Pharmacokinetics and pharmacodynamics of tucaresol, an antisickling agent, in healthy volunteers.

1. Tucaresol is an orally administered antisickling agent which increases the oxygen affinity of haemoglobin. 2. The pharmacokinetics, effects on moderate graded exercise and psychometric performance of tucaresol were examined in a double-blind, placebo-controlled, parallel groups study in 12 healthy men. 3. Three doses of tucaresol were given at 48 h intervals intended to modify 15, 25 and 32.5% of a subject's haemoglobin to a high affinity form (%MOD). 4. Mean peak %MOD was 34%. Mean Cmax values in plasma and erythrocytes were 81.4 and 1459 micrograms ml-1, respectively. 5. Heart rate, compared with baseline, increased in the tucaresol group with the greatest changes at the highest %MOD and workload. There were no differences between groups in psychometric test performance. 6. Three volunteers on active drug developed fever, rash and tender cervical lymphadenopathy with onset 7-10 days from the start of dosing, suggesting an immune mechanism. 7. The acute increase in oxygen affinity with tucaresol is physiologically well-tolerated, but the utility of tucaresol in the management of sickle cell disease will depend on the identification of a dosing regimen with a lower incidence of drug allergy.     

Single- and multiple-dose pharmacokinetics of nufenoxole in healthy human subjects

1. In 12 healthy subjects, after single doses of 20, 40 and 80 mg of nufenoxole, mean peak plasma drug concentrations of 400, 815 and 1463 ng/ml were reached at 2.2, 2.5 and 2.5 h respectively. 2. Nufenoxole was absorbed with an apparent half-life of less than one hour at all three doses. Nufenoxole concentrations declined biphasically after the peak, with an initial and terminal half-life of four to five hours and about 27 h respectively. These half-lives were independent of the administered dose. 3. AUC and Cmax increased with increasing dose, but AUC did not increase proportionately to dose, due to a lower value for 80 mg than expected, possibly reflecting reduced absorption. 4. Observed nufenoxole concentrations, in another 12 healthy subjects receiving single, daily 80 mg oral doses of nufenoxole for eight days, were in excellent agreement with those predicted from single-dose pharmacokinetics.     

Dose-Dependent Pharmacokinetics of L-693,612, a Carbonic Anhydrase Inhibitor,Following Oral Administration in Rats

The disposition of L-693,612, a carbonic anhydrase inhibitor, was examined in rats following oral doses of 0.05 to 25 mg/kg. Area under the blood concentration–time curve (AUC) increased linearly with dose up to 0.25 mg/kg. However, the linear range did not extend to 5 and 25 mg/kg doses; AUC rose only 10-fold overall despite a 500-fold increase in dose. A similar pattern of disproportionality occurring after i.v. administration indicated that the nonlinear behavior after oral doses was not due to dose-limited absorption, but rather it arose because blood clearance increased with dose. Concentration-dependent erythrocyte/plasma partitioning arising from saturation of binding to erythrocyte carbonic anhydrase could explain the dose-dependent blood clearance. At blood concentrations (<25 µM) achieved in the linear dose range, L-693,612 was extensively sequestered in red blood cells, bound to carbonic anhydrase, with a constant low free fraction in plasma available for elimination. At doses which saturated the binding capacity of carbonic anhydrase, blood clearance increased, since for low hepatic extraction compounds, the rate of elimination is dependent upon the free fraction in blood. Dose-dependent increases in distribution volumes were consistent with the view that high-affinity binding to carbonic anhydrase confined this compound largely to blood volume at low doses, but saturation of binding sites increased availability to peripheral tissues after high doses. Increasing the dose had a minimal effect on terminal half-life because it reflected the concentration–time profile during a period of linear distribution into erythrocytes.     

Side effects occurring during administration of epoprostenol (prostacyclin, PGI2), in man.

