Distribution,metabolism, and excretion of a novel surface-active agent,purified poloxamer 188, in rats,dogs, and humans

Purified poloxamer 188 (PP188) is a nonionic, block copolymer surfactant with hemorheologic, antithrombotic, and anti-adhesive properties. PP188 is being studied in phase III clinical trials in sickle cell disease and has been found to be well tolerated and has demonstrated benefit in ameliorating the effects of acute painful vasoocclusive crisis. The disposition of PP188 was studied in rats, dogs, and humans to establish a basis for understanding the safety parameters in support of clinical trials. PP188 was primarily distributed in extracellular water with little or no uptake by red blood cells, and had its highest concentrations in highly perfused tissues such as the kidney, liver, spleen, lymph nodes, and gastrointestinal tract. PP188 had no apparent effect on P450 isozymes in vitro. Metabolism was limited (< 5% of dose) with a higher molecular weight copolymer being the only other material detected in plasma or urine. Renal clearance was the controlling route of clearance for PP188 from the body. The 48-h intravenous infusion doses of PP188 were cleared in all species by approximately 1 week after the cessation of dose administration. PP188's disposition is a model for other nonionic block copolymers with similar physical and chemical properties.     

Pharmacokinetics of quinidine related to plasma protein binding in man

Summary The disposition and plasma protein binding of quinidine after intravenous administration were studied in 13 healthy subjects. Plasma protein binding, expressed as the fraction of quinidine unbound ranged from 0.134–0.303 (mean 0.221). Elimination rate constant () varied from 0.071 to 0.146 h^–1 (mean 0.113), and apparent volume of distribution (V) varied from 1.39–3.20 l · kg^–1 (mean 2.27). Total body clearance was 2.32–6.49 ml min^–1 · kg^–1. There was a positive linear correlation between the plasma fraction of unbound quinidine and both V (r=0.885, p<0.01) and total body clearance (r=0.668, p<0.05). No significant correlation existed between the fraction of unbound quinidine in plasma and the elimination rate constant. The results show that both the apparent volume of distribution and total body clearance of quinidine are proportional to the unbound fraction in plasma. This implies that the total plasma concentration of quinidine at steady state will change with alterations in plasma binding, whilst the concentration of unbound compund and its elimination rate will remain unaffected.     

Interspecies Pharmacokinetics of a Novel Hematoregulatory Peptide (SK&F 107647) in Rats,Dogs, and Oncologic Patients

Purpose. To study the pharmacokinetics of SK&F 107647, a novel hematoregulatory agent, in rats, dogs, and patients with non-lymphoid solid tumor malignancy. Methods. Sprague Dawley rats and beagle dogs (n = 6 each; 3 M, 3 F) were given 25 mg/kg of SK&F 107467 as an iv bolus injection, and patients (n = 6; 4 M, 2 F) received 100 ng/kg as a 2 hour iv infusion. Plasma samples were assayed for drug using either HPLC (rat and dog) or RIA (human). Results. In each species the plasma clearance (CL) of SK&F 107647 was low in relation to hepatic blood flow, and the volume of distribution (Vd_ss) was reflective of distribution to extracellular body water. The plasma CL in humans was near that of average glomerular filtration rate. Using allometric equations for interspecies scaling (Y = a·W^b), body-weight normalized human pharmacokinetic data were reasonably predicted using either the body weight normalized rat or the dog data. The allometric exponents (b) for CL, Vd_ss, and T_1/2 of SK&F 107647 were 0.63, 0.94, and 0.29, respectively. Conclusions. Use of a limited pool of available animal data allowed for reasonable predictions of human pharmacokinetics of SK&F 107647.     

泊洛沙姆188修饰的蜂毒素脂质体在大鼠体内的药动学

目的:考察泊洛沙姆188(poloxamer188)修饰的蜂毒素脂质体在大鼠体内的药动学。方法:大鼠尾静脉分别注射蜂毒素溶液(MLT-I)、2%及5%Poloxamer188修饰的蜂毒素脂质体(MLT-LIPO-2%和MLT-LIPO-5%),采用酶联免疫吸附(ELISA)方法测定大鼠体内的蜂毒素。结果:采用Kinetica4.4统计软件,经统计矩拟合后,与MLT-I相比,MLT-LIPO-2%和MLT-LIPO-5%在大鼠体内的药动学行为发生显著变化,清除率(CL)分别为溶液组的48.3%及33.2%;血药浓度-时间曲线下面积(AUC)分别为溶液组的2.01倍及2.82倍;平均滞留时间(MRT)分别为溶液组的1.80倍及2.18倍。结论:经poloxamer188修饰后的脂质体显著延长了药物在大鼠体内的驻留时间,提高了药物的生物利用度,且与膜修饰剂的用量有一定的正相关性。     

