Pharmacokinetics of carbamazepine polymorphs and dihydrate in rats,related to dogs and humans

Species differences in the oral pharmacokinetics and absolute bioavailability (F _abs ) of carbamazepine polymorphs (form I and form III) and dihydrate were studied. The pharmacokinetics of each form was investigated in rats following a single oral/intravenous administration of 10 mg/kg and an oral dose of 80 mg/kg, which were compared with the published data obtained from dogs and humans. No significant differences were found in their C _max, T _max, AUC_0−∞ and F _abs among the forms at the low dose. However, significant differences were observed at the high dose. The Fabs of each form was markedly reduced with increasing of doses in species (e.g. F _abs in rats ranged from > 82% to 38.4%–56.0%). At a comparable dose, the C _max, and AUC_0−∞ of rats and humans were about 3–10 times higher than in dogs. The absorption rate of form III in rats exhibited a similar trend to that in humans, and was far higher in dogs. A multi-peak phenomenon in plasma curves was observed in rats and humans, but not in dogs. In conclusion, rats appear to be a better predictor of carbamazepine polymorphs absorbed in humans, and form III may be more suitable as a pharmaceutical crystal.     

Pharmacokinetics of magnolin in rats

This study was first conducted to characterize the intravenous and oral pharmacokinetics of magnolin, a major pharmacologically active ingredient of Magnolia fargesii, at various doses in rats. Magnolin was administered to rats by intravenous injection (0.5, 1 and 2 mg/kg doses) and oral administration (1, 2 and 4 mg/kg doses), and serial plasma and urine samples were harvested. Magnolin concentrations were determined by a validated LC/MS/MS assay. After both intravenous and oral administration, the AUCs were linearly increased as the dose increased. Other pharmacokinetic parameters of magnolin (except the V _ss after the intravenous administration) were also independent of the doses. The extent of absolute oral bioavailability ranged from 54.3–76.4% for the oral doses examined. Magnolin was considerably bound to rat plasma proteins and the binding value was constant (71.3–80.5%) over a concentration ranging from 500 to 10000 ng/mL. The pharmacokinetic parameters of magnolin were doseindependent after both intravenous and oral administration. When given orally, magnolin was rapidly absorbed.     

Metabolism and pharmacokinetics in rats of ganoderiol F,a highly cytotoxic and antitumor triterpene from <Emphasis Type="Italic">Ganoderma lucidum</Emphasis>

The metabolism of ganoderiol F (GF), a cytotoxic and antitumor triterpene from Ganoderma lucidum, by intestinal bacteria and its pharmacokinetics in rats were investigated by using liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS). GF was converted to ganodermatriol by anaerobic incubation with bacterial mixtures from rats and humans. This metabolite was detected in rat feces, but not in plasma and urine, after oral administration of GF. The fate of GF after oral (p.o.) and intravenous (i.v.) administration to rats was examined in pharmacokinetics studies. Plasma samples pretreated by solid-phase extraction were quantified by HPLC/MS/MS over a GF concentration range of 1.25–100 ng/ml (S/N = 5). The intra- and interday precision (CV%) was below 8% and accuracy was within the range of 95.9–103.6% for all samples. The range of recovery ratios was 89.2–98.2%. After the administration of GF at 0.5 mg/kg i.v., the plasma concentrations of GF quickly declined and the elimination half-life values (t _1/2α and t _1/2β) were about 2.4 and 34.8 min. On the other hand, the elimination half-life values (t _1/2α) after p.o. administration of GF at doses of 20 and 50 mg/kg were 14.4 and 143.3 min for the former, and 18.6 and 114.6 min for the latter. The AUC_0–t value was 11.17 (ng/ml) h at a GF dose of 0.5 mg/kg i.v., but 49.4 and 111.6 (ng/ml) h at GF doses of 20 and 50 mg/kg p.o., respectively, indicating that the AUC_0–t value is proportional to the administered oral doses. The estimated absolute bioavailability of GF in rats was F = 0.105.     