1 High pressure liquid chromatographic assays for the estimation of sulphinpyrazone and its sulphide, sulphone and p-hydroxy metabolites in plasma and urine are described. 2 Five normal volunteers received 200 mg and 400 mg sulphinpyrazone orally. Sulphinpyrazone was rapidly absorbed and eliminated with a half-life of approximately 4 h irrespective of dose. Peak plasma concentrations and area under the plasma concentration-time curves (AUC) were consistent with linear pharmacokinetic behaviour. 3 Plasma concentrations of the sulphone were low and peaked before those of the sulphide; its mean half-life was 3.1 h. The sulphide, which may be the sulphinpyrazone metabolite with activity on platelets, was eliminated with a mean half-life of 13.4 h. The AUC increases with dose of both metabolites suggested non-linearity. 4 Approximately 45-50% of the administered dose was eliminated in the urine as unchanged drug or as sulphone or p-hydroxy-sulphinpyrazone. The sulphide metabolite was not detected in the urine. The renal clearance of sulphinpyrazone was approximately 18 ml min-1 and that for the sulphone was similar. Sigma minus plots of the urinary excretion yielded half-lives of 3.5 h for the sulphone and 1 h for p-hydroxy-sulphinpyrazone.     

Tissue distribution after intravenous dosing of micafungin, an antifungal drug, to rats

The tissue distribution after an intravenous dose of micafungin (1 mg/kg), a new echinocandin-like lipopeptide antifungal agent, to male rats was investigated. Micafungin in plasma disappeared biexponentially with a terminal half-life of 5.03 h. Micafungin concentrations in liver, kidney, and lung at the first sampling time (5 min) after dosing were 1.15, 1.64, and 2.58-fold higher than the plasma concentration, and the AUC(0- infinity ) were 1.61, 3.42, and 2.89-fold higher than that for plasma. The terminal half-lives for these tissues were 5.14, 4.87, and 5.31 h, respectively, which were comparable to those for plasma. These results suggest that micafungin distributes rapidly and moderately into tissues such as the liver, kidney, and lungs, and that the concentrations in tissues decreased in parallel with the unchanged drug in plasma.     

PHARMACOKINETICS OF AZITHROMYCIN IN LUNG TISSUE, BRONCHIAL WASHING, AND PLASMA IN PATIENTS GIVEN MULTIPLE ORAL DOSES OF 500 AND 1000 MG DAILY

The present study compares the pharmacokinetics of azithromycin in plasma, lung tissue, and bronchial washing after oral administration of 500 mg (standard dose) versus 1000 mg daily for 3 days. Samples were taken during surgery for lung resection at various time points up to 204 h after the last drug dose, and azithromycin levels were analyzed by HPLC method. Azithromycin was widely distributed within the lower respiratory tract; sustained concentrations of the drug were detectable at the last sampling time (204 h) in lung tissue and bronchial washing, with long terminal half-lives of 132.86 and 74.32 h at 500 mg daily and 133.32 and 70.5 h at 1000 mg daily, respectively. Doubling the drug dose resulted in a remarkable increase in lung area under the curve (AUC, 1318 hx microg g(-1) vs 2502 hx microg g(-1)) and peak tissue concentration (9.13+/-0.53 microg g(-1) vs 17.85+/-2.4 microg g(-1)). In addition to this, enhanced azithromycin penetration from plasma into bronchial secretion and lung tissue was evidenced by the increase in the ratio of AUC(bronchial washing) versus AUC(plasma) (2.96 vs 5.27 at 500 and 1000 mg, respectively) and AUC(lung) versus AUC(plasma) (64.35 vs 97.73 at 500 and 1000 mg, respectively). In conclusion, the exposure of lung and bronchial washing to azithromycin is increased by doubling the dose, which results in favorable pharmacokinetic profile of the drug in the lower respiratory tract.     

