Clinical pharmacokinetics of ketobemidone. Its bioavailability after rectal administration

Summary The pharmacokinetic constants and rectal bioavailability of the narcotic analgesic ketobemidone were determined in six male patients after surgery. Plasma concentrations were measured following intravenous administration of Ketogin^? 2 ml, containing ketobemidone chloride 10 mg, and a spasmolytic compound N,N-dimethyl-3,3-diphenyl-1-methylallylamine chloride 50 mg, and following rectal administration of one suppository of Ketogin^?, containing ketobemidone chloride 10 mg and the spasmolytic component 50 mg. Following intravenous administration, the disposition of ketobemidone followed a biexponential pattern with a fast distribution phase and a slower elimination phase: the plasma half-life (t_1/2β) was 2.42±0.41 h (rodel ± SD). After rectal administration, the disposition of ketobemidone fitted a one-compartment model. The elimination half-life was 3.27±0.32 h. The mean rectal bioavailability for ketobemidone was 44%±9%. The pharmacokinetic constants of the spasmolytic component, N,N-dimethyl-3,3-diphenyl-1-methylallylamine, were also determined in five of the patients, both after intravenous and after rectal administration. The plasma half-life was 3.07±0.53 h and 3.79±1.14 h, respectively. The rectal bioavailability was estimated to be 33%±14%.     

Bioavailability and Pharmacokinetics of Sublingual Oxytocin in Male Volunteers

The aim of this investigation was to assess the bioavailability and pharmacokinetics of oxytocin in six male subjects after a sublingual dose of 400 int. units (684 μg) and after an intravenous dose of 1 int. unit (1·71 μg). After intravenous administration, the pharmacokinetic profile could be described with a two-compartment model. The distribution half-life was 0·049 ± 0·016 h, the elimination half-life was 0·33 ± 0·23 h, the total body clearance was 67·1 ± 13·4 Lh^?1 and the volume of distribution was 33·2 ± 28·1 L. After sublingual administration, a poor bioavailability with a 10-fold variation between 0·007 and 0·07% was observed. The pharmacokinetic profile could be described with a one-compartment model. The lag time was subject-dependent and ranged between 0·12 and 0·30 h (40% CV). The absorption half-life was 0·45 ± 0·29 h, and the apparent elimination half-life 0·69 ± 0·26 h. This study showed a very poor and interindividual variability in bioavailability. The sublingual route of administration with its ‘long’ lag time and ‘long’ absorption half-life would not seem a reliable route for accurate high dosing for immediate prevention of post-partum haemorrhage.     

PHARMACOKINETICS AND ABSOLUTE BIOAVAILABILITY OF EPRISTERIDE IN HEALTHY MALE SUBJECTS

The objective of the current investigation was to describe the pharmacokinetics and absolute oral bioavailability of epristeride. Twelve healthy male subjects (mean (SD) age, 27 (6·2) years) received a single oral dose of 5 mg and an intravenous infusion of 4·5 mg over 30 min in a crossover fashion. Blood samples were obtained over 72 h for the determination of epristeride plasma concentrations using a sensitive high-performance liquid chromatography assay. The lower limit of quantification was 5 ng mL⁻¹. Pharmacokinetic analysis of the plasma concentration--time data was performed by both non-compartmental and compartmental methods. Absolute bioavailability was determined using dose-normalized AUC values following oral and intravenous administration. Epristeride plasma concentrations declined in a biexponential fashion with secondary peaks evident around 24 h in a majority of subjects following both routes of administration. Maximal plasma concentrations were typically achieved approximately 4 h after oral dosing. The mean apparent terminal elimination half-life estimates were similar following intravenous and oral administration and were 27·3 and 26·2 h, respectively. The mean plasma clearance and steady-state volume of distribution were 0·33 (0·09) mL min⁻¹ kg⁻¹ and 0·54 (0·17) L kg⁻¹, respectively. The mean absolute bioavailability was 93% (95% CI: 84%, 104%). Following compartmental analysis of the intravenous data, the mean (SD) λ₁ and λ₂ half-life estimates were 2·74 (0·48) and 31·8 (19·5) h, respectively. The % AUC associated with the λ₂ exponential phase was approximately 68%. This long half-life allows for once-daily dosing of epristeride.     

