Blood selenium levels during different stages of selenosis in buffaloes and its evaluation as a diagnostic tool

Selenium (SC) toxicity was experimentally induced in male buffalo calves following repeated oral administration of 0.3 mg selenourea/kg (providing 0.19 mg/Se kg) for 75 d. On the basis of the major toxic effects produced in the experimental animals, 10 additional clinical cases of selenosis were identified from field cases. In experimental selenosis blood Se increased from 0.70 +/- 0.08 microg/ml on day 0 to 3.12 +/- 0.01 microg/ml on day 75. Hair Se rose from 2.42 +/- 0.6 ppm on day 0 to 22.91 +/- 2.6 ppm by the 11th w. The erythrocyte glutathione peroxidase (GSH-Px) activity increased from 5.35 +/- 0.94 Eu/mg Hb (0 day) to 18.81 +/- 0.46 EU/mg Hb in the 11th week. Blood Se was of better diagnostic value than hair Se or erythrocytic GSH-Px activity. Signs occurred when Se levels were about 2.0 microg/ml and were prominent above 2.5-2.6 microg/ml: Se levels > or = 1.5-1.75 microg/ml were diagnostic of impending selenosis. The Se concentrations in blood from the field cases of Se toxicity in buffalo had excellent correlation with Se levels in the experimental cases.     

Pharmacokinetics of diphenhydramine in healthy volunteers with a dimenhydrinate 25 mg chewing gum formulation

This pharmacokinetic study evaluated diphenhydramine in the plasma of healthy volunteers after a single 25 mg oral dose of dimenhydrinate (diphenhydramine theophyllinate), corresponding to 12.7 mg diphenhydramine, in a chewing gum formulation. Seven volunteers (4 men, 3 women; age: 26.3 +/- 1.2 years; body weight: 63.1 +/- 4.1 kg; height: 172.4 +/- 4.6 cm) chewed the gum for 1 h. Blood samples (10 ml) were collected at different time intervals up to 24 h. Blood plasma was subsequently processed and analyzed for diphenhydramine content using a GLC method and an NPD detector. Analytical data revealed the following kinetic parameters: AUC(0-24h): 155.2h x ng x ml(-1); AUC(0-infinity): 195.3 h x ng x ml(-1); Mean resident time: 16 h; t(1/2): 10 h; C(max): 14.5 ng x ml(-1); t(max): 2.6 h; and plasma clearance: 9.0 ml x min(-1) x kg(-1). This study indicates that the pharmaceutical formulation employed provided sustained plasma concentrations of diphenhydramine, presumably sufficient to support its clinical efficacy towards motion sickness owing to the almost complete (> 95%) release by the formulation of the active principle. Moreover, the maximal concentrations of diphenhydramine attained in plasma were much lower than the concentration threshold needed to produce drowsiness.     

Effect of age on the seminal plasma and spermatozoa lead concentrations of bulls

Blood, seminal plasma and spermatozoa lead concentrations were determined in Holstein (29 animals), Brown Swiss (14 animals) and Charoleux (11 animals) bulls aged 1-8 y. Blood concentrations were (mean +/- SD) 21.47 +/- 5.85, 18.71 +/- 6.60 and 23.27 +/- 6.75 ng Pb/ml respectively/each breed. Seminal plasma concentrations were 17.15 +/- 10.37, 13.62 +/- 10.10 and 14.03 +/- 11.31 ng Pb/ml, respectively. Spermatozoa concentrations averaged 74.93 +/- 48.10, 76.60 +/- 33.95 and 63.39 +/- 25.83 ng Pb/10(9) cells respectively. Age appeared to influence seminal plasma and spermatozoa lead levels, gradually decreasing in concentrations as the animals advanced in age.     