Pharmacokinetics of a new histamine H2-receptor antagonist,Z-300, in rat and dog

1. The plasma level of Z-300 reached a maximum (C_max) at 30?min after the oral administration of Z-300 to dog, and disappeared from the systemic circulation with a halflife of 8-9 h. The bioavailability of Z-300 was 52% after the oral administration of Z-300, 3?mg/kg. At doses ranging from 3 to 30?mg/kg, C_max and AUC (area under the plasma concentration-time curve) were proportional to the dose. 2. The plasma level of Z-300 reached C_max at 10?min after the oral administration of Z-300 to rat, and disappeared from the systemic circulation with a half-life of 0.8-1.6 h. The bioavailability of Z-300 was 39% after the oral administration of Z-300, 10?mg/kg, and there was a non-linear relationship between the plasma level-time profile of Z-300 and the administered dose (3-50?mg/kg). 3. The binding of Z-300 to plasma protein was 92% in man, 65% in dog and 25% in rat. It is suggested that these species differences were due to the content of α₁-acid glycoprotein (α₁-AG), because Z-300 bound more strongly to α₁-AG than to albumin.     

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,brain distribution,and plasma protein binding of the antiepileptic drug lacosamide in rats

The study aimed to characterize the pharmacokinetics of lacosamide, a new antiepileptic drug, in rats after intravenous and oral administration at doses of 1, 3, 10, and 30 mg/kg. Moreover, brain distribution and plasma protein binding were estimated. After intravenous injection, terminal half-life, systemic clearance, and steady state volumes of distribution remained unaltered as a function of dose with values in the range 3.01–3.53 h, 221–241 mL/h/kg and 702–732 mL/kg, respectively. Following oral administration, absolute oral bioavailability was not dose dependent and was at 93.3–106%. However, the time to peak concentration and the dose-normalized peak concentration for 30 mg/kg were significantly different with those for other doses. The extent of urinary excretion of lacosamide was 17.1% and 16.5% for intravenous and oral doses, respectively, whereas fecal excretion was negligible. The brain to plasma ratio of lacosamide was consistent regardless of post-dosing time and the brain to plasma partition coefficient was 0.553. Further, the plasma protein binding of lacosamide was concentration independent with free fraction at 95.9%. Lacosamide showed linear pharmacokinetics at an intravenous dose of 1–30 mg/kg and an oral dose of 1–10 mg/kg but non-linear pharmacokinetics at a 30 mg/kg oral dose.     

Enhanced bioavailability of etoposide after oral or intravenous administration of etoposide with kaempferol in rats

This study was to investigate the effect of kaempferol on the pharmacokinetics of etoposide after oral or intravenous administration of etoposide in rats. The oral (6 mg/kg) or intravenous (2 mg/kg) etoposide was administered to rats alone or 30 min after the oral kaempferol (1, 4, or 12 mg/kg) administration. Compared to the oral control group, the presence of kaempferol significantly (4 mg/kg, P < 0.05; 12 mg/kg, P < 0.01) increased the area under the plasma concentrationtime curve (AUC) and the peak concentration (C_max) of the oral etoposide. Kaempferol decreased significantly (4 or 12 mg/kg, P < 0.05) the total body clearance (CL/F) of oral etoposide, while there was no significant change in the terminal halflife (t_1/2), the elimination rate constant (K_el) and the time to reach the peak concentration (T_max) of etoposide in the presense of kaempferol. Consequently, the absolute bioavailability (AB%) of oral etoposide with kaempferol was significantly higher (4 mg/kg, P < 0.05; 12 mg/kg, P < 0.01) than those from the control group. Compared to the intravenous control group, the presence of kaempferol enhanced the AUC of intravenously administered etoposide, however, only presence of 12 mg/kg of kaempferol significant (P < 0.05) increased AUC of etoposide. The enhanced bioavailability of oral etoposide by kaempferol could have been due to an inhibition of cytochrom P450 (CYP) 3A and P-glycoprotein (P-gp) in the intestinal or decreased total body clearance in the liver by kaempferol. The dosage regimen of etoposide should be taken into consideration for potential drug interaction when combined with kaempferol or dietary supplements containing kaempferol in patients.     