Comparative single-dose pharmacokinetics of rasagiline in minipigs after oral dosing or transdermal administration via a newly developed patch

Abstract

1. A rasagiline transdermal patch was developed for the treatment of early and advanced Parkinson’s disease. Relevant pharmacokinetic parameters of rasagiline obtained after transdermal administration to minipigs were compared with those of rasagiline after oral administration.

2. A total of 18 minipigs were randomly divided into three groups (six animals for each group). A single dose of 1?mg rasagiline tablet was orally administrated to one group. Meanwhile, single dose of 1.25 and 2.5?mg (2 and 4?cm²) rasagiline patches were given (at the postauricular skin) to the other two groups, respectively. The pharmacokinetic parameters such as plasma half-life (t_1/2), time to peak plasma-concentration (T_max), mean residence time (MRT), area under the curve (AUC_(0–t)) were significantly (p?<?0.05) different between transdermal and oral administrations.

3. The plasma half-life (t_1/2) of rasagiline (1.25?mg patch: 11.8?±?6.5?h, 2.5?mg patch: 12.5?±?4.7?h) in minipig following transdermal administration was significantly prolonged as compared with that following the oral administration (1?mg tablet: 4.7?±?2.5?h). The dose-normalized relative bioavailability of rasagiline patch in minipig were 178.5% and 156.4%, respectively, for 1.25 and 2.5?mg patches compared with 1?mg rasagiline tablet. The prolonged t_1/2 and increased bioavailability of rasagiline patch suggested a possible longer dosing interval compared with oral tablet.     

THE PHARMACOKINETICS OF 1954U89, 1, 3-DIAMINO-7-(1-ETHYLPROPYL)-8-METHYL-7H-PYRROLO-(3, 2-f )QUINAZOLINE,IN DOGS AND RATS AFTER INTRAVENOUS AND ORAL ADMINISTRATION

1954U89, 1, 3-diamino-7-(1-ethylpropyl)-8-methyl-7H-pyrrolo-(3, 2-f )quinazoline, is a potent, lipid-soluble inhibitor of dihydrofolate reductase. The pharmacokinetics and bioavailability of 1954U89 were examined in male beagle dogs and male CD rats. Dogs received single intravenous (2·5 mg kg⁻¹) and oral (5·0 mg kg⁻¹) doses of 1954U89 with and without successive administration of calcium leucovorin. Single intravenous (5·0 mg kg⁻¹) and oral (10 mg kg⁻¹) doses of [1,3-¹⁴C₂]1954U89 were administered to rats. Plasma concentrations of total radiocarbon were determined by scintillation counting, and intact 1954U89 was measured by HPLC. The mean plasma half-life was 3·2 ± 0·62 and 4·2 ± 0·68 h after intravenous and oral administration, respectively, to dogs. The pooled plasma half-life after intravenous administration to rats averaged 1·2 h; a reliable plasma half-life value after oral administration could not be determined. Mean total-body clearance was 2·4 ± 0·39 and 4·5 ± 1·1 L h⁻¹ kg⁻¹ after intravenous and oral administration, respectively, to dogs, and averaged 12 and 77 L h⁻¹ kg⁻¹ after intravenous and oral administration, respectively, to rats. Neither clearance nor bioavailability of 1954U89 in dogs was affected significantly by administration of calcium leucovorin. Absolute bioavailability was 54 ± 12% in dogs and 16% in rats. © 1997 John Wiley & Sons, Ltd.     

DISCONTINUOUS ORAL ABSORPTION PHARMACOKINETIC MODEL AND BIOAVAILABILITY OF 1-(2-FLUORO-5-METHYL-β-L-ARABINOFURANOSYL)URACIL (L-FMAU) IN RATS