Plasma concentrations of high-dose olanzapine in a double-blind crossover study

Olanzapine is structurally similar to clozapine but has not been shown at routine doses to share the superiority of clozapine to traditional antipsychotics in treatment-resistant patients. Olanzapine, however, has been increasingly used in higher doses as clinicians attempt to find a more tolerable therapy for those refractory to conventional agents. This study examined the relationship of high-dose olanzapine plasma concentrations to symptoms, adverse effects, smoking, and gender. Thirteen patients participated in a double blind 16-week crossover study (8 weeks each arm) of olanzapine (50 mg/day) compared to clozapine (450 mg/day). Women had significantly higher plasma olanzapine levels than men at each time point in each arm (weeks 4, 6, and 8). At 8 weeks women had a steady-state olanzapine level of 278 +/- 62 ng/ml while men had a steady-state level of 127 +/- 47 ng/ml (p = 0.005). At week 4, olanzapine levels tended to be higher in those who had been on clozapine previously (205 ng/ml) compared to those who received olanzapine in the first arm (105 ng/ml). Cigarette intake was negatively correlated to olanzapine plasma concentrations (week 8: r = -0.86, p < 0.05). Plasma levels were significantly higher in those experiencing constipation (176 vs. 82 ng/ml; p = 0.022). Plasma levels of olanzapine were not associated with symptom response and anticholinergic effects were seen at greater frequency with higher olanzapine concentrations. In conclusion, this study reports plasma olanzapine levels at high fixed doses of olanzapine (50 mg/day) in relation to side effects, symptoms, smoking, and gender.     

Lack of significant pharmacokinetic interaction between haloperidol and grapefruit juice

The effects of repeated ingestion of grapefruit juice, an inhibitor of cytochrome P4503A4 (CYP3A4), on the steady-state plasma concentrations of haloperidol and reduced haloperidol were examined. Twelve schizophrenic inpatients receiving haloperidol 12 mg/day, ingested grapefruit juice 600 ml/day for 7 days. Blood samples were collected before and during grapefruit juice coadministration and 1 week after its discontinuation together with an assessment of clinical status. Plasma drug concentrations were measured using high-performance liquid chromatography. Clinical status for each patient was assessed by the Brief Psychiatric Rating Scale (BPRS) and the UKU side-effect rating scale (UKU). Plasma concentrations of haloperidol and reduced haloperidol during grapefruit juice coadministration (9.0 +/- 3.0 and 2.6 +/- 1.4 ng/ml, respectively) were not significantly different from those before grapefruit juice coadministration (9.1 +/- 2.8 and 2.6 +/- 1.5 ng/ml) or those 1 week after its discontinuation (8.8 +/- 2.7 and 2.6 +/- 1.3 ng/ml). There was no change in the scores of BPRS or UKU during the study period. The present results shows that grapefruit juice does not affect the plasma concentrations of haloperidol and reduced haloperidol or clinical status in patients receiving haloperidol.     

An assessment of the contribution of clonidine metabolised from alinidine to the cardiovascular effects of alinidine.

Five healthy volunteers (mean age 20.6 years, mean weight 71 kg) received in random order on day 1 and day 8 a single dose of alinidine 40 mg, clonidine 0.1 mg or placebo and on days 2-7 alinidine 40 mg, clonidine 0.1 mg or placebo given three times a day with 1 week between treatment periods. Blood samples were taken for measurement of concentrations of alinidine and clonidine during alinidine administration and of clonidine during clonidine dosing. Heart rate and blood pressure were recorded in supine and standing positions and heart rate after 3 min exercise. Plasma concentrations of alinidine reached a maximum of 163.6 +/- 10.0 ng/ml 2 h after alinidine administration on day 1 and during chronic administration similar concentrations were achieved. Clonidine plasma concentrations reached 0.3 +/- 0.11 ng/ml 6 h after alinidine 40 mg on day 1, and during chronic administration of alinidine, increased to a steady state on day 5 with trough and 2 h values of 0.73 +/- 0.15 and 0.86 +/- 0.14 ng/ml respectively. After the first dose of clonidine on day 1, the maximum plasma concentration of clonidine was 0.32 +/- 0.1 ng/ml at 4 h, during chronic administration clonidine plasma concentration rose to 1.04 +/- 0.14 ng/ml 2 h after a dose on day 5. Alinidine produced a greater reduction in the exercise tachycardia than clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Significant pharmacokinetic interaction between risperidone and carbamazepine: its relationship with CYP2D6 genotypes

