pravastatin was 249 microg x hr/L (range, 104 to 1026 microg x hr/L) after a single dose (day 1) and 241 microg x hr/L (114 to 969 microg x hr/L) after multiple doses (day 28) and was fivefold higher than values reported in the absence of cyclosporine. The median AUC(0-24) of lovastatin was 243 microg x hr/L (105 to 858 microg x hr/L) on day 1 and 459 microg x hr/L (140 to 1508 microg x hr/L) on day 28. Besides a significant accumulation during the study period (p < 0.001), the lovastatin AUC(0-24) values were twentyfold higher than values reported without cyclosporine. Coadministration of pravastatin or lovastatin did not alter cyclosporine pharmacokinetics. In this study, 20 mg/day doses of both drugs resulted in a significant improvement of the lipid profile and were well tolerated. CONCLUSIONS: In contrast to lovastatin, pravastatin did not accumulate over the study period, which is probably one of the reasons rhabdomyolysis has been reported in lovastatin-treated but not pravastatin-treated transplant patients receiving cyclosporine immunosuppression.     

Dialysis clearance of buflomedil in hemodialysed patients

Buflomedil (CAS 55837-25-7, Fonzylane) is a peripherally vasoactive drug which improves nutritional blood flow in ischaemic tissue of patients with peripheral vascular disease by the way of an increase of perfusion in the microcirculation. Ten hemodialysed patients with chronic renal failure treated with intravenous infusion of 400 mg of buflomedil during 4 h of dialysis were included in the first study. This study was carried out to determine the dialysis plasma clearance and the amount of drug dialysed during the first intravenous administration of buflomedil. The dialysis clearance calculated from the amount recovered in dialysate was (mean +/- SD) 25.4 +/- 25.6 ml/min. The drug recovery resulting from hemodialysis represented a small fraction of the dose (< or = 5%). A second study was carried out to determine the accumulation of buflomedil in chronic hemodialysed patient. The drug concentration were measured before and at the end (4 h) of the infusion of buflomedil in six other patients maintained on intermittent hemodialysis (3 per week) for 4 weeks. The average Cmin and Cmax were stable during the 12 successive dialyses (mean +/- SD intervals were between 0.36 +/- 0.53 and 0.66 +/- 0.79 microgram/ml for Cmin and between 5.15 +/- 2.19 and 7.37 +/- 1.76 micrograms/ml for Cmax), showing no trend of accumulation of buflomedil. These results agree with the pharmacokinetics of the drug which is mainly metabolised in the liver and has a low renal clearance. Dialysis is unable to modify significantly the plasma concentration of the drug in regularly dialysed patients.     

Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patients. A prospective study

The pharmacokinetics of itraconazole formulated in a hydroxypropyl-beta-cyclodextrin oral solution was determined for two groups of human immunodeficiency virus (HIV)-infected adults with oral candidiasis (group A, 12 patients with CD4+ T-cell count of >200/mm3 and no AIDS, and group B, 11 patients with CD4+ T-cell count of <100/mm3 and AIDS). Patients received 100 mg of itraconazole every 12 h for 14 days. Concentrations of itraconazole and hydroxyitraconazole, the main active metabolite, were measured in plasma and saliva by high-performance liquid chromatography. Pharmacokinetic parameters determined at days 1 and 14 (the area under the concentration-time curve from 0 to 10 h, the maximum concentration of drug in plasma [Cmax], and the time to Cmax) were comparable in both groups. Trough levels in plasma (Cmin) were similar in both groups for the complete duration of the study. An effective concentration of itraconazole in plasma (>250 ng/ml) was reached at day 4. At day 14, Cmin values of itraconazole were 643 +/- 304 and 592 +/- 401 ng/ml for groups A and B, respectively, and Cmin values of hydroxyitraconazole were 1,411 +/- 594 and 1,389 +/- 804 ng/ml for groups A and B, respectively. In saliva, only unchanged itraconazole was detected, and mean concentrations were still high (>250 ng/ml) 4 h after the intake, which may contribute to the fast clinical response. In conclusion, the oral solution of itraconazole generates effective levels in plasma and saliva in HIV-infected patients; its relative bioavailability is not modified by the stage of HIV infection.     

