Pharmacokinetics of vinpocetine (Cavinton) in dog

The pharmacokinetics of vinpocetine after 10 mg po and iv doses was studied in six beagle dogs treated in cross-over design. The concentration of the drug in plasma was determined by gas-liquid chromatography using N-P FID and capillary column. The elimination half-live and clearance values calculated from time plasma concentration data for iv administration were 8.9 +/- 2.87 h and 4.2 +/- 1.06 1/kg/h, respectively. The bioavailability of the drug was found to be 21.5 +/- 19.3%.     

Pharmacokinetics of eltoprazine in the dog

Pharmacokinetics of eltoprazine in male and female beagle dogs was studied in two separate cross-over experiments after administration of different intravenous and oral doses. After intravenous administration of 0.5 mg.kg-1, the mean volume of distribution was 5.7 +/- 1.1 l.kg-1. Clearance was 25.5 +/- 1.4 ml.min-1.kg-1. About 25% of the doses was excreted in urine, resulting ina renal clearance of 6.1 +/- 1.4 ml.min-1.kg-1. The mean elimination half-life (t1/2) after intravenous dosing was about 2.6 h. After oral dosing the plasma peak levels (Cmax) were proportional with the dose. The mean time to reach Cmax (tmax) varied between 1.5 and 1.9 h, and t1/2 was about 2.4 h, which was not significantly different (p greater than 0.05) from the half-life obtained after intravenous dosing. Plasma pharmacokinetics after single and multiple dosing of 4 mg.kg-1 showed no difference. Absolute bioavailability was 67% +/- 20%.     

The disposition and metabolism of [14C]piritrexim in dogs after intravenous and oral administration.

The disposition of [14C]piritrexim ([14C]PTX) in male dogs after iv and po doses of 1.8 mg/kg was examined. After either route of administration, greater than 90% of the dose was recovered in the exreta within 72 hr; approximately 20% was recovered in urine and 70% in feces. [14C]PTX was extensively metabolized by dogs; unchanged drug accounted for less than 15% of the dose in the excreta. The O-demethylated metabolites, 2'- and 5'-demethyl PTX, the glucuronide conjugate of 2'-demethyl PTX, and the sulfate conjugate of 5'-demethyl PTX were the major metabolites. Unchanged drug accounted for a large proportion of the drug-related radiocarbon in plasma. The average plasma half-life of PTX after iv administration was 2.6 +/- 0.3 hr, and the average total body clearance was 0.33 +/- 0.13 liter/hr/kg. After po administration, peak plasma concentrations of 0.9 +/- 0.3 micrograms/ml occurred about 1.1 hr after the dose; the absolute oral bioavailability of PTX was 0.63 +/- 0.14. Because the O-demethyl metabolites were active dihydrofolate reductase inhibitors, 2'- and 5'-demethyl PTX were synthesized, and the pharmacokinetics and bioavailability of these compounds in dogs after iv and po administration (5 mg/kg) were examined. The plasma concentration-time data for both compounds after iv doses were described by a two-compartment model, with t1/2 beta = 1.3 and 0.8 hr for the 2'- and 5'- demethyl compounds, respectively. Neither compound showed significant advantages over PTX in terms of pharmacokinetics or bioavailability.     

The pharmacokinetics and metabolism of CP-191,166, an angiotensin II receptor antagonist, in rats and dogs