ICI 141,292 (epanolol) —pharmacokinetics after single and repeated oral administration in the elderly with moderate renal impairment

Summary The pharmacokinetics of ICI 141,292 (epanolol) were studied over 3 days after a single oral 200 mg dose and then over 24 h after 12 consecutive daily oral 200 mg doses in 16 elderly subjects (aged 65 to 94 years) with moderate renal impairment (mean creatinine clearance 33.2 ml · min⁻¹). There was wide inter-individual variability in peak plasma ICI 141,292 concentrations (C_max) but no significant difference was found between mean C_max after a single dose (44.3 ng. ml⁻¹) and after 12 doses (37.4 ng. ml⁻¹). The mean observed time to peak plasma ICI 141,292 concentration (t_max) after a single dose (1.61 h) did not differ significantly from that after 12 doses (1.75 h). On several occasions an analytically significant second peak in ICI 141,292 plasma concentration was observed. Following the peak(s), the plasma concentrations declined biphasically and a mean terminal phase plasma half-life (t11/2) of 28.3 (range 10.2–84.8) h was calculated after a single dose. The inter-individual variability in the area under the plasma concentration-time curve to 24 h AUC (0-24) was 54 fold but there was no significant difference between AUC (0-24) after a single dose (mean 226.0 rig·h·m1⁻¹) and AUC (0-24) after 12 consecutive doses of ICI 141,292 (mean 232.4 ng·h·ml⁻¹). The results show that consecutive daily administration of 12 oral doses of IC1 141,292 (200 mg) does not result in significant accumulation of drug in elderly subjects with moderate renal impairment.     

Contradistinction between doxorubicin and epirubicin: in-vitro interaction with blood components.

The molecular structure and anti-tumour activity of doxorubicin and epirubicin are similar. However, the incidence of their cardiotoxicity occurs at different cumulative dose concentrations. The purpose of this study was to investigate the in-vitro interaction of these two drugs with different blood components, namely intact erythrocytes, haemoglobin and erythrocyte ghosts. Plasma protein binding was also evaluated. The intended goal was to identify the most relevant samples among total blood, plasma or blood cells for pharmacokinetic analysis. The methodology involved the incubation of each of the blood components (the intact erythrocytes, erythrocyte ghosts, haemoglobin and plasma proteins) at physiological pH and temperature with different concentrations of each drug, followed by measurement by HPLC and fluorometry at excitation and emission wavelengths of 480 and 580 nm, respectively. The results indicated that the binding of doxorubicin and epirubicin to plasma proteins, erythrocyte ghosts and intact erythrocytes was essentially the same. However, the binding of both compounds to intact erythrocytes was significantly different from erythrocyte ghosts, which indicates that haemoglobin plays an important role in the binding to and uptake by erythrocytes. The isotherms of binding to haemoglobin revealed that the maximum binding of doxorubicin was approximately 0.42 microg mg(-1) haemoglobin; for epirubicin this value was ten times greater than for doxorubicin. The Scatchard plot of binding of both drugs to haemoglobin exhibited two distinct binding sites for each drug. The constant of association of high affinity and low capacity binding sites was significantly greater for epirubicin, whereas the constant of association of low affinity and high capacity binding sites was significantly higher for doxorubicin. The number of high affinity binding sites per mg of haemoglobin was estimated to be 0.072 for doxorubcin and 0.030 for epirubicin. The number of low affinity binding sites was significantly greater for epirubicin (1.963) than for doxorubicin (0.305). Since the combined number of binding sites for epirubicin was more than doxorubicin, and the total uptake by erythrocytes remained the same for both drugs, it was concluded that epirubicin, being a more lipophilic compound, may diffuse more freely into the cells. Therefore, it binds more to haemoglobin, whereas doxorubicin remains more adsorbed on the surface of the cells due to its self-association property. It was concluded that the interaction of both drugs with erythrocytes, although it appears to be similar, is significantly different due to the interaction with haemoglobin. The difference in this interaction is expected to influence the disposition of both drugs in-vivo.     

A pharmacokinetic and tolerance study of Ro13-9904, a new cephalosporin antibiotic.

1 Six healthy male volunteers received a total of 2500 mg of a new cephalosporin antibiotic Ro13-9904 by intramuscular injection in five divided doses at intervals of 12 h. 2 No significant systemic side-effects were observed and this was confirmed haematologically and biochemically. 3 The drug was distributed following intramuscular injection reaching a mean peak plasma concentration of 55 micrograms ml-1 (range 46-66) 1 to 2 h after the first injection. 4 Monoexponential elimination of drug was demonstrated. No significant difference was recorded in the plasma half-life after the initial dose (mean 6.7 h) and at steady state (mean 6.7 h). The half-life is long compared with other cephalosporin antibiotics. 5 On the basis of the observed half-life, steady state should be reached within 48 h. A mean peak plasma concentration of 74 micrograms ml-1 (range 65-87) was recorded at steady state. Steady state plasma concentrations of Ro13-9904 with a dose of 500 mg every 13 h may be predicted from the pharmacokinetics of a single dose.     