The effects of carbamazepine coadministration (400 mg/day for 1 week) on plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone were studied in 11 schizophrenic inpatients treated with 6 mg/day risperidone. Blood samplings were performed before and during carbamazepine coadministration, and 1 week after its discontinuation. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using liquid chromatography-mass spectrometry-mass spectrometry. CYP2D6 genotypes were determined using the polymerase chain reaction method. Plasma concentrations of risperidone and 9-hydroxyrisperidone during carbamazepine coadministration (2.5+/-3.6 ng/ml and 19.4+/-4.1 ng/ml) were significantly ( P<0.01) lower than those before carbamazepine coadministration (5.0+/-7.9 ng/ml and 34.6+/-9.8 ng/ml). The changes in risperidone concentrations were positively correlated to the concentration ratios of risperidone/9-hydroxyrisperidone (r(s)=0.90, P<0.01), which were closely associated with CYP2D6 genotypes. The present study suggests that carbamazepine induces the metabolism of risperidone and 9-hydroxyrisperidone, and that the decrease in risperidone concentration is dependent on the CYP2D6 activity.     

Lack of effect of propranolol on the steady-state plasma levels of ketanserin

The effect of propranolol treatment on the steady-state plasma levels of ketanserin was evaluated in 6 patients suffering from borderline hypertension and in 2 healthy volunteers. All subjects received ketanserin 40 mg b.i.d. for 21 days. From day 8 to 14 of the study propranolol was given additionally in a dose of 80 mg bid. This dose of propranolol had to be reduced in 3 subjects because of side effects. Steady-state plasma concentrations (measured 4-6 h after the dose) of ketanserin varied from 51.0 +/- 13.6 to 67.8 +/- 13.8 ng/ml (mean +/- SEM) during the entire study period. Treatment with propranolol (plasma concentrations ranged from 45.7 +/- 15.8 to 65.7 +/- 11.4 ng/ml) did not significantly alter the plasma concentrations of ketanserin. The same was true for the minimal plasma concentrations of ketanserin measured at the end of each treatment period. Blood pressure decreased during the 21 days treatment period with ketanserin (mean systolic blood pressure decreased from 144 +/- 5 to 123 +/- 7 and diastolic from 81 +/- 3 to 72 +/- 5 mmHg). Propranolol had a slight additional hypotensive effect. Heart rate decreased during treatment with propranolol. It is concluded that simultaneous oral treatment with propranolol in doses up to 160 mg/day does not alter the first-pass metabolism and the elimination kinetics of ketanserin.     

Limited sex differences in response to "binge" smoked cocaine use in humans.

The subjective and physiological effects of repeated smoked cocaine self-administration were compared in 11 men and 9 women. Twice a day, on 2 consecutive days, participants smoked up to six 50-mg doses of cocaine base, at 14 min intervals. Men and women self-administered a similar number of cocaine doses (21.7 and 21.6, respectively). The most striking sex difference was that women had higher cocaine plasma concentrations than men (632.7 ng/ml vs. 376.7 mg/ml) after the sixth cocaine dose of the first session. After the first cocaine dose, women reported that they would spend significantly less for the dose than men ($1.58 vs. $3.15). Although cocaine produced similar effects in men and women 4 min after each dose, 15 min after the last dose of the session, heart rate and blood pressure remained elevated in women, but ratings of "I want cocaine" were lower in women as compared to men. Thus, smoking cocaine produced similar acute subjective effects in men and women, but prolonged cardiovascular effects and higher cocaine plasma concentrations in women.     

The relative bioavailability of paracetamol and codeine after oral administration of a combination of buclizine, paracetamol and codeine, with or without docusate, and of paracetamol alone in healthy volunteers

A randomized, double-blind, crossover study was carried out in 10 healthy volunteers to investigate whether the inclusion of the wetting agent docusate sodium (10 mg) in a combined oral formulation ('Migraleve') with buclizine hydrochloride (6.25 mg), codeine phosphate (8 mg) and paracetamol (500 mg) had any effect on the bioavailability of the analgesics. On 3 occasions at weekly intervals, the subjects were given 2 tablets of the standard formulation, the combination without docusate or 500 mg paracetamol alone. Blood samples were taken before and at fixed times during the 4 hours after administration of each preparation for estimation of plasma concentrations of paracetamol, by gas-liquid chromatography, and of codeine, by radioimmunoassay. The results showed that there were no significant differences between the mean paracetamol concentrations achieved after administration of each of the 3 preparations at any of the time points. Peak paracetamol plasma concentrations were 11.25 +/- 1.74 micrograms/ml at 0.5 hours, 9.6 +/- 1.04 micrograms/ml at 0.75 hours, and 9.53 +/- 1.66 micrograms/ml at 0.5 hours, respectively, after the standard formulation, the combination without docusate, and paracetamol alone. Mean elimination half-lives for paracetamol were 2.83 +/- 0.51, 1.92 +/- 0.20 and 2.49 +/- 0.46 hours, respectively, and the differences were not significant. The difference between mean plasma concentrations of codeine after the two preparations including this analgesic bordered on significance at 3 hours and was significant at 4 hours, but the areas under the curve were not significantly different. Peak codeine plasma concentrations after the standard formulation were 42.1 +/- 9.4 ng/ml at 0.75 hours compared with 36.9 +/- 3.4 ng/ml at 1.5 hours after the combination without docusate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of a guanfacine extended-release formulation in children and adolescents with attention-deficit-hyperactivity disorder