CP-191,166 is an orally active, non-peptide angiotensin II (AII) receptor antagonist developed for the treatment of hypertension and congestive heart failure (CHF). In this study, the intravenous (iv) and oral (po) single dose pharmacokinetics (PK), oral multiple dose PK and P450-mediated metabolism of CP-191,166 were determined in rats and dogs. CP-191,166 was administered in both single and multiple (22-29 day) doses to Sprague-Dawley rats (3 mg/kg iv and 5, 10, 25 and 200 mg/kg po) and to beagle dogs (5 mg/kg iv and 5, 15 and 50 mg/kg po). Blood samples were collected between 0 and 48 h and plasma CP-191,166 concentrations were determined using high performance liquid chromatography (HPLC) with ultraviolet (UV) detection. The in vitro metabolism of CP-191,166 was also evaluated with rat and dog liver microsomes. The results of these studies suggest that in both species, there may be saturable clearance occurring with higher doses, T(max) was at or near the earliest sample time point for all doses, suggesting that the drug was rapidly absorbed, and CP-191,166 was eliminated with t(1/2) values of 8-9 h. No rat or dog microsomal metabolism was observed, suggesting that metabolites detected in vivo in dogs were non-P450-mediated.     

Disposition and metabolism of carbovir in mice dosed intravenously or orally

To determine the disposition of carbovir and [3H]carbovir in mice, HPLC and thin-layer chromatographic assays were developed and mice were dosed iv and by gavage. Carbovir had no lethal effect at iv doses up to 500 mg/kg and was stable for 24 hr in mouse plasma at temperatures ranging from 0-37 degrees C. Binding to plasma proteins was minimal. Following an iv dose of 500 mg/kg of carbovir or [3H] carbovir, elimination phases with half-lives of 26-37 min (alpha) and 206-330 min (beta) were observed for plasma. For mice dosed with 27 mg/kg of [3H]carbovir, however, only a single phase with a half-life of 17 min was noted. Of several tissues examined, kidney contained the highest concentration of radioactivity. For the high dose, 19.0 +/- 2.6% was excreted in the urine in 24 hr as unchanged carbovir and 42.2 +/- 2.4% as metabolites; for the low dose, 54.5 +/- 6.1% was excreted as carbovir and 26.5 +/- 5.0% as metabolites. When mice were dosed orally with 500 mg/kg, plasma concentrations of carbovir were low. The initial plasma half-life for carbovir was 69 min; the terminal half-life was 822 min. Urinary excretion of unchanged carbovir was 21.3 +/- 7.1%. These results indicate that clearance of high doses of carbovir is limited and that its absorption is poor after oral dosing.     

Antitumor efficacy of AG3340 associated with maintenance of minimum effective plasma concentrations and not total daily dose, exposure or peak plasma concentrations

Oral administration of AG3340, a novel metalloprotease (MMP) inhibitor, suppresses the growth of human colon adenocarcinoma (COLO-320DM) tumors in vivo (Proc Am Assoc Cancer Res 39: 2059, 1998). In this report, we tested the hypothesis that the growth inhibition of these tumors is associated with maintaining minimum effective plasma concentrations of AG3340. Nude mice were given a total oral daily dose of 25 or 200 mg/kg; 6.25 mg/kg was given four times per day (QID) (25 mg/kg/day), and 100 mg/kg was given in two daily doses (BID) (200 mg/kg/day). Peak plasma concentrations (Cmax) of 83 +/- 43 (mean +/- SD) and 1998 +/- 642 ng/ml were detected 30 min after a single dose with 6.25 mg/kg and 100 mg/kg AG3340, respectively. AUC(0-24 h) values estimated from dosing with 25 and 200 mg/kg/day AG3340 were 672 and 10882 ng*h/ml, respectively. Importantly, both regimen inhibited tumor growth equivalently (74 to 82%). Efficacy was also compared at a total daily dose of 25 mg/kg by giving AG3340: QID (6.25 mg/kg per dose), BID (12.5 mg/kg per dose), and once daily (25 mg/kg per dose). The Cmax of these regimens was 83 +/- 43, 287 +/- 175 and 462 +/- 495 ng/ml, respectively. AG3340 did not inhibit tumor growth with the latter two regimens. The efficacy of 6.25 mg/kg QID (25 mg/kg/day) was superior to the efficacy of 25 mg/kg BID (50 mg/kg/day), substantiating the independence of efficacy from the total daily dose and Cmax. Expectedly, peak to trough fluctuations were significantly smaller with the QID regimen than with BID and QD dosing. After 24 h, the trough was greater than 1 ng/ml with QID dosing but was less than 1 ng/ml after QD and BID dosing. These results suggest that the antitumor efficacy of AG3340 was associated with maintaining minimum effective plasma concentrations of AG3340 and demonstrate that the antitumor efficacy of AG3340 was independent of the total daily dose, peak plasma concentration, and drug exposure in this tumor model.     