Genotypically dependent effects of cyromazine on reproduction and offspring development in the Australian Lucilia cuprina (Diptera: Calliphoridae)

Various factors may influence bioavailability and blood concentrations of cyclosporine, a problem that may be compounded by diseases such as cystic fibrosis in which impaired absorption through the gastrointestinal tract is common. Neoral, a microemulsion formulation of cyclosporine, has improved bioavailability and more stable blood concentrations than earlier formulations. We conducted a prospective, open, crossover study to examine whether these findings held true in 12 clinically stable patients with cystic fibrosis who had undergone lung transplantation at least 6 months earlier. In the first arm, patients continued their usual dosage of cyclosporine twice/day. In the second arm they received Neoral for at least 1 week before having blood studies. For each arm whole blood trough concentrations were drawn for 7-10 successive days, together with a pharmacokinetic study with concentrations drawn at times zero, 1, 2, 3, 4, 6, 12, and 24 hours. Variance was assessed from morning concentrations. Area under the curve from zero to 12 hours (AUC12), maximum concentration (Cmax), and time to Cmax (Tmax) were calculated for each arm. Eleven subjects completed the protocol. The daily variance for Neoral was significantly less than for cyclosporine (p=0.04). The AUC12 for Neoral and cyclosporine were 4164+/-1467 and 5318+/-1670 microg x L/hour (p=0.09), respectively. Respective Cmax were 613+/-242 and 931 +/-458 microg/L (p=0.08) and relative Cmax and AUC12 were 1.91 and 1.47 (p<0.05). Thus Neoral had a superior pharmacokinetic profile and less day-to-day variability in patients with cystic fibrosis who had undergone lung transplantation.     

Comparison of the effect of lansoprazole and omeprazole on intragastric acidity and gastroesophageal reflux in patients with gastroesophageal reflux disease

A prospective study of the pharmacokinetics of itraconazole solution was performed in 11 patients who underwent allogeneic BMT (day of BMT = day 0) after a conditioning regimen including total body irradiation (TBI). Itraconazole solution (400 mg once a day) was given 7 days before BMT and continued up to the end of neutropenia unless another antifungal treatment was necessary. Blood samples were collected before itraconazole intake (Cmin) and 4 h later (Cmax) every other day for assays of itraconazole (ITRA) and its active metabolite hydroxy-itraconazole (OH-ITRA). The mean values of Cmin ITRA and OH-ITRA, respectively, were 287 +/- 109 ng/ml and 629 +/- 227 ng/ml at day -1 and 378 +/- 147 ng/ml and 725 +/- 242 ng/ml at day +1. The maximum Cmin values were observed at day +3. Six patients at day -1 (54%) and 8 at day +1 (72%) had satisfactory residual plasma concentrations of at least 250 ng/ml of unchanged ITRA. From day +1 to day +9, eight patients discontinued the itraconazole treatment, five of them had satisfactory plasma residual concentrations at this time. This work shows a good bioavailability of itraconazole oral solution during the early phase after allogeneic BMT, but more data are needed for the late phases.     

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)     

Are there special considerations in the prescription of serotonin reuptake inhibitors for women?