1-(2-fluoro-5-methyl-β-L-arabinofuranosyl)uracil (L-FMAU), the L isomer of FMAU, has shown potent activity against hepatitis B virus and Epstein--Barr virus. L-FMAU showed double peaks in the plasma concentration versus time profiles following oral administration to rats, indicating discontinuous oral absorption. The objective of this study was to characterize the bioavailability and pattern of L-FMAU absorption using a pharmacokinetic model which incorporated two separate absorption processes following oral administration of the nucleoside in an animal model, the rat. Simultaneous fitting of differential equations to L-FMAU plasma concentrations following oral and intravenous administration was performed using PCNONLIN. Total clearance of L-FMAU was moderate, averaging 0·47±0·16 L h⁻¹ (mean±SD). Distributional clearance averaged 0·18±0·14 L h⁻¹. The volume of the central compartment averaged 0·30±0·09 L, and the volume of the peripheral compartment averaged 0·15±0·08 L. The first-order absorption rate constants describing the first and second absorption phases averaged 1·22±1·56 and 4·14±5·42 h⁻¹, respectively. Oral bioavailability was calculated by three methods: AUC, urinary excretion data, and a discontinuous oral absorption pharmacokinetic model. Bioavailability averaged 0·59±0·16, 0·64±0·23, and 0·63±0·13, respectively, for the three methods. The discontinuous oral absorption pharmacokinetic model is a promising new method for estimating absorption from two phases and for calculating oral bioavailability.     

PHARMACOKINETICS OF ELEMENTAL PLATINUM (ULTRAFILTRATE AND TOTAL) AFTER A THIRTY MINUTE INTRAVENOUS INFUSION OF ORMAPLATIN

Preclinical data suggest that ormaplatin (tetrachloro-(d1-trans)-1, 2-diamminocyclohexaneplatinum) has substantial activity in cisplatin-resistant tumor models and may be less nephrotoxic than cisplatin. Based on these data we initiated a phase I clinical trial in patients with refractory metastatic cancer. This report characterizes the pharmacokinetic profile of both the total plasma concentrations of elemental platinum and the unbound ultrafiltrate concentrations of elemental platinum, following a 30 min intravenous infusion of ormaplatin. Platinum concentrations were determined by AAS, and pharmacokinetic parameters for both the total plasma concentration and the ultrafiltrate concentration of elemental platinum were determined using both compartmental and noncompartmental methods. Twenty-eight patients (14 males and 14 females; median age, 58) received ormaplatin. There was a linear relationship between C_max and dose (r²=0·945) and AUC and dose (r²=0·976). Ormaplatin is more accurately described by a two-compartment model than by a one-compartment model. The distribution half-life (t_1/2α) was 0·3 h and the terminal half-life (t_1/2β) was 39·1 h. The volume of the central compartment (V) was 68·6 L and the volume of distribution at steady state (V_dss) was 183 L. Like total plasma platinum, unbound platinum is also best characterized by a two-compartment model. The elimination of free platinum is also biphasic with a distribution half-life (t_1/2α) of 0·3 and a terminal half-life (t_1/2β) of 19·3 h. The mean volume of the central compartment (V) was 200·5 L, and the mean volume of distribution at steady state (V_dss) was 560·5 L. Clinical development of ormaplatin has been terminated due to increased frequency of neurological complications noted over other platinum agents; however, the pharmacokinetics are, in general, similar to those of other clinically used platinum compounds. ©1997 by John Wiley & Sons, Ltd.     

间尼索地平控释微丸Beagle犬体内药动学研究

目的建立间尼索地平血药浓度的高效液相色谱-质谱联用方法,研究Beagle犬单剂量口服间尼索地平控释微丸的药动学。方法用HPLC-MS法测定健康Beagle犬单剂量口服间尼索地平控释微丸和普通微丸的血药浓度,以DAS 2.0软件计算药动学参数。结果单剂量给药后,控释微丸和普通微丸的tmax分别为(11.154±0.5077)h和(2.213±0.3225)h,Cmax分别为(79.40±10.60)ng.mL1和(116.7±20.35)ng.mL1,AUC分别为(1227.8±296.0)ng.h.mL1和(867.8±146.7)ng.h.mL1,控释微丸的相对生物利用度为141.5%。结论本方法准确、灵敏,间尼索地平控释微丸血药浓度平稳,可较长时间保持血药浓度。     

Pharmacokinetic evaluation of β-caryophyllene alcohol in rats and beagle dogs

1.?β-caryophyllene alcohol (BCPA) has shown therapeutic promise in the treatment of asthma and inflammation with low toxicity. The aim of the current study was to report the pharmacokinetic profiles of BCPA in rats and dogs.