Bioavailability and mammary excretion of bisphenol a in Sprague-Dawley rats.

This study reports the absolute oral bioavailability and mammary excretion of bisphenol A in rats. The oral bioavailability was determined after administration of relatively low iv (0.1 mg/kg) and oral (10 mg/kg) doses of bisphenol A to rats. After iv injection, serum levels of bisphenol A declined biexponentially, with the mean initial distribution and terminal elimination half-lives being 6.1 +/- 1.3 min and 52.5 +/- 2.4 min, respectively. The systemic clearance (Cls) and the steady-state volume of distribution (Vss) averaged 107.9 +/- 28.7 m/min/kg and 5.6 +/- 2.4 L/kg, respectively. Upon oral administration, the maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 14.7 +/- 10.9 ng/ml and 0.2 +/- 0.2 h, respectively. The apparent terminal elimination half-life of bisphenol A (21.3 +/- 7.4 h) after oral administration was significantly longer than that after iv injection, indicating the flip-flop of the absorption and elimination rates. The absolute oral bioavailability of bisphenol A was low (5.3 +/- 2.1%). To determine the extent of mammary excretion, bisphenol A was given by simultaneous iv bolus injection plus infusion to steady state at low, medium, and high doses. The steady-state serum levels of bisphenol A were linearly increased with higher dosing rates. The systemic clearance (mean range, 119.2-154.1 ml/min/kg) remained unaltered over the dosing rate studied. The levels of bisphenol A in milk exceeded those in serum, with the steady-state milk to serum concentration ratio being 2.4-2.7.     

Pharmacokinetics of pyridostigmine in dogs

The pharmacokinetics of the cholinesterase inhibitor pyridostigmine has been studied in six male Beagle dogs after iv infusion and after oral doses as an immediate-release syrup and as an extended-release tablet, all at a level of approximately 0.6 mg/kg. Pyridostigmine was characterized as a drug of relatively long terminal half-life (8.3 h +/- 2.1 SD), low systemic clearance (13 mL/min/kg +/- 1 SD) and high volumes of distribution (Vd lambda z, 8.7 L/kg +/- 1.9 SD and Vdss, 3.9 L/kg +/- 0.9 SD). The ratio of mean residence times in tissues and plasma was greater than 4, indicating a high affinity of peripheral tissues for the drug. This ratio was about twofold higher in three of the dogs than in the others. Pyridostigmine was slowly and incompletely bioavailable in these dogs; the systemic availability was 44.4% +/- 4.3 SD from the syrup and 33.6% +/- 9.5 SD from the tablet. Pyridostigmine disposition in these dogs was largely determined by distribution processes.     

Pharmacokinetics of nilvadipine, a new dihydropyridine calcium antagonist, in mice, rats, rabbits and dogs

1. The pharmacokinetics of nilvadipine in male and female rats, and in male mice, rabbits and dogs were studied after i.v. and oral dosing. 2. After i.v. dosing (0.1 mg/kg), the plasma concentrations of nilvadipine declined two- or three-exponential with terminal half-lives of 0.73 h in mice, 1.2 h in male and female rats, 3.7 h in rabbits and 5.0 h in dogs. Sex difference in pharmacokinetics after i.v. dosing in rats was not found. The systemic plasma clearance was in the order of mice greater than rats greater than rabbits greater than dogs, and nearly equalled the hepatic blood flow in each species. The volume of distribution at steady-state was high (greater than 4 L/kg) in all species. 3. After oral dosing, plasma concentrations of nilvadipine peaked within 1 h in all species except for middle and higher doses (4 and 16 mg/kg) in dogs. The area under the plasma concentration-time curves in male rats (3.2-100 mg/kg) and dogs (1-16 mg/kg) increased in proportion to the dose. Bioavailability was low in male rats (3-4%) and rabbits (2%), but in other species was 29-44%. The oral clearance in male rats was about 8 times higher than in female rats. 4. The free fraction of nilvadipine in plasma was 1.94% in mice, 1.89% in rabbits and 0.85% in dogs, with no dependence on plasma concentration over a range of 10-100 ng/ml.     