STUDY OBJECTIVE: To evaluate the single- and multiple-dose pharmacokinetics of an oral extended-release formulation of guanfacine in children and adolescents with a diagnosis of attention-deficit-hyperactivity disorder (ADHD). DESIGN: Phase I-II, open-label, dose-escalation study. SETTING: Clinical study center. PATIENTS: Fourteen children (aged 6-12 yrs) and 14 adolescents (aged 13-17 yrs) with ADHD. INTERVENTION: All patients received guanfacine as a single 2-mg dose on day 1. They received a daily dose of 2 mg on days 9-15, 3 mg on days 16-22, and 4 mg on days 23-29. MEASUREMENTS AND MAIN RESULTS: Blood samples, vital signs, and electrocardiograms (ECGs) were obtained before dosing on day 1 and at intervals over 24 hours, with repeat measurements on days 14 and 28. Guanfacine demonstrated linear pharmacokinetics. Mean plasma concentrations, peak exposure (C(max)), and total or 24-hour exposure (area under the concentration-time curve [AUC](0-infinity) or AUC(0-24), respectively) were as follows in children and adolescents, respectively: after a single 2-mg dose, AUC(0-infinity) was 65.2 +/- 23.9 ng x hour/ml and 47.3 +/- 13.7 ng x hour/ml and C(max) was 2.55 +/- 1.03 ng x ml and 1.69 +/- 0.43 ng/ml after multiple 2-mg doses, AUC(0-24) was 70.0 +/- 28.3 ng x hour/ml and 48.2 +/- 16.1 ng x hour/ml and C(max) was 4.39 +/- 1.66 ng/ml and 2.86 +/- 0.77 ng/ml; and after multiple 4-mg doses, AUC(0-24) was 162 +/- 116 ng x hour/ml and 117 +/- 28.4 ng x hour/ml and C(max) was 10.1 +/- 7.09 ng/ml and 7.01 +/- 1.53 ng/ml. After a single 2-mg dose, half-life was 14.4 +/- 2.39 hours in children and 17.9 +/- 5.77 hours in adolescents. The most frequent treatment-emergent adverse events were somnolence, insomnia, headache, blurred vision, and altered mood. Most were mild to moderate in severity, with the highest frequency associated with the 4-mg doses. Blood pressure, pulse, and ECG reading.hour/ml s were all within normal limits. CONCLUSION: Guanfacine extended-release formulation demonstrated linear pharmacokinetics. Plasma concentrations and concentration-related pharmacokinetic parameters were higher in children than in adolescents. These differences are likely due to heavier body weights in adolescents and young male subjects. No serious adverse events were reported.     

Selenium effects on human neutrophilic granulocyte function in vitro

The effects of an inorganic selenium salt on phagocytic functions of human neutrophilic granulocytes from donors with a low activity of glutathione peroxidase have been investigated. Granulocytes were exposed for 60 min in vitro to sodium selenite in two physiological concentrations (100 and 200 ng Se/ml) and one unphysiologically high concentration (2000 ng/ml). The spontaneous and chemotactic migration, the nitroblue tetrazolium reduction, the phagocytosis of fluorescein-labeled yeast particles and the intracellular killing of staphylococci were then studied in such granulocytes and compared to control cells, which had not been exposed to selenium. The migration and nitroblue tetrazolium reduction abilities of granulocytes were not affected by selenium exposure. The phagocytic and bactericidal activities were significantly increased in granulocytes exposed to selenium in physiological concentrations. However, at 2000 ng Se/ml these activities were found to be equal to or lower than control levels. Thus selenium supplementation might enhance phagocytic and bactericidal functions of human granulocytes, thereby improving the host defense against bacterial infections.     