Pharmacokinetics of pindolol in man

Summary The kinetics of absorption, distribution and excretion of pindolol have been investigated in 17 volunteers after an oral dose or intravenous infusion of 5 mg. The calculated absorption was 92%. The time course of the plasma levels appeared to follow first order kinetics with an apparent half life of 3.6 (oral) and 3.1 (i.v.) hours. The cumulative urinary excretion att= was 36.1% and 39.2% of the dose administered, respectively, indicating extensive metabolism of the drug. The distribution volume was 136 l. Peak plasma levels were found 80 min after oral administration and they showed up to 4-fold variation after identical doses. Renal clearance was 216 ml×min^–1 and total clearance was 483 ml×min^–1. In plasma 57% of pindolol was bound to protein.     

Pharmacokinetic properties of TDP4815 after single intravenous and oral administrations to rat, rabbit, monkey, dog and in vitro drug metabolism

The pharmacokinetics of TDP4815 was evaluated in rats, rabbits, dogs and monkeys. After intravenous administration, TDP4815 achieved C(O) of 3255 ng/ml in rats at 5 mg/kg, 9066 ng/ml in rabbits and 7858 ng/ml in monkeys at 6 mg/kg, and 4457 ng/ml in dogs at 3 mg/kg. The clearance (C(L)) was 3105, 1692, 835 and 640 ml/h/kg in rats, rabbits, monkeys and dogs, respectively. The volume of distribution (V(Z)) was more than 3861 ml/kg in all species, except 1915 ml/kg in monkeys. The oral bioavailability was rabbit >rat> monkey compared at 100 mg/kg, but it was much higher in dogs (>64%) after oral administrations. The calculated intrinsic clearance data suggested that the clearance of dog and human was restricted by binding to the plasma protein, and the clearance of rat and monkey was dependent on both the free fraction of plasma protein binding and the liver blood flow rate. The unbound hepatic intrinsic clearance of monkey was close to its C(L) suggesting that the hepatic clearance was an important excretion in monkeys. The poor oral bioavailability in the monkey may be related to the extensive glucuronidation. The V(Z).kg and C(L).kg in test species showed good correlation with the animal body weights (R(2)=0.87 and 0.96).     

Pharmacokinetics of Nitrazepam in Saliva and Serum after a Single Oral Dose

Abstract The pharmacokinetics of nitrazepam in saliva and serum was studied in 12 healthy volunteers after a single administration of a 5 mg nitrazepam tablet. The binding of nitrazepam to plasma proteins was determined 4 hours after the administration by ultracentrifugation. The analysis of nitrazepam concentrations was performed by ⁶³Ni-EC-GLC. The pharmacokinetic parameters were evaluated manually or by AUTOAN-program in serum, and manually in saliva. The concentrations of nitrazepam in serum and saliva correlated significantly (r=0.472, P<0.001, n=97). The ratio saliva: serum was, however, time dependent. The protein free fraction in serum was significantly higher (P<0.01) than the salivary concentration at the same time (4 hours after administration). The peak concentrations in serum and saliva were 40.7 and 1.9 ng/ml (P<0.001) and the times to reach the peak maximum 2.4 and 2.5 hours, respectively (difference not significant). The mean half-life of nitrazepam in serum was 30.5 hrs and in saliva 39.9 hrs, the difference being significant at P<0.05. The distribution phase parameters, poorly described before, were calculated. The clinical value of nitrazepam analysis in saliva seems to be negligible.     

Pharmacokinetics of albendazole in man

Summary The pharmacokinetics of albendazole were investigated in healthy volunteers and in patients receiving albendazole for treatment of hydatid disease. Unchanged albendazole was below detectable limits in plasma, urine, bile and cyst fluid. The major metabolite present in all fluids was the sulfoxide. Maximum concentrations of albendazole sulfoxide in plasma were very variable, probably due to variable absorption of albendazole.     