2.?Following intravenous administration, BCPA exhibited moderate volumes of distribution (V_z) ranging from 5.63 to 8.97?L/kg in rats and low V_z (2.89?±?1.12?L/kg) in dogs. Systemic plasma clearance was high in both species, resulting in a short elimination half-life ranging from 29.6 to 48.3?min. In rats, the intravenous pharmacokinetics was dose dependent. The measured oral bioavailability was low in rats for BCPA solution (1.17?±?0.78%), suspension (1.21?±?0.33%) and PEG formulation (6.22?±?2.63%). The bioavailability was lower in dogs for BCPA solution (0.12?±?0.05%) and PEG formulation (0.25?±?0.07%), indicating significant species difference. However, treatment of plasma samples with β-glucuronidase increased the systematic exposure of BCPA as assessed from AUC _(0-∞) by 24.7- or 2.62-fold in rats and dogs, respectively, which suggested glucuronidation was a significant metabolic pathway for BCPA possibly due to first-pass metabolism.

3.?In summary, this was the first preclinical pharmacokinetic investigation of BCPA in animals, providing vital knowledge for further preclinical research and subsequent clinical trials.     

Determination of cepharanthine in rat plasma by LC–MS/MS and its application to a pharmacokinetic study

Context: Cepharanthine (CPA) has been reported to possess a wide range of pharmacological activities.

Objective: This study investigates the pharmacokinetic characteristics after oral or intravenous administration of CPA by using a sensitive and rapid LC–MS/MS method.

Materials and methods: A sensitive and rapid LC–MS/MS method was developed for the determination of CPA in Sprague–Dawley rat plasma. Twelve rats were equally randomized into two groups, including the intravenous group (1?mg/kg) and the oral group (10?mg/kg). Blood samples (250?μL) were collected at designated time points and determined using this method. The pharmacokinetic parameters were calculated.

Results: The calibration curve was linear within the range of 0.1–200?ng/mL (r?=?0.999) with the lower limit of quantification at 0.1?ng/mL. After 1?mg/kg intravenous injection, the concentration of CPA reached a maximum of 153.17?±?16.18?ng/mL and the t_1/2 was 6.76?±?1.21?h. After oral administration of 10?mg/kg of CPA, CPA was not readily absorbed and reached C_max 46.89?±?5.25?ng/mL at approximately 2.67?h. The t_1/2 was 11.02?±?1.32?h. The absolute bioavailability of CPA by oral route was 5.65?±?0.35%, and the bioavailability was poor.

Discussion and conclusions: The results indicate that the bioavailability of CPA was poor in rats, and further research should be conducted to investigate the reason for its poor bioavailability and address this problem.     

HMS-01在大鼠体内的药动学研究

目的研究HMS-01在大鼠体内的药动学,为后续研究提供支持。方法采用液相色谱-串联质谱(LCMS/MS)技术,建立灵敏、特异的测定血浆等生物样品中HMS-01浓度的分析方法,用建立的方法开展HMS-01在大鼠体内药动学研究。在SD大鼠上分别进行了1个剂量单次灌胃给药、1个剂量单次静注给药的药动学研究,以获得基本药动学参数。结果大鼠静脉注射1 mg/kg的HMS-01后,雄性与雌性大鼠血浆浓度-时间曲线下面积(AUC0-t)分别为221和409 ng·h/ml,平均清除率分别为4.53和2.41 L/h·kg,平均血浆消除半衰期分别为0.786和1.27 h,表观分布容积分别为5.13和3.82 L/kg。灌胃给予30 mg/kg的HMS-01后,在大鼠体内血浆浓度达峰时间tmax为1.17 h,达峰浓度cmax为1243 ng/ml,消除半衰期(t1/2)为2.00 h。雄、雌大鼠AUC0-t分别为2271和8529 ng·h/ml,生物利用度分别为34.3%和69.5%。结论HMS-01在大鼠体内的药动学过程存在显著的性别差异,口服吸收较好,雌性大鼠的生物利用度远高于雄性。     

The comparative pharmacokinetics and gastric toxicity of bezafibrate and ciprofibrate in the rat

1. The comparative gastric toxicology and pharmacokinetics of two phenoxyisobutyrate derivatives have been evaluated in the Fischer rat.