The aim of this study was to evaluate and compare the pharmacokinetics of naftidrofuryl (CAS 3200-06-4) after single oral administration of a 200 mg naftidrofuryl tablet (Praxilene) in Caucasian male and female elderly healthy volunteers versus young healthy volunteers. Thirty healthy volunteers were included in a randomised phase I trial in 3 parallel groups of 10 subjects aged 18-35 years (group 1), 60-70 years (group 2) and 70-80 years (group 3). Blood samples were taken over a period of 24 h after dosing for evaluation of the pharmacokinetics of naftidrofuryl. The Cmax, tmax, AUC0-t parameters were measured and t1/2 and AUC0-alpha were calculated by a model independent method. The mean (+/- SD) pharmacokinetic parameters of naftidrofuryl after single oral administration of 200 mg of naftidrofuryl for group 1 were as follows: tmax 3.5 h (median), Cmax 284 +/- 136 ng/ml, t1/2 3.69 +/- 1.30 h, AUC0-t 1865 +/- 905 h.ng/ml and AUC0-inf 2055 +/- 901 h.ng/ml; for group 2: tmax 2.75 h (median), Cmax 282 +/- 165 ng/ml, t1/2 3.03 +/- 1.08 h, AUC0-t 1783 +/- 1147 h.ng/ml and AUC0-inf 1856 +/- 1158 h.ng/ml; for group 3: tmax 2.5 h (median), Cmax 271 +/- 86 ng/ml, t1/2 3.50 +/- 1.29 h, AUC0-t 1742 +/- 544 h.ng/ml and AUC0-inf 1834 +/- 549 h.ng/ml. Statistical analysis was performed on the pharmacokinetic parameters with one-way ANOVA in order to compare each age group. The results of the pharmacokinetic and statistical analysis showed no significant difference between each age group. The mean pharmacokinetic parameters of naftidrofuryl after single oral administration of 200 mg of naftidrofuryl in the whole population were as follows: tmax 2.75 h (median), for Cmax 279 +/- 128 ng/ml, t1/2 3.41 +/- 1.22 h, AUC0-t 1797 +/- 870 h.ng/ml for AUC0-inf 1910 +/- 877 h.ng/ml. In conclusion, advanced age did not appear to influence the pharmacokinetic profile of oral naftidrofuryl, and therefore it is not necessary to adjust the dosage of naftidrofuryl in this population.     

Pharmacokinetic study of an oral cephalosporin, cefdinir, in hemodialysis patients

The pharmacokinetics of cefdinir were investigated in six hemodialysis patients. For the present study, two tests were carried out, one with 4 h of hemodialysis and the other without hemodialysis. Cefdinir was given orally to each patient in a dose of 100 mg, and blood was collected serially for 48 h after dosing in the test without dialysis and for 72 h in the test with dialysis. In the test without dialysis, the maximum plasma concentration (Cmax) was 2.36 +/- 0.53 micrograms/ml (mean +/- standard deviation) and the time to Cmax was 9.00 +/- 2.45 h. The terminal elimination half-life (t1/2) and area under the concentration-time curve (AUC) were 16.95 +/- 1.20 h and 69.05 +/- 14.84 micrograms.h/ml, respectively. In the test with dialysis, t1/2 during hemodialysis decreased approximately to one-sixth of that obtained in the test without dialysis, although t1/2 in the latter elimination phase did not differ from that in the nondialysis test. AUC was reduced to 43% of that in the test without dialysis. The fractional removal of cefdinir by hemodialysis was 61%. These findings indicate that clearance of cefdinir is prolonged in patients with renal failure, and cefdinir is well removed by introduction of hemodialysis, although t1/2 (during hemodialysis) and AUC were two and eight times higher than the data previously reported for healthy volunteers, respectively. The pharmacokinetic data suggest that 100 mg of oral cefdinir once a day would result in a sufficient concentration in plasma in hemodialysis patients, but this remains to be confirmed by multiple-dose studies.     

Sudden deafness: a randomized comparative study of 2 administration modalities of hyperbaric oxygenotherapy combined with naftidrofuryl

The pharmacokinetics of a single, oral dose of 750 mg of ciprofloxacin were studied in 35 subjects with various degrees of renal function (Group 1, Clcr > or = 80 ml/min; Group II, Clcr 50-79 ml/min; Group III, Clcr 10-49 ml/min) and on hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Blood, urine and CAPD dialysate samples were collected over a period of 48 hours after dosing. Data were fitted using non-linear, least squares regression. The mean Cmax was 3.4 +/- 1.0 mg/l and tmax was 2.3 +/- 0.9 hours. The mean AUC in Group I was 14.7 mg.h/l, Group II was 33.7 (p < 0.001), Group III 63.8 (p < 0.001), HD 57.9 (p < 0.0001) and CAPD 44.3 (p < 0.001). Half-life in Group I was 4.6 h, and was shorter than Group III (11.1 h, p < 0.001), HD (13.4 h, p < 0.001) and CAPD (8.9 h, p < 0.001). Total body clearance and renal clearance demonstrated significant differences also. The dialysis clearance in CAPD patients was 0.53 +/- 0.39 l/h. Peritoneal effluent concentrations varied from 0.6 mg/l during the first exchange, to a peak of 2.2 mg/l during the second, to 0.13 mg/l in the 48 hour (9th) exchange. Dosage adjustments of ciprofloxacin in the presence of renal insufficiency are indicated for subjects with a Clcr < 20 ml/min/1.73m2.     