Spline functions in convolutional modeling of verapamil bioavailability and bioequivalence. II: study in healthy volunteers.

The pharmacokinetics of a new verapamil retard tablet formulation have been investigated in a randomized cross-over bioequivalence study on 12 healthy subjects. The drug was given orally at a single new or standard retard tablet dose of 240mg and at a single intravenous dose of 5mg. Plasma verapamil concentrations were determined by HPLC. New retard tablets produced peak plasma verapamil concentrations of 81.34+/-5.69microg/l, time to peak plasma concentrations of 4.91+/-0.89h and an AUC (0-24h) of 1291+/-103.4h x microg/l, with a terminal phase half-life of 55.1+/-14.9h. After intravenous administration verapamil exhibited biphasic elimination kinetics with a terminal plasma half-life of 2.36+/-0.42h and systemic clearance of 34.32+/-5.81 l/h. Bioavailability of the new peroral retard formulation ranged from 19.49+/-4.41% to 67.69+/-11.70%. Absorption rates and amounts were evaluated by means of the spline-convolutional method. Input rates for the new verapamil retard formulation ranged from 0.77+/-0.20mg/h to 5.57+/-1.58mg/h. The cumulative amount of verapamil input was 39.17+/-9.71% for the new retard tablets. All pharmacokinetic parameters for the new verapamil retard tablet formulation, were in reasonable agreement with the data obtained on already registered verapamil retard formulations, indicating their bioequivalence.     

Dose-escalation study of ICA-17043 in patients with sickle cell disease

STUDY OBJECTIVE: To determine the dose tolerance, safety, and pharmacokinetics of a single oral dose of ICA-17043 in patients with sickle cell disease. DESIGN: Phase I, randomized, double-blind, placebo-controlled, single-dose, dose-escalation study. SETTING: Four university medical centers. PATIENTS: Twenty-eight patients with sickle cell disease, aged 18-60 years, who were otherwise healthy and in a noncrisis state. INTERVENTION: Patients in three separate dose cohorts--50 mg, 100 mg, and 150 mg--received single doses of ICA-17043 or placebo. MEASUREMENTS AND MAIN RESULTS: The mean area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-infinity)) for ICA-17043 increased in a dose-related manner (11,827, 19,697, and 30,676 ng.hr/ml for 50, 100, and 150 mg, respectively). Overall mean half-life was 12.8 days. Mean peak plasma concentrations rose between the 50- and 100-mg dose levels but plateaued at 150 mg (59.1, 108.7, and 109.1 ng/ml, respectively). Weekly pharmacokinetic and safety assessments were conducted in each patient during the follow-up phase for 56 days. No dose-limiting adverse events were noted in any of the patients. CONCLUSION: Total systemic exposure of ICA-17043 after a single oral dose, as measured by AUC(0-infinity), increased nearly proportionally with the dose. The rate of absorption, however, appeared to be delayed at doses greater than 100 mg. With the long half-life of ICA-17043 demonstrated in this study, once-daily dosing is probably adequate to maintain steady-state plasma concentrations. In addition, single doses of ICA-17043 were well tolerated.     

Tizanidine — Initial pharmacokinetic studies in patients with spasticity

The time-course of plasma concentrations of the antispasticity agent tizanidine were measured by a specific radioimmune-assay in six adults who had severe spasticity due to multiple sclerosis. The drug was given as a single oral 4 mg dose to each subject. The drug had a mean absorption half-life of 0.30 +/- 0.155 h following a mean lagtime of 0.361 +/- 0.118 h, and a mean terminal elimination half-life of 4.16 +/- 2.06 h. Only 2.65 +/- 0.82% of the dose was excreted unchanged in urine in 2 h. Calculated values of clearance and apparent volume of distribution were almost certainly overestimates as it seems probable that the orally-administered drug undergoes significant presystemic elimination (its bioavailability was not determined in the investigation here reported). Relief of spasticity, from the dosage used, was relatively slight and appeared greatest at the time of peak plasma levels of the drug.     