2. After oral administration of single daily doses for 7 days, the plasma elimination half-life for bezafibrate was rapid (t_1/2 of 4–5?h) in comparison to ciprofibrate (t_1/2 of 76?h).

3. The area under the plasma drug concentration versus time curve (AUC) _0–24 (μg±?h/ml± SD) for bezafibrate (dose 125mg/kg per day) was 1553±334, which was less than half the value of 3748±358 achieved by ciprofibrate (10?mg/kg per day) after 7 days.

4. Oral administration of ciprofibrate at 10?mg/kg every 48?h produced similar sustained plasma concentrations to those achieved by bezafibrate 125?mg/kg dosed every 12?h. The AUC0–48 values (μg±h/ml±SD) achieved were 5124±450 for bezafibrate compared to 4207±240 for ciprofibrate.

5. In chronic oral multidose studies with ciprofibrate and bezafibrate, similar gastric toxicity (neuroendocrine cell hyperplasia) occurred in the rat when dose regimens were adjusted to compensate for the pharmacokinetic differences between these two drugs.     

Pharmacokinetics and bioavailability of oral and intramuscular artemether

Objective: The pharmacokinetics and bioavailability of artemether and dihydroartemisinin were investigated in eight Thai males following the administration of single oral and intramuscular doses of artemether (300 mg) in a randomized two-way cross-over study. Results: Both oral and intramuscular artemether were well-tolerated. In most cases, artemether and dihydroartemisinin were detected in plasma after 30 min and declined to levels below the limit of detection within 18–24 h. Compared with intramuscular administration, oral administration of artemether resulted in a relatively rapid but incomplete absorption [C_max: 474 vs 540 ng · ml⁻¹; t _max: 2.0 vs 3.9 h; AUC: 2.17 vs 5.20 μg · h · ml⁻¹]. Geographic means of lag-time and absorption half-life (t _1/2a) of oral vs intramuscular artemether were 0.28 and 1.1 h vs 0.30 and 2 h, respectively. t _1/2z was significantly shortened after the oral dose [2.8 vs 6.9 h]. Mean oral bioavailability relative to intramuscular administration was 43.2%. The ratio of the AUCs of artemether to dihydroartemisinin was significantly lower after the oral than after the intramuscular dose (geometric mean: 0.29 vs 0.60). Received: 18 October 1996 / Accepted in revised form: 28 January 1997     

Pharmacokinetics and Absolute Bioavailability of Cyclosporin Following Intravenous and Abomasal Administration to Sheep

Abstract— Cyclosporin A pharmacokinetics were studied following intravenous and abomasal dosing in an open, crossover study in healthy, merino ewes. Five different doses of cyclosporin A were dispersed in milk and administered into the abomasum through a surgically inserted fistula which simulates oral administration. Cyclosporin A was well tolerated. Whole blood concentrations of cyclosporin A were measured by HPLC and mean clearance (0·45 ± 0·05 L h^?1 kg^?1), distribution volume (4·4 ± 2·0 L kg^?1), mean residence time (9·6 ± 4·1 h) and half-life (12·1 ± 3·1 h) were calculated. Negligible cyclosporin A was excreted in urine or bile. Area under the curve increased proportionally with doses up to 26·3 mg kg^?1, but was curvilinear above this dose. Abomasal bioavailability at 6·4 mg kg^?1 was 0·26 ± 0·09, and mean absorption time was 4·7 ± 11·1 h. Considerable pharmacokinetic variability was observed, particularly after abomasal administration. Cyclosporin A pharmacokinetics in sheep lie within the values reported in man after renal, bone marrow and cardiac transplantation.     

Investigation on pharmacokinetics,tissue distribution and excretion of a novel platinum anticancer agent in rats by Inductively Coupled Plasma Mass Spectrometry (ICP-MS)

Abstract

1.?DN604 is a new platinum agent with encouraging anticancer activity. The present study was to explore the pharmacokinetic profiles, distribution and excretion of platinum in Sprague–Dawley rats after intravenous administration of DN604. A sensitive and selective inductively coupled plasma mass spectrometry (ICP-MS) method was established for determination of platinum in biological specimens. The pharmacokinetic parameters were calculated by a non-compartmental method.