Disposition of acrivastine in the male beagle dog.

Three male beagle dogs were given 10 mg/kg iv and oral doses of [14C]acrivastine, a novel nonsedating antihistaminic agent, in a nonrandomized crossover experiment. Urine and feces were collected for 72 hr after dosing. After iv dosing, a mean of 34% was recovered in the urine, and 63% was recovered in the feces. After po dosing, a mean of 29% of the radiocarbon was recovered in the urine, and 63% was recovered in the feces (dose adjusted for 14% lost in vomitus). Acrivastine and three major metabolites were detected in the excreta. The metabolites were identified as a side-chain-reduced analog of acrivastine (metabolite 3, 270C81), a gamma-aminobutyric acid analog of 270C81 (metabolite 2), and a benzoic acid analog of 270C81 (metabolite 1). After iv dosing, 34% of the dose was excreted as parent drug, 21% as metabolite 3, 15% as metabolite 2, and 6% as metabolite 1, while after po dosing, 35% of the dose was excreted as parent drug, 18% as metabolite 3, 11% as metabolite 2, and 7% as metabolite 1. Pharmacokinetic analysis of acrivastine plasma concentration-time curves after both routes of administration indicated a mean total body clearance of 17.3 ml/min/kg, a Vss of 0.93 liter/kg, a terminal half-life of 0.7 hr, and an oral bioavailability of 40%. The apparent plasma half-life of the metabolite, 270C81, was 1.5 hr. Analysis of AUC values indicated that greater amounts of 270C81 than acrivastine circulated in plasma after both iv and po dosing, and that first-pass metabolism of acrivastine to 270C81 occurred. The results indicated that acrivastine was extensively metabolized in the dog to 270C81 and suggested that 270C81 itself underwent further metabolism to metabolites 1 and 2.     

Pharmacokinetics of aminolevulinic acid after oral and intravenous administration in dogs.

The purpose of these studies was to examine the pharmacokinetics, oral bioavailability, and systemic side effects of aminolevulinic acid (ALA) in beagle dogs after oral and i.v. administration. Oral and i.v. doses of ALA (128 mg of ALA hydrochloride, equivalent to 100 mg of ALA) were administered to four animals using a crossover design. Animals were allowed a 2-week washout period between doses. Plasma ALA concentrations were determined using precolumn fluorescent derivatization and reversed-phase HPLC. Plasma concentrations after i.v. administration declined rapidly with a terminal half-life of 19.5 +/-2.5 min (mean +/- S.D.). Total body clearance and volume of distribution at steady state averaged 6.79+/-1.77 ml/min/kg and 259+/- 128 ml/kg, respectively. Peak plasma concentrations of ALA after oral administration ranged from 1.27 to 9.42 microgram/ml. Oral bioavailability in these animals averaged 41.2+/-14.8% (range, 23.5-58.5%). These studies demonstrate that oral administration may provide a convenient and efficient route of delivery of ALA for photodynamic therapy in patients.     