Pharmacokinetics of intravenously administered bumetanide in man

Disposition of [ ¹⁴C] bumetanide administered intravenously to four healthy volunteers could be described by a triexponential equation. The mean half-lives associated with each exponent were 5.9 min, 46 min, and 3.1 hr, respectively. The largest fraction of dose was eliminated during the second phase; only 17% was eliminated during the last phase. The total plasma clearance averaged 228 ml/min, with renal clearance about one-half of this value. The recovery of unchanged bumetanide in urine over 2 days was 47% of the dose, while the total recovery of radioactivity in urine averaged 82% of dose. In plasma 93% of bumetanide was bound to proteins. Thus bumetanide is rapidly eliminated by both renal and nonrenal mechanisms. The elimination kinetics resembled those described for furosemide.     

Pharmacokinetics of fluocortolone in man

Summary The kinetics of the synthetic corticoid fluocortolone was determined in 9 healthy female volunteers after a single oral dose of 20 mg. The maximal plasma level fluocortolone (C_max) of 202±70 ng/ml occurred within 85±32 min of oral intake after which it declined monoexponentially. Total plasma clearance was 6.48±2.07 ml/min·kg and the clearance of unbound fluocortolone was 60.38±26.67 ml/min·kg. Plasma protein binding was 83 to 95%. The volume of distribution at steady-state was 1.01±0.34 l/kg for total fluocortolone and 11.21±3.77 l/kg for unbound drug. The results of the study characterize the kinetics of unbound fluocortolone for the first time. In addition, the kinetics of total fluocortolone presented here confirm values calculated previously.     

Pharmacokinetics of cefroxadin (CGP 9000) in man

The pharmacokinetics of cefroxadin have been studied after the administration of single oral and intravenous doses to healthy volunteers. Cefroxadin was assayed by HPLC. The kinetics in plasma following i.v. administration were described by using a three-compartment model. An additional disposition phase was observed following oral administration that could not be detected after the low i.v. dose. The terminal half-life was 1.03 h. The apparent volume of distribution at the steady state was consistent with a diffusion of the antibiotic in all extracellular fluids. The AUCafter oral administration was linearly related to the dose. The urinary excretion amounted to 95% of the dose with virtually complete absorption of orally administered drug.     

Pharmacokinetics of intravenous 2-mercaptopropionylglycine in man

Summary The pharmacokinetics of 2-mercaptopropionylglycine (2-MPG) was studied in ten healthy volunteers after a single i. v. injection of 250 mg (1532 μmol). The total and non-protein-bound concentrations versus time curves were best described by a three-exponential function with terminal half-lives of 55 and 59 h respectively. Body clearance based upon the total concentration was estimated to be 105 and 231 ml/min based on the non-protein-bound 2-MPG. The corresponding values for V_ss were 99 l and V_ss,n 173 l, and for V_γ485 l and V_γ,n 1121 l respectively. 75% of the dose was excreted in the urine, mainly during the first 6 h after injection. The proportion of non-protein-bound 2-MPG diminished exponentially during the first 15 h and then levelled off at about 30%. There was a nonlinear increase in the non-protein-bound fraction of 2-MPG as the total plasma concentration of the drug increased.     

Pharmacokinetics of benzquinamide in man

Using a newly developed sensitive gas chromatograph-mass spectrometer assay for benzquinamide, pharmacokinetics have been determined in man follovnng the administration of intramuscular, oral, and rectal suppository doses. Drug is absorbed most rapidly from the intramuscular dose and least rapidly from suppositories. The mean apparent elimination half-life is 1.0–1.6 hr from all formulations. Benzquinamide is 33–39% bioavailable from the capsule and suppository formulations, relative to the intramuscular formulation. A high correlation between capsule and suppository bioavailabilities suggests that first-pass metabolism may account for at least part of the incomplete availability.     

Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man

1. Pharmacokinetics were studied in mouse, rat, rabbit, dog and man after single intravenous and/or oral doses of sildenafil or [14C]-sildenafil (Viagra). 2. In man, absorption from the gastrointestinal tract was essentially complete. With the exception of male rat, Tmax occurred at approximately 1 h or less. Bioavailability was attenuated by pre-systemic hepatic metabolism in all species. 3. The volume of distribution was similar in rodents and humans (1-2 l/kg) but was greater in dog (5.2 l/kg), due to lower plasma protein binding (84 versus 94-96% respectively). 4. High clearance was the principal determinant of short elimination half-lives in rodents (0.4-1.3 h), whereas moderate clearance in dog and man resulted in longer half-lives (6.1 and 3.7 h respectively). Clearances were in agreement with in vitro metabolism rates by liver microsomes from the various species. 5. After single oral or intravenous doses of [14C]-sildenafil, the majority of radioactivity was excreted in the faeces of all species. No unchanged drug was detected in the excreta of man. 6. Five principal pathways of metabolism in all species were piperazine N-demethylation, pyrazole N-demethylation, loss of a two-carbon fragment from the piperazine ring (N,N'-deethylation), oxidation of the piperazine ring and aliphatic hydroxylation. Additional metabolites arose through combinations of these pathways. 7. Sildenafil was the major component detected in human plasma. Following oral doses, AUC(infinity) for the piperazine N-desmethyl and piperazine N,N'-desethyl metabolites were 55 and 27% that of parent compound respectively.     

Pharmacokinetics and bioavailability of indoprofen in man

Summary In a pharmacokinetic study of the new analgesic and anti-inflammatory drug indoprofen, plasma levels and urinary excretion were determined in four healthy volunteers after 100 mg and 200 mg iv, and after 100 mg (capsules) and 200 mg (tablets) oral doses. After iv administration, the mean biological half-life (t1/2 ) was about 2 h (range 1.4 to 3.2 h). The apparent volume of distribution Vd ranged between 11 to 17 % of body weight, indicating its limited extravascular distribution. Most of the drug was excreted in urine as glucuronide and a smaller proportion as unchanged indoprofen: the 24 h urinary excretion of these compounds accounted for 67 to 95 % of an iv dose. Peak plasma levels occurred between 30 and 120 minutes after oral administration of 100 mg as capsules or 200 mg as tablets. The mean biological half-life was about 2 h, as after iv administration. The bioavailability of oral doses was assessed using both plasma levels and urinary excretion data. The absorption of capsules and tablets was practically complete, that of the former being faster.     

Pharmacokinetics and allometric scaling of levormeloxifene,a selective oestrogen receptor modulator

The pharmacokinetics of a new selective oestrogen receptor modulator levormeloxifene was investigated in mice, rats, cynomolgus monkeys and humans by compartmental pharmacokinetics. Levormeloxifene was administered as an oral solution in all studies. Allometric scaling was used to predict human pharmacokinetic parameters and the performance of the approach was evaluated. Mean values of clearance confounded by F(CL/F) were 0.073, 0.29, 3.18 and 2.4 l/h in mice, rats, monkeys and humans, respectively. Values of distribution volume at steady state confounded by F(V(ss)/F) were 0.073 and 7.5 l in mice and rats. In monkeys, values of the central volume F(V(c)/F) and volume at steady state F(V(ss)/F) were 28.9 and 57.9 l, respectively. In humans, values of V(c)/F and V(ss)/F were 106 and 587 l, respectively. Predicted CL/F and V(ss)/F showed a linear relationship when plotted vs BW on a log-log scale; for CL/F, r was 0.95-0.98 and for V(ss)/F, r was 0.99. Using allometric scaling the predicted human V(ss)/F deviated 3-fold from the experimentally determined values. Observed values of CL/F deviated 21-25 fold from the predicted, the latter depending on the scaling method. Confidence intervals for the predicted parameters showed major lack of precision for all the allometric scaling methods.     

Pharmacokinetics of fentanyl in man and the rabbit

Summary Plasma levels and urinary excretion of³H-fentanyl were studied in 5 human subjects after intravenous injection of this drug. After an initial rapid decline, the plasma level of fentanyl decreased slowly and approximately exponentially. The plasma concentration of metabolites remained almost steady from 1–3 h after injection. More than 60% of the administered radioactivity was excreted through the kidneys within 4 days. Only a small proportion of it was unchanged fentanyl. The rates of fall of plasma concentration and of urinary excretion were slower in man than in rabbits. — The time courses of plasma concentrations and of urinary excretion were simulated on an analogue computer. The results support the assumption that the different time courses of concentrations in man and rabbits are caused by slower metabolism in man. It seems likely that redistribution plays a dominant part in the short duration of action of fentanyl in man.     