2.?The area under concentration–time curve AUC_0?t and AUC_0?∞ for platinum originating from DN604 at 10?mg/kg were 25.15?±?1.29 and 28.72?±?1.04?μg/hml, respectively. The mean residence time MRT was 36.59?±?6.65?h. The volume of distribution V_z was 11.42?±?2.49?l/kg and clearance CL was 0.18?±?0.01?l/h/kg. In addition, the elimination half-life T_1/2z was 44.83?±?9.75?h. After intravenous administration of DN604, platinum was extensively distributed in most of tested tissues except brain. The majority of platinum excreted via urine, and its accumulative excretion ratio during the period of 120?h was 63.5%?±?7.7% for urine, but only 6.94%?±?0.11% for feces.

3.?The satisfactory half-life, wide distribution and high excretion made this novel platinum agent worthy of further research and development.     

Stability and pharmacokinetic studies of a new immunosuppressant,mycophenolate mofetil (RS-61443), in rats

Mycophenolate mofetil (MPM), a new immunosuppressant, is a morpholinoethyl ester of mycophenolic acid (MPA). The enzymatic and non-enzymatic hydrolysis was studied in an artifical digestive fluid, rat plasma, and tissue homogenates. MPM was chemically stable in the artificial digestive fluid. In rat tissue homogenates and plasma, MPM was rapidly hydrolysed to MPA. The conversion rate of MPM to MPA in various rat tissue homogenates was in the order of liver > kidney > plasma > small-intestinal epithelial cells. After the intravenous injection of MPM at 16.7 mg kg^?1, the terminal elimination half-life,-t_1/2β, was 4.74 ± 0.33 (mean ± SD)h, and the area under the plasma concentration versus time curve, AUC, was 48.78 ± 6.01 μg h mL^?1. After intraduodenal (ID) administration of MPM at 16.7 mg kg^?1, t_1/2β was 3.92 ± 1.05 h, and the AUC was 38.08 ± 8.30 μg h mL^?1. The systemic availability of MPA after ID MPM dosing was 1.52 times higher than that after ID administration of MPA. This result supports the usefulness of MPM as an oral produrg of MPA as a new oral immunosuppressant.     

Determination of dihydromyricetin in rat plasma by LC-MS/MS and its application to a pharmacokinetic study

Context: The pharmacokinetics properties of dihydromyricetin (DHM) are still unknown.

Objective: This study investigates the pharmacokinetic characteristics of DHM using a sensitive and reliable LC-MS/MS method.

Materials and methods: A rapid and sensitive LC-MS/MS method was developed for the determination of DHM in male Sprague–Dawley rat plasma. Twelve rats were equally randomized into two groups, including the intravenous group (2?mg/kg) and the oral group (20?mg/kg). Blood samples (250?μL) were collected at designated time points and analyzed using this method. The pharmacokinetic parameters were calculated using DAS 3.0 pharmacokinetic software.

Results: The calibration curve was linear within the range of 0.5–200?ng/mL (r?>?0.998) with the lower limit of quantification at 0.5?ng/mL. After the intravenous injection, DHM reached a maximum concentration of 165.67?±?16.35?ng/mL, and t_1/2 was 2.05?±?0.52?h. However, DHM was not readily absorbed and reached C_max 21.63?±?3.62?ng/mL at approximately 2.67?h following the oral administration of DHM, and t_1/2 was 3.70?±?0.99?h. The MRT for the intravenous group and the oral group were 2.62?±?0.36 and 5.98?±?0.58?h, respectively. The AUC_(0-t) for the intravenous group and the oral group were 410.73?±?78.12 and 164.97?±?41.76?ng·L/mL, respectively, so the absolute bioavailability of DHM was 4.02% which was poor.

Discussion and conclusion: The results indicated that the bioavailability was poor. Further work needs to be conducted to investigate the reason for poor bioavailability and improve this situation.     

Pharmacokinetics of isoforskolin after administration via different routes in guinea pigs

1.?The objective of this study was to characterize the pharmacokinetics of isoforskolin after oral, intraperitoneal and intravenous administration, as well as to compare bioavailability.