A simplified dosing method for initiating vancomycin therapy

Vancomycin dosing regimens should be individualized for each patient. The routine use of standard doses 500 mg every 6 hours or 1.0 g every 12 hours regardless of patients' age, weight or kidney function is no longer appropriate. A simplified method for initiating vancomycin therapy was developed and evaluated prospectively in 30 patients. Average doses of 8.3 +/- 0.6 mg/kg lean body weight (rounded to the nearest 50 mg) were administered to patients with varying degrees of renal function (estimated creatinine clearances 19-113 ml/min). The dosing interval was predicted by the patient's estimated creatinine clearance. Our simplified schedule resulted in desired serum levels and required no modification in 25 of 30 patients. Only slight dosage changes were needed in the remaining five patients. Mean peak and trough serum concentrations of vancomycin were 26.9 +/- 5.8 micrograms/ml (range 18.8-39.7 micrograms/ml) and 7.7 +/- 2.0 micrograms/ml (range 4.5-11.8 micrograms/ml) respectively. Our regimen is practical and simple and requires limited patient information.     

Pharmacokinetics of recombinant human superoxide dismutase.

Superoxide dismutase (SOD) disposition was studied in order to design a rational approach for drug administration in the setting of acute myocardial infarction. Four chronically instrumented conscious dogs received the following dosage regimens of recombinant human SOD (rhSOD) on successive days: (a) 5 mg/kg left atrial (LA) bolus, (b) 5 mg/kg central vein (CV) bolus, (c) 15 mg/kg CV bolus, and (d) 5 mg/kg CV infusion over 60 min; additionally, all dogs received (e) a 5 mg/kg CV bolus under pentobarbital anesthesia. Serial serum samples were obtained after each dose and serial myocardial samples were obtained after dose (e). The serum rhSOD concentration was measured by radioimmunoassay and the data were fit to a two-compartment model. The distribution half-life was 7.8 +/- 1.7 min (mean +/- SEM), and the elimination half-life was 51.1 +/- 5.9 min; the central compartment volume of distribution (Vc) was 81 +/- 26 ml/kg and the steady-state volume of distribution was 156 +/- 20 ml/kg. The dosage regimen had no influence on clearance rates. Peak plasma concentrations (micrograms/ml) for the dosage regimens were (a) 65 +/- 28, (b) 89 +/- 19, (c) 214 +/- 61, (d) 20 +/- 5, and (e) 86 +/- 9. The peak level following continuous infusion did not occur until 50 min of infusion and was only one-fourth of the level achieved with a bolus of the same dose. Myocardial levels were less than 1% of serum levels, suggesting negligible rhSOD penetration into the myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Importance of oral dosing rate on the hemodynamic and pharmacokinetic profile on nilvadipine

Nilvadipine was administered as an oral solution formulation to 12 normotensive subjects in a three-way randomized crossover study at a dose of 16 mg as three different dosing regimens: 1) as a single 16 mg dose, 2) as a 1.6 mg dose given hourly for 10 doses, and 3) as an initial dose of 4.8 mg, followed by 1.6 mg doses given every hour for seven additional doses. After each dose, clinical effects, hemodynamic changes and the pharmacokinetic profile of the drug were determined. The mean maximum changes in diastolic (DBP) and systolic (SBP) blood pressure and heart rate (HR) after dosing regimens 1, 2, and 3 were: -33, -13 and +46%; -17, -14 and +38%; and -24, -14 and +36%, respectively. There was a relationship between the changes in DBP and HR and plasma concentrations of nilvadipine only after dosing regimen 1. The effect-concentration relationships were fit to a modified Emax model. There was no relationship between the change in SBP and plasma concentration after any of the dosing regimens. While there were no significant differences in the mean area under the plasma concentration-time curve (AUC0----infinity) between dosing regimens 2 (38.7 ng.hr/mL) and 3 (42.1 ng.hr/mL) (P greater than 0.05), the mean AUC0----infinity after regimen 1 (76.3 ng.hr/mL) was significantly greater than after dosing regimens 2 or 3 (P less than 0.05). The mean maximal plasma concentrations (Cmax) were 31.6, 1.3 and 6.3 ng/mL after dosing regimens 1, 2 and 3, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased amikacin dosage requirements in burn patients receiving a once-daily regimen