In-vitro Interaction of Artemisinin with Intact Human Erythrocytes,Erythrocyte Ghosts,Haemoglobin and Carbonic Anhydrase

The kinetics of the interaction of the antimalarial compound artemisinin with human erythrocytes, erythrocyte ghosts, haemoglobin and carbonic anhydrase were evaluated in-vitro. Artemisinin plasma concentrations, measured by HPLC (high pressure liquid chromatography), decreased with time during incubations with whole blood and erythrocyte suspensions of varying haematocrit. Artemisinin concentrations declined more rapidly during incubations under oxygen-poor as compared to oxygen-rich conditions. Artemisinin concentrations did not decrease during incubation with erythrocyte ghosts suspended in plasma suggesting that the drug does not bind avidly to red blood cell membranes. There was no decline in concentrations of artemisinin in the presence of carbonic anhydrase. The disappearance of the drug in solutions containing haemoglobin was very rapid and was even more so when the incubation was performed under an argon- instead of oxygen-rich atmosphere. The results suggest that drug blood clearance may be considered for inclusion in a pharmacokinetic model, but does not invalidate in-vivo plasma concentration-time data and their relevance for clinical effects. Furthermore, caution is advised when relating measurements of in-vitro potency to drug levels in patients. Finally, the enhanced artemisinin disappearance when oxygen tension is low may contribute towards the explanation of the selective toxicity of the endoperoxide drugs to Plasmodium falciparum parasite.     

Single- and multiple-dose pharmacokinetics of an oral once-a-day osmotic controlled-release OROS (methylphenidate HCl) formulation

Methylphenidate is used for the treatment of attention deficit hyperactivity disorder (ADHD). OROS (methylphenidate HCl) is an osmotic controlled-release delivery system designed for once-daily oral dosing. The pharmacokinetics of OROS (methylphenidate HCl) 18 mg qd, sustained-release (SR) methylphenidate 20 mg qd, and the immediate-release (IR) formulation given as three 5 mg doses every 4 hours (tid) were compared in adults. In addition, the single- and multiple-dose pharmacokinetics of the OROS formulation were studied. Following OROS (methylphenidate HCl), there was a gradual increase in the mean methylphenidate plasma concentrations with peak concentrations noted at 6 to 8 hours. With the SR formulation, peak plasma concentrations were noted at approximately 4 hours. Following the IR regimen, methylphenidate plasma concentrations fluctuated in tandem with oral dosing; peak concentrations were noted at 6.5 hours. The terminal half-life of methylphenidate was similar for the three formulations. The dose-normalized methylphenidate Cmax for OROS (methylphenidate HCl) was significantly lower than for IR and SR methylphenidate. The bioavailability of methylphenidate and PPA from OROS (methylphenidate HCl) relative to the IR and SR formulations was complete. Mean methylphenidate AUC and terminal half-life were similar after single (32.9 ng.h/mL and 3.9 hours) and multiple doses (35.2 ng.h/mL and 3.9 hours) of OROS (methylphenidate HCl).     

Plasma pharmacokinetics of etoposide (VP-16) after i.v. administration to children

The pharmacokinetics of etoposide (VP-16), a semi-synthetic derivative of podophyllotoxin, were studied in 16 pediatric patients (median age 8.3 years; range 4 months to 22 years) including two girls with Down's syndrome (DS). The drug was administered as infusions (1-3 h) in a wide range of doses (9-322 mg, corresponding to 32-210 mg/m2). The area under the plasma concentration versus time curve (AUC), dose normalized by the body surface area, was independent of age, while AUC normalized by the dose in mg/kg increased with increasing age of the patients. The interpatient variability of AUC, normalized for the dose in mg/m2, was 23% (CV) compared to 32% (CV) normalized for the dose in mg/kg. The terminal half-life time was 4.1 h (median value; range 2.0-7.8 h). The pharmacokinetics of etoposide in children with DS and chromosomally normal children were very similar with regard to systemic drug exposure and plasma half-life time. From the pharmacokinetic point of view it was therefore not necessary to make any dose modifications in the two girls with DS. The two DS patients did not experience any enhanced degree of toxicity from their etoposide treatments. The results support that dosing of etoposide to children should be based on body surface area.     