2.?Isoforskolin was administered to guinea pigs at a dose of 2?mg/kg. Plasma concentrations were determined by high-performance liquid chromatography–electrospray ionization–tandem mass spectrometry (HPLC–ESI–MS/MS) method. The pharmacokinetic parameters were calculated by a noncompartmental method. A compartment model was also adopted to describe the pharmacokinetic profiles.

3.?The pharmacokinetic behavior of intravenously administered isoforskolin was characterized by rapid and extensive distribution (V_z?=?16.82?±?8.42?L/kg) followed by rapid elimination from the body (Cl?=?9.63?±?4.21?L/kg/h). After intraperitoneal administration, isoforskolin was absorbed rapidly (T_max?=?0.12?±?0.05?h). The pharmacokinetic profiles of isoforskolin were similar after intraperitoneal and intravenous administration, except for the concentrations at the initial sampling times. Isoforskolin was also absorbed rapidly following oral dosing; however, the concentration–time data were best fit to a one-compartment model, which was different from that observed after intravenous and intraperitoneal administration. Following intraperitoneal and oral administration, the absolute bioavailability of isoforskolin was 64.12% and 49.25%, respectively.

4.?Isoforskolin is a good candidate for oral administration because of its good oral bioavailability.     

Localization and disposition of a non-peptide angiotensin II type 1 receptor antagonist,and its glucuronide metabolite,in rat

1. The disposition of radioactivity of a non-peptide angiotensin II type 1 receptor antagonist (E4177) has been studied in groups of male rats after a single oral 1?mg/kg dose of ¹⁴C-E4177 was administered by gavage. We have also used light-microscopic autoradiography to investigate the localization of radioactivity in the target tissues for this angiotensin II receptor antagonist. 2. The radioactivity was absorbed quickly, and the maximum blood levels (C_max) were reached at 0·38 ± 0·14?h after dosing. The concentrations then declined bi-exponentially with a mean apparent half-life for the first phase (t_½α) of 0·46 ± 0·07?h and a terminal half life (t_½β) of 6·22 ± 1·08?h. By 24 h, the levels had decreased to 2·7 ± 1·5% C_max. The blood beta max levels radioactivity at 48?h after administration were below the limit of quantification. 3. Radioactivity was distributed throughout the body at 15?min after administration. Tissues inwhich radioactivity was present at higher levels thaninplasma were the liver and kidney. Radioactivity was rapidly eliminated from the tissues and was not retained in any individual organ. 4. The major route of excretion was via the bile. Since > 90% of the administered radioactivity was recovered by 24?h after administration, the excretion was relatively rapid. The major metabolite in bile was a glucuronide of E4177 biphenylcarboxylic acid (E4177- Glu). 5. Light-microscopic autoradiographic observations revealed a strong localization of radioactivity throughout the surface cells of the adrenal glomerulosa, the blood vessels in kidney and the surface of the aortic smooth muscle cells, which are all rich in angiotensin II type 1 (AT1) receptors.     

Pharmacokinetic and Pharmacodynamic Aspects of Artelinic Acid in Rodents

Abstract— The efficacy of artelinic acid and artemisinin, orally administered at 10 and 50 mg kg^?1 day^?1, was compared in Plasmodium berghei infected mice. Subsequently, the pharmacokinetics of artelinic acid after intravenous, intramuscular, oral and rectal administration of a 20 mg kg^?1 aqueous solution to rabbits were studied in a four-way randomized cross-over experiment. After intravenous administration, artelinic acid concentrations in blood plasma were high (C₀: 76 ± 15 mg L^?1), and the drug was rapidly eliminated from the central compartment, showing linear elimination kinetics with an elimination half-life of 15 ± 3 min. A large inter-subject variation appeared in the absorption rate and the extent of absorption (2–92%) over the 120 min interval after intramuscular administration. Also, a large inter-subject variation in individual rectal bioavailability (17–100%) was shown, which was dependent on the site of absorption in the rectum. The estimated oral bioavailability was low (4·6 ± 1·7%), probably due to a high first-pass effect and possible decomposition in the acidic gastric environment.