Gender differences in labetalol kinetics: importance of determining stereoisomer kinetics for racemic drugs

STUDY OBJECTIVE: To evaluate the impact of gender on labetalol kinetics. DESIGN: Part of a randomized, crossover study. SETTING: Academic medical center. PATIENTS: Nineteen hypertensive patients (14 men, 5 women; 6 blacks, 13 whites). INTERVENTIONS: Participants had labetalol dosages titrated to a specific antihypertensive response, then underwent ambulatory blood pressure monitoring (ABPM) and a pharmacokinetic study. Labetalol plasma concentrations were measured by high-performance liquid chromatography (HPLC) and labetalol stereoisomer ratios were determined in a single plasma sample by chiral HPLC, both with fluorescence detection. MEASUREMENTS AND MAIN RESULTS: Labetalol concentrations were 80% higher in women (area under the concentration-time curve [AUC]/dose x 1000: 6.79 +/- 2.11 in women vs 3.82 +/- 1.37 hr/L in men, p<0.05), yet both genders had a similar antihypertensive response by 24-hour ABPM. Dose-corrected AUC (AUC/dose x 1000) for labetalol's stereoisomers in women and men, respectively, were S,R-labetalol 7.55 +/- 1.47 and 4.83 +/- 1.54 hr/L (p<0.05), S,S-labetalol 8.23 +/- 2.93 and 4.65 +/- 1.78 hr/L (p<0.05), R,S-labetalol 6.99 +/- 3.30 and 4.25 +/- 2.35 hr/L (p=0.11), and R,R-labetalol 3.91 +/- 2.57 and 3.55 +/- 3.08 hr/L (NS). CONCLUSION: The higher labetalol concentration in women than in men was explained largely by differences in inactive and alpha1-blocking stereoisomers. However, concentrations were similar between genders for the beta-blocking stereoisomer (R,R-labetalol), possibly explaining the similarity in antihypertensive response to the drug. This study highlights the importance of determining stereoisomer kinetics for agents administered as racemates, particularly when relating concentrations to pharmacologic response.     

Effect of CYP2D6 genotypes on the metabolism of haloperidol in a Japanese psychiatric population.

We investigated the effect of CYP2D6 genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 88 Japanese schizophrenic inpatients being treated with HAL. Some subjects carrying CYP2D6*5 allele (CYP2D6*1/CYP2D6*5, CYP2D6*5/CYP2D6*10) showed extremely high concentrations of both HAL and RHAL, and the groups with CYP2D6*5 allele seemed to have higher plasma concentrations of HAL (1.14+/-0.69 ng/ml/mg) and RHAL (1.10+/-1.05 ng/ml/mg) than the other groups. Among those without CYP2D6*5 allele, there were no significant differences in plasma concentrations of HAL and RHAL between those without CYP2D6*10 allele (HAL=0.68+/-0.31 ng/ml/mg, RHAL=0.28+/-0.37 ng/ml/mg), those with one CYP2D6*10 (HAL=0.70+/-0.23 ng/ml/mg, RHAL=0.31+/-0.16 ng/ml/mg) and those with two CYP2D6*10 alleles (HAL=0.69+/-0.14 ng/ml/mg, RHAL=0.40+/-0.09 ng/ml/mg), although there was a tendency of higher plasma concentration of RHAL in those with two CYP2D6*10 alleles. At a lower daily dosage of HAL (<10 mg/day), the subjects with two or one CYP2D6*10 allele(s) showed significantly higher plasma concentrations of RHAL (0.43+/-0.23 ng/ml/mg, 0.34+/-0.16 ng/ml/mg) than those without CYP2D6*10 allele (0.18+/-0.16 ng/ml/mg). The results of this study indicate that CYP2D6*10 allele plays significant but modest role in HAL metabolism in Japanese; nevertheless, we should not lump CYP2D6*10 allele with CYP2D6*5 allele because these two mutated alleles seem to have different impacts in the metabolism of HAL.     