Physiological disposition of CGS 16617 in rat, dog, and man

The disposition and metabolism of CGS 16617 (3-[(5-amino-1-carboxy-1S-pentyl)amino],2,3,4,5-tetrahydro-2-oxo-3S-1H-1 - benzazepine-1-acetic acid), and angiotensin l-converting enzyme inhibitor, were investigated in rats, dogs, and man. In rats, a single oral dose of 10 mg/kg 14C-CGS 16617 afforded peak plasma concentrations of drug between 0.5 and 6 hr of dosing. The AUC was on average 9.6% of that after iv administration of the same dose, indicating low oral absorption of the drug. The apparent volumes of distribution, V1 and Vdss, were 0.45 and 2.5 liters/kg, respectively. Disappearance of the drug from plasma after the iv dose was biphasic, with mean half-lives of 0.5 and 13 hr, respectively, for the lambda 1 and lambda 2 phases. After single iv doses (10 mg/kg) to dogs and rats, 14CGS 16617 was almost exclusively eliminated by the renal route, with urinary recoveries of greater than 90% of dose. The same dose administered orally gave urinary recoveries of less than 10% of the dose in rats and about 15% in the dog. The remainder of the dose was eliminated in the feces. Bile duct-cannulated rats excreted less than 3% of an oral 10 mg/kg dose in the bile, in 24 hr. In man (N = 4), a single oral dose of 100 mg 14C-CGS 16617 resulted in peak plasma concentrations of 0.02-0.07 microgram of drug eq/ml between 4 and 6 hr of dosing. The mean terminal half-life was estimated at 81 hr.(ABSTRACT TRUNCATED AT 250 WORDS)     

Safety, tolerability, and pharmacokinetic profile of BIA 2-093, a novel putative antiepileptic, in a rising multiple-dose study in young healthy humans

This was a double-blind, randomized, placebo-controlled study to investigate rising oral doses of BIA 2-093 (S-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide), a putative new antiepileptic drug. Within each of 4 dosage groups of 8 healthy male adult subjects, 2 subjects were randomized to receive placebo, and the remaining 6 subjects were randomized to receive BIA 2-093 (200 mg bid, 400 mg qd, 800 mg qd, and 1200 mg qd) for 8 days. Concentrations of BIA 2-093 in plasma or urine were generally not measurable. Median maximum plasma concentrations of the major metabolite (licarbazepine, (+/-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide) were attained (t(max)) at 2 to 3 h postdose; thereafter, plasma concentrations declined with a mean apparent terminal half-life of 9 to 13 h following repeated dosing. The extent of systemic exposure to licarbazepine increased in an approximately dose-proportional manner following single and repeated administration. Licarbazepine accumulated in plasma following repeated administration of BIA 2-093; the mean extent of accumulation (R(O), calculated from AUC(0-tau) (day 8)/AUC(0-tau) (day 1)) was 3.0 after repeated, twice-daily dosing and 1.4 to 1.7 after once-daily dosing. Steady-state plasma licarbazepine concentrations were attained at 4 to 5 days of once- or twice-daily dosing, consistent with an effective half-life on the order of 20 to 24 h. The mean renal clearance of licarbazepine from plasma was approximately 20 to 30 mL/min, which is low compared with the glomerular filtration rate. The total amount of licarbazepine recovered in urine was approximately 20% within 12 h postdose and 40% within 24 h postdose. All adverse events were mild in severity, except for 1 case of somnolence of moderate severity, which occurred in a subject receiving 1200 mg BIA 2-093. The incidence of adverse events was similar between all treatment groups, including placebo. There were no serious adverse events. In conclusion, BIA 2-093 was well tolerated and appeared to be rapidly and extensively metabolized to licarbazepine following single and repeated administration to healthy young subjects.     