In Vitro and In Vivo pharmacokinetic studies of bulaquine (analogue of primaquine), a novel antirelapse antimalarial, in rat, rabbit and monkey--highlighting species similarities and differences

Bulaquine (BQ) is a potent antirelapse antimalarial developed by CDRI, India. Bulaquine was rapidly absorbed in rats and rabbits with no distinct absorption phase while in monkeys a variable irregular absorption profile was observed. BQ was extensively converted to primaquine (PQ) after oral administration and the conversion was maximum in rats and minimum in rabbits, which is possibly due to the species difference. Clearance was higher in rats (3.2 l/h/kg) than in rabbits and monkeys (1.2 l/h/kg) and it was found be negligibly excreted in rat urine and feces. The elimination half-life in rats and rabbits was comparable after both oral and i.v. administration ( approximately 1.2 h). In all three species, PQ was resident in the body for a period longer than BQ. PQ, being the major active metabolite of BQ, might be responsible for the extended therapeutic effect of BQ. The oral bioavailability of BQ was 3.12%, 5.3% and 12% in rats, rabbits and monkeys, respectively, which could be mainly due to the high instability of BQ at acidic pH as demonstrated from a simulated gastric fluid stability study. Protein binding in various species was in the range 50-65% while the partition coefficient between RBCs and plasma (K(rbc/pl)) was between 0.75 and 1, indicating significant RBC uptake.     

Pharmacokinetics of a novel agent, R667, in patients with emphysema

AIMS: To evaluate the pharmacokinetics of R667, a novel emphysema agent, in patients with moderate to severe emphysema. METHODS: Multiple-dose pharmacokinetics of R667 and its metabolites in emphysematous patients were studied in a multicentre, randomized, single-blind, and placebo-controlled trial. Four groups of 10 patients per group received placebo, 0.2, 0.5, or 1 mg R667 once a day for 14-16 days. On day 14 (+/-1), blood samples were taken at predose and 1, 2, 3, 4, 6, 8, 10, 12, 16 and 24 h after dosing. RESULTS: Pharmacokinetic analysis of the data indicated that the mean steady-state C(max) and AUC(0,tau) of R667 appeared to be dose proportional over the dose range of 0.2-1 mg when administered to emphysematous patients. Mean metabolite to R667 ratios for C(max) or AUC(0,tau) were, in general, similar across the dose range of 0.2-1 mg. CONCLUSIONS: The pharmacokinetics of R667 and its metabolites appeared to be similar for patients with emphysema and healthy volunteers. Multiple-dose administration of 0.2-1 mg of R667 for up to 16 days was well tolerated in patients with emphysema.     

Interspecies pharmacokinetic scaling of a new carbapenem,DA-1131, in mice,rats, rabbits and dogs,and prediction of human pharmacokinetics

The total body clearance (Cl), renal clearance (Cl_r), and apparent volume of distribution at steady state (V_ss) of DA-1131, a new carbapenem, after intravenous (iv) administration of the drug, 50 mg kg⁻¹, to mice, rats, rabbits, and dogs were analysed as a function of species body weight (W) using the allometric equation for interspecies scaling, and were used to predict these parameters in humans. Significant linear relationships were obtained between log[Cl (L h⁻¹)] and log[W (kg)] (r = 0.995; p = 0.00503), log[Cl_r (L h⁻¹)] and log[W (kg)] (r = 0.998; p = 0.0429), and log[V_ss (L)] and log[W (kg)] (r = 0.987; p = 0.0126). The corresponding allometric equations were Cl = 0.706W^0.811, Cl_r = 0.318W^0.888, and V_ss = 0.194W^0.981. These allometric equations were extrapolated to predict the Cl and V_ss for DA-1131 in humans based on 70 kg body weight. The Cl and V_ss for humans predicted from the four animal data well fitted to regression lines of animal data. Interspecies scale-up of plasma concentration–time data for the four species using a complex Dedrick plot resulted in similar profiles. In addition, the concentration in plasma–time profile predicted using the four animal data well fitted to a complex Dedrick plot of animal data. Our results indicate that the DA-1131 data obtained from laboratory animals could be utilized to generate preliminary estimates of the pharmacokinetic parameters in humans. These parameters can serve as guidelines for better planning of clinical studies. © 1998 John Wiley & Sons, Ltd.