Tissue absorption and distribution of ketoprofen after patch application in subjects undergoing knee arthroscopy or endoscopic carpal ligament release

The diffusion into the target tissues of ketoprofen (CAS 22071-15-4), a widely used nonsteroidal anti-inflammatory drug, from a new topical patch has been studied after repeated patch application in comparison with its plasma level. Ten patients (5 women and 5 men) with a mean age of 45.0 +/- 12.3 years (mean +/- SD), scheduled for arthroscopic meniscectomy (5 subjects) or endoscopic carpal tunnel decompression (5 subjects), were asked to apply one patch with 100 mg ketoprofen on the affected body site once a day during the 6 days before the scheduled surgery. The last patch was kept for 6 h, and removed just a few minutes before surgery, when venous blood was drawn. Biopsies of the synovial tissue of the medial compartment and of the anterior fat pad (Hoffa's tissue) or of the ulnar bursa were taken during knee arthroscopy or endoscopic carpal tunnel release, respectively. An average plasma value of 52.8 +/- 30.1 (SD) ng/ml of ketoprofen was obtained in the 10 patients. The tissue concentrations of ketoprofen in the 5 subjects undergoing knee arthroscopy were 27.9 +/- 26.1 ng/g (range 7.2-67.1 ng/g) in the anterior fat pad and 239.0 +/- 163.0 ng/g (range 20.0-430.5 ng/g) in the synovial tissue. Drug concentrations up to 1000 times higher were found in the tendon sheath tissue of the ulnar bursa of the five patients undergoing endoscopic carpal tunnel release: average values of 20,107 +/- 7359 ng/g (range 13,004-32,578 ng/g) were obtained in this tissue. Data observed in this trial are consistent with those previously published by other authors, and demonstrate that ketoprofen applied on the skin is able to enter the subcutaneous and intra-articular tissues, reaching concentrations markedly higher than in plasma, and is further able to produce the desired pharmacological activity in situ, whereas plasma concentrations are too low to produce any systemic activity or side effect.     

Comparison of the pharmacokinetics of moxidectin and ivermectin after oral administration to beagle dogs

This study compares plasma disposition kinetics of ivermectin and moxidectin after oral administration to beagle dogs experimentally infected with the filarial parasite, Brugia pahangi. Sixteen dogs were selected and randomly allocated into two groups of eight dogs each. Animals in each group received either ivermectin or moxidectin by oral route at a dose of 250 microg/kg. Blood samples were collected from 0.5 h up to 56 days post-treatment and the plasma was analysed by high performance liquid chromatography (HPLC). The obtained data were analysed by compartmental and non-compartmental pharmacokinetic techniques. Peak plasma concentrations (C(max)) of 234.0 +/- 64.3 ng/ml (mean +/- SD) were obtained for moxidectin and 132.6 +/- 43.0 ng/ml for ivermectin. The terminal elimination half-life was significantly (p<0.01) longer in the moxidectin treated group (621.3 +/- 149.3 h) than for ivermectin treated group (80.3 +/- 29.8 h). A significantly (p< 0.01) larger V(ss)/F was obtained for moxidectin (19.21 +/- 3.61 l/kg) compared with ivermectin (5.35 +/- 1.29 l/kg). The mean estimates of CL/F of moxidectin and ivermectin were 0.0220 +/- 0.00381 and 0.0498 +/- 0.0179 l/h/kg, respectively. The comparative plasma disposition kinetics of ivermectin and moxidectin in dogs is reported for the first time.     

Effect of sex and AIDS status on the plasma and intrapulmonary pharmacokinetics of rifampicin