Altered pharmacokinetics in burn patients may affect antibiotic plasma concentrations. Typical once-daily dosing (ODD) of 15 mg/kg amikacin (AMK) in burn patients does not always produce peak concentrations (C(max)) reaching the therapeutic objective of six to eight times the minimal inhibitory concentration (MIC). We recorded plasma concentrations following administration of 20 mg/kg AMK in burn patients and studied factors affecting pharmacokinetics. Mean C(max) was 48.3+/-10.8 mg/L and the C(max)/MIC ratio was 6+/-1.35. Statistical analysis demonstrated a relationship between C(max) and the area of the burn and Unit Burn Standard, and between AMK clearance and creatinine clearance (Cl(CR)). We conclude that ODD regimens of AMK in patients with burns >15% body surface area and/or with Cl(CR) >120 mL/min could require doses >20 mg/kg to reach adequate C(max). In all cases, patient therapeutic drug monitoring is essential to ensure the safe usage of these dosing recommendations.     

Evaluation of an empirical dosing schedule for gentamicin in neonates

The standard gentamicin dosing recommendations for neonates appear to be inappropriate because they fail to consider the influence of neonatal development on gentamicin pharmacokinetics. Recent reports have emphasized that the standard regimens of 2.5 mg/kg q8-12h produce steady-state trough serum concentrations greater than 2 micrograms/ml in up to 91 percent of preterm infants of less than 35 weeks' gestation. A new dosing schedule based on postconceptional age (PCA) was developed to provide a better guideline for initiating and maintaining gentamicin therapy in neonates: PCA greater than 34 weeks, 2.5 mg/kg iv q12h; PCA 28-34 weeks, 2.5 mg/kg iv q16h; PCA less than 28 weeks, 2.5 mg/kg iv q24h. The new dosing schedule reduced the number of neonates with elevated trough concentrations (greater than 2 micrograms/ml) from 68.4 percent to 33-40 percent. Pharmacokinetic parameters for gentamicin in the various PCA groups were determined. Volume of distribution was constant across age groups (0.5 +/- 0.09 L/kg). Elimination rate constants (kel), half-lives, and clearance rates (Cl) ranged from 0.069 +/- 0.02 to 0.14 +/- 0.04 h-1, 10.71 +/- 2.92 to 6.04 +/- 1.24 h, and 0.58 +/- 0.25 to 0.93 +/- 0.24 ml/kg/min, respectively. Significant relationships were found between kel and Cl and patient age and weight; significant correlations were found between actual and estimated (based on PCA and weight) kel and Cl. Variability in kel and Cl estimated was considerable in spite of the correlations. The observed variability stresses again the need for pharmacokinetic monitoring of gentamicin therapy in neonates.     

Pharmacokinetics of morphine and its surrogates. III: Morphine and morphine 3-monoglucuronide pharmacokinetics in the dog as a function of dose.

The pharmacokinetics of morphine and its derived metabolite, morphine 3-monoglucuronide, were studied in normal and bile-cannulated dogs. High doses (7.2-7.7 mg/kg iv) caused renal and biliary shutdowns and time lags in urinary drug and metabolite excretion and in biliary secretion of the hepatically formed conjugate. Intermediate doses (0.41-0.47 mg/kg iv) inhibited urine flow but not renal clearance. Low doses (0.019-0.07 mg/kg iv) had no apparent effect. Dose-related effects on the total, metabolic, and biliary clearances imply saturable enzymes and/or dose-inhibited hepatic flows, accounting for the major elimination half-lives of 83 +/- 8 and 37 +/- 13 min at the high and low doses, respectively. The slow terminal phase in plasma morphine and metabolite elimination and urinary accumulation is due apparently to the enterohepatic metabolite recirculation after biliary excretion, gastrointestinal hydrolysis, and hepatic first-pass reconjugation. Bile-cannulated dogs showed no fecal drug and no slow terminal plasma and urine elimination phases. Intravenous morphine 3-monoglucuronide was eliminated only renally and showed neither biliary excretion nor prolonged hepatically formed glucuronide elimination. Hepatic morphine clearances at normal therapeutic doses parallel hepatic blood flow and explain the lack of oral morphine bioavailability by anticipating complete first-pass liver metabolism. Renal morphine and morphine conjugate clearances were 85 (+/- 9 SEM) and 41 (+/- 4 SEM) ml/min, respectively, indicating glomerular filtration for the latter and glomerular filtration plus tubular secretion for the former. Urinary morphine and morphine conjugate excretion accounted for approximately to 83% of the dose. Biliary secretion accounted for 11-14% of the dose. Morphine showed dose-independent plasma protein binding of 36 (+/- 1 SEM) % and a red cell-plasma water partition coefficient of 1.11 +/- 0.04 SD. New equations were developed to model the discontinuous morphine and morphine metabolite pharmacokinetics.     