Pharmacokinetics of sarizotan after oral administration of single and repeat doses in healthy subjects

OBJECTIVE: Sarizotan is a 5-HTIA receptor agonist with high affinity for D3 and D4 receptors. Here we report the pharmacokinetic and tolerability results from four Phase 1 studies. MATERIALS: Two single-dose (5 -25 mg, n = 25, 0.5 - 5 mg, n = 16) and two multiple-dose (10 and 20 mg b.i.d., n = 30, 5 mg b.i.d., n = 12) studies with orally administered sarizotan HCl were carried out in healthy subjects. METHODS: Plasma sarizotan HCl concentrations were measured using a validated HPLC method and fluorescence or MS/MS detection. Pharmacokinetic parameters were obtained using standard non-compartmental methods. RESULTS: Sarizotan was rapidly absorbed, group-median times to reach maximum concentration (tmax) ranged from 0.5 -2.25 h after single doses and during steady state. Maximum plasma concentration (Cmax) and tmax were slightly dependent on formulation and food intake, whereas area under the curve (AUC) was unaffected by these factors. AUC and Cmax increased dose-proportionally over the tested dose range. Independently of dose and time, sarizotan HCl plasma concentrations declined polyexponentially with a terminal elimination half-life (t1/2) of 5 - 7 h. Accumulation factors corresponded to t1/2 values, and steady state was reached within 24 h. Plasma metabolite concentrations were considerably lower than those of the parent drug. The ratio metabolite AUC : parent drug AUC was time- and dose-independent for all three metabolites suggesting that the metabolism of sarizotan is non-saturable in the tested dose range. CONCLUSIONS: The pharmacokinetics of sarizotan were dose-proportional and time-independent for the dose range 0.5 -25 mg). The drug was well-tolerated by healthy subjects up to a single dose of 20 mg.     

Gender differences in pharmacokinetics of oral warfarin in rats

Gender different pharmacokinetics of warfarin were investigated after oral administration at a dose of 2 mg/kg to male and female rats. The concentrations of warfarin in rat plasma were analysed by the HPLC method. Noncompartmental analysis was used for the calculation of the total area under the plasma concentration-time curve from time zero to time infinity (AUC) and terminal half-life of warfarin. After oral administration of warfarin to female rats, the AUC was significantly greater (345 compared with 180 microg h/ml) than that in male rats.     

Clinical pharmacology of pravastatin,a selective inhibitor of HMG-CoA reductase

Summary Pravastatin, lovastatin and simvastatin are HMG-CoA reductase inhibitors with very similar structures. However, minor substitutions in the decalin ring have resulted in major differences in physicochemical, pharmacological, and pharmacokinetic properties. Both in vitro and in vivo studies have demonstrated that lovastatin and simvastatin are non-selective lipophilic inhibitors, while pravastatin is a selective hydrophilic inhibitor. An extensive clinical pharmacology program has been conducted for pravastatin. Radiolabelled studies demonstrated oral absorption and bioavailability values of 34% and 17%, respectively. The parent drug is cleared equally by renal and non-renal routes. Peak blood level after oral administration is reached at approximately 1 h and the mean plasma elimination half-life is 1.8 h. Binding of total radioactivity to plasma proteins averages 45%. Non-radiolabelled studies showed that mean areas under the plasma concentration-time curves (AUC) and maximum plasma concentrations (C_max) are proportional to the doses administered, whereas times to reach C_max (T_max) and plasma elimination half-life values are independent of dose. Measurement of trough plasma concentrations of pravastatin at steady state showed no evidence of drug accumulation. Pharmacodynamic studies demonstrated an average LDL-C decrease of 30–35% at a daily dose of 40 mg. HDL-C increases are between 10% and 25% and triglyceride decreases, between 10% and 25%. These results indicate that pravastatin is very effective in lowering LDL-C. With its consistent decrease in triglycerides and increase in HDL-C, pravastatin offers a well-balanced lipid-modulating response.