OBJECTIVE: To compare the steady-state plasma and intrapulmonary concentrations of oral rifampicin (rifampin) in men and women with and without AIDS. DESIGN: Prospective nonblinded pharmacokinetic study. PARTICIPANTS: Ten men with AIDS, ten men without AIDS, ten women with AIDS, and ten women without AIDS. METHODS: Rifampicin 600 mg was administered orally once daily for 5 days to 40 adult volunteers. Blood was obtained 2 hours after the last dose and at the time of bronchoalveolar lavage (BAL) performed 4 hours after the last dose. Rifampicin was measured in plasma, epithelial lining fluid (ELF) and alveolar cells. Standardised BAL was performed without systemic sedation. The volume of ELF was calculated by the urea dilution method, and alveolar cells were recovered by a standardised centrifugation technique. The volume of alveolar cells was calculated from the cell count and differential performed on the BAL fluid. Rifampicin was measured by high-performance liquid chromatography. RESULTS: Sex or AIDS status had no effect on plasma concentrations of rifampicin at 2 hours, 4 hours, or in ELF. Plasma concentrations (mean +/- SD) of rifampicin at 2 hours (9.15 +/- 5.4 mg/L) were not significantly different (p > 0.05) from those at 4 hours (9.10 +/- 5.6 mg/L) following the last dose. The ELF concentration was 2.0 +/- 1.6 mg/L with a range of 0-7.3 mg/L and the ELF/plasma ratio at 4 hours was 0.2 +/- 0.2. Rifampicin was not detectable in ELF in eight subjects (three with AIDS and five without AIDS) or in alveolar cells in three subjects without AIDS. There was no significant effect of AIDS on alveolar cell concentrations of rifampicin. Alveolar cell concentrations of rifampicin were significantly greater in women (13.9 +/- 6.7 mg/L) than in men (6.6 +/- 4.1 mg/L) [p = 0.0003]. Alveolar cell rifampicin concentrations were 78% greater in smoking women (17.8 +/- 7.0 mg/L) than in nonsmoking women (10.0 +/- 2.4 mg/L), but the difference was not significant (p > 0.05). CD4+ cell counts in the AIDS subjects were not correlated with the concentrations of rifampicin in plasma, ELF or alveolar cells. CONCLUSIONS: The absorption of oral rifampicin was not affected by sex or AIDS. Plasma and alveolar cell concentrations were not significantly different, were both greater than ELF concentrations, and were adequate to inhibit Mycobacterium tuberculosis. Considerable interpatient variability was detected despite witnessed drug administration. The clinical significance of these findings is unknown but merits further investigation.     

Effects of gender and race on albuterol pharmacokinetics

We evaluated the effects of race and gender on albuterol pharmacokinetics in 30 patients with moderate asthma (15 blacks, 15 whites, 16 men, 14 women). Subjects received a single dose of albuterol 8 mg oral solution and had blood samples collected at various times for 12 hours after the dose. Albuterol plasma concentrations were determined by HPLC with fluorescence detection, and pharmacokinetics were determined by compartmental analysis. The apparent volume of distribution of albuterol was significantly higher in men than in women (631+/-171 and 510+/-109 L, respectively, p<0.05). Consequently, the maximum concentration was lower in men than women (10.3+/-2.1 and 12.0+/-1.9 ng/ml, respectively, p<0.05). Elimination rates were 0.136+/-0.008 and 0.160+0.012 hour(-1), respectively (p<0.10). When corrected for ideal body weight, apparent volume of distribution was not different by gender. No differences between blacks and whites other than lag time were noted in albuterol kinetics. The greater apparent volume of distribution in men is likely explained by differences in ideal body weight or lean body mass.     

Disposition of paclitaxel (Taxol) and its metabolites in patients with advanced breast cancer (ABC) when combined with trastuzumab (Hercpetin).

Monoclonal antibodies are capable of modulating drug metabolising enzymes resulting in unexpected plasma concentrations of a drug when given concomitantly. Therefore plasma concentration of paclitaxel (PTX) and its metabolites has been monitored in 10 patients with advanced breast cancer during treatment with PTX alone or combined with trastuzumab (TMAB, paired cross over design). Compared to the MONO regimen PTX peak plasma concentrations were about 25% lower in the TMAB schedule: cmax = 3294 +/- 1174 ng/ml (MONO: 4368 +/- 1887 ng/ml). TMAB also caused lower peak plasma concentration of the main metabolite 6-hydroxy PTX (248 +/- 89 ng/ml) compared to the MONO schedule (194 +/- 82 ng/ml). Cmax of the minor metabolites was distinctly below 100 ng/ml and consequently differed negligible in both schedules. The similar apparent formation rate of the metabolites in both schedules (range from 30 to 50 min) as well as identical tmax values (range 170-190 min) suggested that TMAB had no influence on PTX metabolism. In accordance to plasma concentrations, AUClast of PTX was lower in the MONO schedule (733 +/- 197 microg/ml*min, AUClast = 669 +/- 248 microg/ml*min for TMAB) but without significance. In summary no indices for an altered plasma disposition of PTX and its metabolites could be found when TMAB was given concomitantly.