Pharmacokinetics and metabolism of the pharmacologically active 4'-hydroxylated metabolite of propranolol in the dog

The disposition of 4'-hydroxypropranolol (HOP) was determined after iv administration to dogs (2 mg/kg; N = 5) and the pharmacokinetic parameters were calculated from plasma measurements. The clearance of HOP, 66 +/- 6 ml/min/kg (mean +/- SE), was considerably higher than that of propranolol previously determined, suggesting extrahepatic as well as hepatic clearance of HOP. The plasma half-life of HOP, 77 +/- 6 min, was shorter than that of propranolol. Although HOP is considerably less lipophilic than propranolol, its volume of distribution, 6.4 +/- 0.8 liter/kg, surprisingly, was larger. Like propranolol, HOP appeared to be cleared entirely by metabolism. Whereas propranolol is metabolized mainly by oxidation, HOP was metabolized to sulfate (HOPS) and glucuronic acid (HOPG) conjugates. The plasma half-lives of these conjugates were 2 to 3 times longer than for HOP, reflecting a slow, continuous formation from HOP. This was established for HOPS by iv administration of synthetic HOPS. Morover, after HOP administration both formation and renal clearance of HOPS were stereoselective in favor of the R-enantiomer. In summary, the main conclusion of this study is that the large volume of distribution as well as high clearance through sulfation and glucuronidation may explain the low plasma HOP levels observed during propranolol therapy.     

溴泰君(W198)在大鼠和比格狗体内的药代动力学

目的研究溴泰君(W198)在大鼠和比格狗的药代动力学。方法采用HPLC紫外检测方法测定大鼠及比格狗注射W198后血清药物浓度。结果大鼠iv W198 10,20和40 mg·kg^-1 3个剂量的T_1/2β分别为6.60,7.36和6.77 h,AUC_0-24h分别为3.797,7.371和15.192 mg·h·L^-1,V_d分别为7.14,4.33和4.13 L·kg^-1,CL分别为2.83,2.60和2.71 L·(kg·h)^-1。大鼠im W198 20 mg·kg^-1后T_1/2β为11.61 h,AUC_0-24h为4.191 mg·h·L^-1,im的生物利用度为56.9%。比格狗iv W198 5 mg·kg^-1,T_1/2β为11.72 h,AUC_0-24h为12.646 mg·h·L^-1,V_d为0.70 L·kg^-1,CL为0.46 L·(kg·h)^-1。W198与人血浆蛋白的结合率平均为78.0%。结论W198 im的T_1/2β比iv的略长,其生物利用度为56.9%。在10～40 mg·kg^-1剂量内的吸收呈现一级动力学特征。     

Pharmacokinetics of dexloxiglumide after administration of single and repeat oral escalating doses in healthy young males