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.     

Pharmacokinetics,biodistribution and bioavailability of isoliquiritigenin after intravenous and oral administration

Context: Isoliquiritigenin (ISL) has been shown to exhibit a variety of biological activities. However, there is little research on the pharmacokinetic behavior and tissues distribution of ISL.

Objective: Pharmacokinetics, biodistribution and bioavailability of ISL after intravenous and oral administration were determined by systematic investigation in Sprague–Dawley rats.

Materials and methods: ISL was dissolved in medicinal ethanol-Tween 80–0.9% sodium chloride saline in a volume ratio of 10:15:75. The ISL solution was injected in rats via a tail vein at a single dose of 10, 20 and 50?mg/kg and administered orally in rats at a single dose of 20, 50 and 100?mg/kg, respectively. Blood samples were collected at time intervals of 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 6, 8 and 12?h after intravenous injection. Tissues of interests in mice were collected immediately at each determined time point (0.5, 1, 2, 3 and 6?h) after cervical dislocation.

Results: The dose-normalized AUC values were 7.3, 7.6 and 8.7?μg?×?h/ml (calculated based on the dose of 10?mg/kg) for intravenous doses of 10, 20 and 50?mg/kg, respectively. The elimination half-lifes (t_1/2λ) were 4.9, 4.6 and 4.8?h at 10, 20 and 50?mg/kg intravenous doses, respectively. The F values were 29.86, 22.70, 33.62% for oral doses of 20, 50 and 100?mg/kg, respectively. Liver, heart and kidney were major distribution tissues of ISL in mice. The plasma protein binding of ISL in rats was 43.72%.

Conclusion: The work may useful for further study of the bioactive mechanism of ISL.     

Dose escalation pharmacokinetics and lipid lowering activity of a novel farnesoid X receptor modulator: 16-Dehydropregnenolone

Objectives:

To study the dose escalation pharmacokinetics and lipid lowering activity of a novel FXR modulator, 16-Dehydropregnenolone (DHP).

Materials and Methods:

The disposition of DHP following oral (36, 72, 100 and 150 mg/kg) and intravenous (1, 5 and 10 mg/kg) administration and its dose-response relationship were carried out in Sprague–Dawley rats. DHP and its metabolite 5-pregnene-3β-ol-16, 17-epoxy-20-one (M1) were analyzed by a validated LC-MS/MS method in plasma after intravenous and oral administration. Dose escalation lipid lowering activities were carried out by triton-induced hyperlipidemic model.

Results:

Oral administration resulted in higher amount of M1 formation as compared to intravenous administration. Dose escalation intravenous administration (1, 5 and 10 mg/kg) resulted in nonlinear increase in AUC of DHP. This was due to saturation of metabolism. On the contrary, systemic AUC and C_max after oral administration show non-linear pharmacokinetics where saturated systemic DHP and M1 pharmacokinetics was observed above 72 mg/kg, indicating saturated oral absorption. Lipid lowering activity by its oral route of administration was in accordance with its pharmacokinetic profile and reached saturation above 72 mg/kg.

Conclusion:

DHP exhibits route and dose-dependent pharmacokinetics. Pharmacokinetic and lipid lowering activity by oral route indicate saturation of oral absorption at higher doses. The study contributes to the understanding of the plasma disposition pharmacokinetics of DHP and its metabolite in rats by oral and intravenous route of administration.KEY WORDS: Dose-escalation pharmacokinetics, lipid-lowering activity, 80/574     

Pharmacokinetics of sildenafil after intravenous and oral administration in rats: hepatic and intestinal first-pass effects