Effect of antacid on bioavailability of a sustained-release theophylline preparation

The effect of coadministration of an antacid on bioavailability of a sustained-release theophylline tablet preparation (Theo-Dur) was studied by crossover comparison in five young, healthy, nonsmoking volunteers. Water 90 ml, or "high potency" aluminum-magnesium hydroxide antacid (Mylanta II) 10 ml and water 80 ml were administered concurrently with sustained-release theophylline 600 mg. Eleven blood samples were collected over the next 24 hours. Serum was analyzed with high pressure liquid chromatography technique to determine theophylline concentration. Peak serum concentration (Cmax) and time to peak concentration (tmax) were determined, and area under the 24-hour serum concentration-time curve (AUC) was calculated by the trapezoidal rule for each subject at each study interval. The Student's paired t-test was used to compare Cmax, tmax, and AUC for both treatments. A uniform difference was found between groups in Cmax. Cmax was higher in subjects when treated with the antacid (10.45 +/- 3.03 vs. 8.30 +/- 2.90 micrograms/ml, p less than 0.05) than when given theophylline alone. The mean tmax for the two treatments did not differ (10.4 +/- 1.67 h-combination vs. 10.8 +/- 1.1 h-theophylline, p greater than 0.05). Likewise, mean AUC was unchanged by the coadministration of antacid (140.65 +/- 41.6 micrograms/ml.h--combination vs. 155.13 +/- 46.6 micrograms/h--theophylline, p greater than 0.05). The use of a high-potency antacid product did not decrease the extent of theophylline absorption from this sustained-release product, but did increase Cmax and, presumably, rate of absorption. High-potency aluminum-magnesium antacids can probably be used in combination with this sustained-release theophylline tablet without detriment to therapy.     

Steady state disposition of 5-aminosalicyclic acid following oral dosing

In 18 healthy volunteers the steady state disposition of 5-aminosalicylic acid (5-ASA, mesalazine, CAS 89-57-6; 500 mg tid) was evaluated following the last oral dose in form of slow release tablets (Salofalk) either containing 500 mg or 250 mg 5-ASA. In none of the pharmacokinetic parameters of 5-ASA characterizing bioavailability (e.g. AUC approximately 6 ug/ml x h; Cmax approximately 1.7 micrograms/ml; tmax approximately 5 h; Cminss approximately 0.5 micrograms/ml; Cavss approximately 0.75 microgram/ml) differences between both forms were observed and the calculated 90% confidence intervals and point estimates indicated bioequivalence. Following the delayed absorption 5-ASA was rapidly eliminated (t1/2 = 1.4 +/- 0.5 h).     

Topical versus intravenous administration of tranexamic acid: a comparison of intraocular and serum concentrations in the rabbit

Digoxin, a cardiac glycoside, is a substrate of the multidrug transporter P-glycoprotein (Pgp), and in rats has also been identified as a substrate for cytochrome P450 3A (CYP3A). Ketoconazole, an antifungal agent, was shown to inhibit Pgp in a multidrug-resistant cell line, and is known to be a potent inhibitor of CYP3A. Here, we determined the effects of ketoconazole on digoxin absorption and disposition in rats. Digoxin was administered intravenously or orally with or without a concomitant oral dose of ketoconazole. When given intravenously, digoxin AUC increased from 93 +/- 22 to 486 +/- 26 microg x h/l with ketoconazole administration. Similarly, ketoconazole raised the AUC of orally administered digoxin from 63 +/- 17 to 411 +/- 50 microg x h/l. Concomitant ketoconazole administration prolonged digoxin elimination, yielding a nonlinear pharmacokinetic profile. Using time-averaged values, digoxin bioavailability increased from 0.68 +/- 0.18 to 0.84 +/- 0.10, while mean absorption time was reduced from 1.1 +/- 0.4 to 0.3 +/- 0.1 h. Thus, in rats, ketoconazole increases digoxin plasma concentrations, rate of absorption and bioavailability. Although the effects of ketoconazole on AUC could be explained by inhibition of both CYP3A and Pgp, which cannot be differentiated in this study, the decreased mean absorption time can only be explained by inhibition of Pgp in the intestine.     