OBJECTIVE: To assess the pharmacokinetics, safety and tolerability of dexloxiglumide, a new CCK1 receptor antagonist currently under development for the treatment of the constipation-predominant irritable bowel syndrome. SUBJECTS AND METHODS: Twelve volunteers were enrolled in the present study and received orally 100, 200 and 400 mg of dexloxiglumide as tablets as a single dose followed by repeated t.i.d. doses for 7 days according to a randomized, double-blind, double-dummy complete crossover design. Plasma and urine were collected before drug administration and up to 72 h after dosing. Dexloxiglumide plasma and urinary concentration, determined using validated HPLC methods with UV detection, were used for the pharmacokinetic analysis by standard noncompartmental methods. In addition, dexloxiglumide safety and tolerability were evaluated throughout the study period by performing standard laboratory tests, by recording vital signs and ECGs and by monitoring the occurrence and severity of adverse events. RESULTS: After a single oral administration, dexloxiglumide was rapidly bioavailable with mean t(max) ranging from 0.9 - 1.6 h at all doses. The mean peak plasma concentrations (Cmax) were 1.7+/-0.6, 5.4+/-1.7, and 11.9+/-4.7 microg/ml, and the mean area under the plasma concentration-time curves (AUC) were 4.4+/-3.3, 8.6+/-3.6, and 18.3+/-5.9 microg x h/ml at the 3 doses, respectively. Apparent plasma clearance (CL/F) was 30.8+/-13.9, 27.2+/-10.6, and 21.1+/-8.6 l/h at the 3 doses, respectively. The apparent elimination half-life from plasma (t1/2) ranged from 2.6 - 3.3 h at the 3 doses. The excretion of unchanged dexloxiglumide in 0 - 72 h urine accounted for approximately 1% of the administered dose and this was true for all doses. Dexloxiglumide renal clearance (CLR) averaged 0.4+/-0.4, 0.4+/-0.2, and 0.3+/-0.3 l/h for the 3 doses, respectively. After the last dose of the repeated dosing period dexloxiglumide Cmax occurred at 1.1 - 1.6 h after drug administration and averaged 2.4+/-1.3, 7.1+/-2.9, and 15.3+/-2.7 microg/ml for the 3 doses, respectively. The AUC values averaged 5.9+/-3.0, 16.0+/-8.8, and 50.8+/-38.1 microg x h/ml, respectively. The area under the plasma concentration-time curve calculated at steady state within a dosing interval (AUCss) averaged 4.6+/-1.6, 11.3+/-3.6, and 28.4+/-8.2 microg x h/ml, whereas CL/F averaged 20.3+/-8.3, 16.3+/-9.0, and 10.3+/-5.0 l/h at the 3 doses, respectively. Dexloxiglumide t1/2 could not be accurately calculated due to the high inter-subject variability and to sustained dexloxiglumide plasma concentrations that precluded the identification ofthe terminal phase of the plasma concentration-time profiles. However, it appeared that dexloxiglumide t1/2 was considerably prolonged at the dose of 400 mg. CLR averaged 0.4+/-0.4, 0.3+/-0.3, and 0.3+/-0.1 l/h for the 3 doses, respectively. After a single dose, the plasma pharmacokinetics of dexloxiglumide were dose-independent in the dose range 100 - 400 mg. After repeated dose the pharmacokinetics of dexloxiglumide were virtually dose-independent in the dose range 100 - 200 mg. A slight deviation from linear pharmacokinetics was found with a dose of 400 mg. Dexloxiglumide plasma pharmacokinetics were also time-independent in the dose range 100 - 200 mg with a deviation from expectation based on the superimposition principle with a dose of 400 mg. Dexloxiglumide urinary excretion and renal clearance were both dose- and time-independent in the dose range 100 - 400 mg. The safety and tolerability of dexloxiglumide administered to healthy young males was good up to the maximum investigated dose of 400 mg both after single and after repeated doses. CONCLUSIONS: The safety and pharmacokinetic profile of dexloxiglumide when the drug is administered as single and repeated doses in the dose range 100 - 400 mg provides the rationale for the choice of the treatment schedule (200 mg t.i.d.) for the efficacy trials in patients with (constipation-predominant) irritable bowel syndrome.