Pharmacokinetics of sildenafil after intravenous and oral administration at various doses and first-pass effect at 30 mg/kg were evaluated in rats. After intravenous administration (10, 30, and 50 mg/kg), the dose-normalized AUC values were proportional to intravenous doses studied. However, after oral administration (10, 30, and 100 mg/kg), the dose-normalized AUC values increased significantly with increasing doses, possibly due to saturation of metabolism of sildenafil in rat intestinal tract. After oral administration (30 mg/kg), approximately 0.626% was not absorbed and F was 14.6%. The AUC after intragastric administration was significantly smaller (71.4% decrease) than that after intraportal administration, however, the values were not significantly different between intragastric and intraduodenal administration. The above data suggested that intestinal first-pass effect of sildenafil was approximately 71% of oral dose in rats. The AUC values after intraportal administration were significantly smaller (49% decrease) than that after intravenous administration. This suggested that hepatic first-pass effect of sildenafil after absorption into the portal vein was approximately 49% of oral dose in rats (approximately 49% was equivalent to approximately 13.7% of oral dose). The low F of sildenafil at a dose of 30 mg/kg in rats could be mainly due to considerable intestinal first-pass effect.     

Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam

Objective: Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam. Methods: A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and orally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, α-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. Results: Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC_0–3, AUC_0–17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (C_max) 2- to 2.5-fold compared with placebo. The AUC_0–3 and the C_max of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases. Conclusion: We conclude that the metabolism of orally␣administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole. Received: 1 July 1996 / Accepted in revised form: 4 September 1996     

Toxicokinetics of p-tert-octylphenol in male Wistar rats

Only weak oestrogenic activity has been reported for p-alkylphenols compared with the physiological hormone 17β-estradiol. Despite the low potency, there is concern that due to bioaccumulation oestrogenically efficient blood levels could be reached in humans exposed to trace levels of p-alkylphenols. To address these concerns, toxicokinetic studies with p-tert-octylphenol [OP; p-(1,1,3,3-tetramethylbutyl)-phenol] as a model compound have been conducted in male Wistar rats. OP blood concentrations were determined by GC-MS in rats receiving either single oral (gavage) applications of 50 or 200mg OP/kg body wt or a single intravenous injection of 5mg/kg body wt. The OP blood concentration was ∼1970ng/ml immediately after a single intravenous application, decreased rapidly within 30 min, and was no longer detectable 6–8h after application. The curve of blood concentration vs time was used to calculate an elimination half-life of 310min. OP was detected in blood as early as 10min after gavage administration, indicating rapid initial uptake from the gastrointestinal tract; maximal blood levels reached 40 and 130ng/ml after applications of 50 and 200mg/kg, respectively. Using the area under the curve (AUC) of blood concentration vs time, low oral bioavailabilities of 2 and 10% were calculated for the 50 and 200mg/kg groups, respectively. OP toxicokinetics after repeated administration was investigated in male Wistar rats receiving daily gavage administrations of 50 or 200mg OP/kg body wt for 14 consecutive days. Profiles of OP blood concentration vs time determined on day 1 and day 14 were similar, indicating that repeated oral gavage administration did not lead to increased blood concentrations. Another group of rats received OP via drinking water saturated with OP (∼8mg/l, corresponding to a mean daily dose of ∼800μg/kg) over a period of up to 28 days. OP was not detected in any blood sample from animals treated via drinking water (detection limit was 1–5ng/ml blood). OP concentrations were also analysed in tissues obtained from the repeated gavage (14 days) and drinking water groups (14 and 28 days). In the 50mg/kg group, low OP concentrations were detected in fat and liver from some animals at average concentrations of 10 and 7ng/g tissue, respectively. OP was not detected in the other tissues analysed from this group. In the 200mg/kg group, OP was found in all tissues analysed except testes (fat, liver, kidney, muscle, brain and lung had average concentrations of 1285, 87, 71, 43, 9 and 7ng/g tissue, respectively). OP was not detected in tissues of animals receiving OP via drinking water for 14 or 28 days, except in muscle and kidney tissue of one single animal receiving OP for 14 days. Using rat liver fractions it was demonstrated that OP was conjugated via glucuronidation and sulphation in vitro. A V _max of 11.24 nmol/(min * mg microsomal protein) and a K _m of 8.77μmol/l were calculated for enzyme-catalysed OP glucuronidation. For enzyme-catalysed sulphation, a V _max of 2.85nmol/(minT15*mg protein) and a K _m of 11.35μmol/l were calculated. The results indicate that OP does not bioaccumulate in rats receiving low oral doses, in agreement with the hypothesis of a rapid first-pass elimination of OP by the liver after oral ingestion, via glucuronidation and sulphation. Only if these detoxification pathways are saturated may excessive doses lead to bioaccumulation. Received: 22 March 1996/Accepted: 12 June 1996     