Bioavailability and pharmacokinetic properties of 2 sustained-release formulations of diclofenac sodium, Voltaren vs inflaban: effect of food on inflaban bioavailability

In this study, in vitro characterization, bioavailability and pharmacokinetics of 2 different sustained-release diclofenac sodium dosage forms were compared, Voltaren (100 mg tablets), manufactured by Ciba-Geigy and Inflaban (100 mg enteric-coated tablets), manufactured by the Arab Pharmaceutical Manufacturing Company. The in vitro results demonstrated a faster rate of dissolution for Inflaban as compared to Voltaren, but both products exhibited a sustained-release pattern. The bioavailability study was conducted on 20 healthy male subjects who received a single oral dose (100 mg) of each product according to a randomized 2-way crossover design. Blood samples were obtained over a 26-hour period, and drug concentrations were determined by an HPLC method. Concentration time profiles revealed a sustained-release pattern for both products. The Tlag for Voltaren was 0.8 +/- 0.2 h, significantly shorter than for Inflaban (1.7 +/- 0.2 h) indicating a faster rate of absorption from the upper gastrointestinal tract. The Cmax obtained with Voltaren was significantly higher than that obtained with Inflaban (1,161 +/- 102 and 799 +/- 83, respectively). With respect to Tmax and AUC0-26h parameters, both products were not found to be statistically different. Tmax for Voltaren and Inflaban was 4.2 +/- 0.5 and 4.5 +/- 0.4 h, respectively, whereas AUC0-26h values for both products were 5,423 +/- 562 and 5,237 +/- 520 ng x h/ml, respectively. It is believed that the observed differences between Voltaren and Inflaban are mainly due to the fact that Inflaban is designed as an enteric-coated tablet form, with a core tablet having different sustained-release behavior. In addition, the effect of food on the bioavailability of Inflaban was evaluated in randomly selected 6 male volunteers. Our results revealed that, following light and heavy meals, the AUC0-30 and Cmax were minimally affected by food whereas a significant increase in Tmax and Tlag as compared to fasting conditions was observed.     

Pharmacokinetics of orally administered estradiol valerate. Results of a single-dose cross-over bioequivalence study in postmenopausal women

A randomized, single-dose cross-over study in 32 postmenopausal women was performed to demonstrate bioequivalence of two estradiol valerate containing formulations (first sequence of Klimonorm as test preparation). The serum levels of estradiol, free and conjugated estrone were measured until 48 h after an oral dosage of 4 mg estradiol valerate (CAS 979-32-8). The mean AUC(0-48) of estradiol was calculated as 1006.6 +/- 479.4 h x pg x ml-1 (Test) and 1015.2 +/- 555.2 h x pg x ml-1 (Reference). The corresponding (AUC(0-48) of the active metabolite, free estrone, exceeded that of estradiol at 3578.3 h x pg x ml-1 (Test) and 3485.1 h x pg x ml-1 (Reference). Much higher was the AUC(0-48) for conjugated estrone at 132.4 h x ng x ml-1 (Test) and 133.6 h x ng x ml-1 (Reference). Mean estradiol Cmax values of 39.8 +/- 17.7 pg/ml (Test) and 42.9 +/- 21.0 pg/ml (Reference) were attained 8.2 +/- 4.5 h (Test) and 10.0 +/- 5.9 h (Reference) after the administration of 4 mg estradiol valerate. Maximal free estrone concentrations of 163 pg/ml (Test) and 174.3 pg/ml (Reference) were reached after 7.2 h (Test) and 7.5 h (Reference). Maximal conjugated estrone concentrations of 15.5 ng/ml (Test) and 16.2 ng/ml (Reference) were reached after 2.4 h (Test) and 2.0 h (Reference). The terminal elimination half-life of estradiol was calculated at 16.9 +/- 6.0 h (Test) and 15.0 +/- 4.8 h (Reference), that of free estrone at 16.3 h (Test) and 13.5 h (Reference), that of conjugated estrone at 11.8 h (Test) and 10.6 h (Reference). After logarithmic transformation, the 90% confidence intervals of the AUC(0-48) and Cmax ratios for estradiol and also for the metabolites (free and conjugated estrone) were within the acceptance ranges for bioequivalence. Therefore the test preparation and the reference preparation are bioequivalent.