Pharmacokinetics and systemic availability of the antihypertensive agent indoramin and its metabolite 6-hydroxyindoramin in healthy subjects

Summary We have studied the pharmacokinetics and absolute systemic availability of indoramin (50 mg) given orally in solution or as a tablet with reference to intravenously administered drug (0.15 mg/kg) in 9 healthy volunteers. After intravenous administration the median apparent volume of distribution was 6.3l·kg⁻¹, plasma clearance was 20.0 ml·min⁻¹·kg⁻¹, and terminal half-time was 4.1 h. When given by tablet indoramin was absorbed with moderate rapidity, with a median t_max of 1.5 h. The median systemic availability was 24%. After oral administration in solution the drug was more rapidly absorbed, with a median t_max of 1.0 h (p<0.01). The median systemic availability was 43% (15–85%). Plasma concentrations of an active metabolite, 6-hydroxyindoramin, after single oral doses in either dosage form, were of a similar order to those of unchanged drug and fell with similar rapidity. After intravenous administration, however, concentrations of the metabolite were negligible.     

Effects of grapefruit juice ingestion – pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men

Objective: To examine the effect of grapefruit juice on the metabolism of felodipine following intravenous and oral administration. Methods: The study had a randomised, four-way, crossover design in 12 healthy males. Single doses of felodipine were given as an intravenous infusion for 1 h (1.5 mg) or as an oral extended release (ER) tablet (10 mg). Grapefruit juice (150 ml) or water was ingested 15 min prior to drug intake. Results: Intake of grapefruit juice did not significantly alter the intravenous pharmacokinetics of felodipine compared to control treatment, whereas after oral drug administration it did lead to an increase in the mean AUC and C_max by 72% and 173%, respectively, and the mean absolute bioavailability was increased by 112%. The fraction of the oral felodipine dose reaching the portal system was increased from 45% to 80% when intake of drug was preceded by grapefruit juice ingestion. The pharmacokinetics of the primary metabolite, dehydrofelodipine, was affected by the intake of juice, resulting in a 46% increase in C_max. Juice intake immediately before oral felodipine resulted in more pronounced haemodynamic effects of the drug as measured by diastolic blood pressure and heart rate. However, the haemodynamic effects of the intravenous administration were not altered by juice intake. Vascular-related adverse events were reported more frequently when oral drug administration was preceded by juice intake compared with control treatment. Taking grapefruit juice immediately prior to intravenous felodipine administration did not cause any alteration in the adverse event pattern. Conclusion: The main acute effect of the grapefruit juice on the plasma concentrations of felodipine is mediated by inhibition of gut wall metabolism. Received: 24 April 1996 / Accepted in revised form: 25 November 1996     

Pharmacokinetics of chlorogenic acid and corydaline in DA-9701, a new botanical gastroprokinetic agent,in rats

Abstract

1.?Few studies describing the pharmacokinetic properties of chlorogenic acid (CA) and corydaline (CRD) which are marker compounds of a new prokinetic botanical agent, DA-9701, have been reported. The aim of the present study is to evaluate the pharmacokinetic properties CA and CRD following intravenous and oral administration of pure CA (1–8?mg/kg) or CRD (1.1–4.5?mg/kg) and their equivalent dose of DA-9701 to rats.

2.?Dose-proportional AUC and dose-independent clearance (10.3–12.1?ml/min/kg) of CA were observed following its administration. Oral administration of CA as DA-9701 did not influence the oral pharmacokinetic parameters of CA. Incomplete absorption of CA, its decomposition in the gastrointestinal tract, and/or pre-systemic metabolism resulted in extremely low oral bioavailability (F) of CA (0.478–0.899%).

3.?CRD showed greater dose-normalized AUC in the higher dose group than that in lower dose group(s) after its administration due to saturation of its metabolism via decreased non-renal clearance (by 51.3%) and first-pass extraction. As a result, the F of CRD following 4.5?mg/kg oral CRD (21.1%) was considerably greater than those of the lower dose groups (9.10 and 13.8%). However, oral administration of CRD as DA-9701 showed linear pharmacokinetics as a result of increased AUC and F in lower-dose groups (by 182% and 78.5%, respectively) compared to those of pure CRD. The greater oral AUC of CRD for DA-9701 than for pure CRD could be due to decreased hepatic and/or GI first-pass extraction of CRD by other components in DA-9701.     

Pharmacokinetics of YJC-10592, a novel chemokine receptor 2 (CCR-2) antagonist,in rats

YJC-10592, a novel chemokine receptor 2 (CCR-2) antagonist, was developed for treating asthma and atopic dermatitis. We studied the pharmacokinetic characteristics of YJC-10592 after intravenous (5, 10 and 20 mg/kg) and oral (100 and 200 mg/kg) administration of the drug to rats. Tissue distribution of YJC-10592 was also evaluated after intravenous administration of YJC-10592, 10 mg/kg, to rats. The pharmacokinetics of YJC-10592 was dose-dependent from 20 mg/kg after intravenous administration to rats. The values of the area under the plasma concentration–time curve from time zero to infinity (AUC) of YJC-10592 were dose-dependent from 20 mg/kg and the time-averaged total body (CL) and nonrenal (CL_NR) clearances of YJC-10592 were significantly lower at dose of 20 mg/kg, suggesting that saturable metabolism may be involved. The absolute bioavailability (F) of YJC-10592 was generally low (<2.55 %) for both oral doses due to incomplete absorption and low urinary excretion. YJC-10592 had a great affinity to all rat tissues studied except brain, which was supported by a relatively high value of the apparent volume of distribution at steady state (V _ss) (890–1385 mL/kg). In conclusion, YJC-10592 showed dose-dependent pharmacokinetics and low F value due to slower elimination and incomplete absorption.     

Influence of dose and route of administration on the kinetics of fluoxetine and its metabolite norfluoxetine in the rat

Fluoxetine (FL) is being used in neuropharmacology as a tool for studying various functional roles of serotoninergic neurons. Its kinetics was studied in rats, a species widely used in neurochemical studies, after IV (2.5–10 mg/kg) and oral (5–20 mg/kg) administration. When injected IV the drug followed apparent first-order kinetics up the 10 mg/kg dose. Its volume of distribution was large and total body clearance was relatively high compared to liver blood flow. The mean elimination half-lives (t _1/2) of FL and its active metabolite norfluoxetine (NFL) were about 5 and 15 h, respectively. The mean blood:plasma concentration ratios of FL and NFL approached unity and plasma protein binding was 85–90% for both compounds. After oral doses the kinetics of FL were complex. At the lowest dose tested (5 mg/kg) the drug was efficiently extracted by the liver (extraction ratio about 60%), resulting in bioavailability of only about 38%. Plasma areas under the curve (AUC) of the metabolite were approximately the same as after IV injection of the same dose; consequently the metabolite-to-parent drug ratio after oral administration (about 5) was approximately twice that after IV injection of FL (about 2.5). At higher doses, however, the oral bioavailability (e.g.C _max and AUC) appeared greater than expected, possibly because of transient saturation of FL first-pass metabolism in the case of the 10 mg/kg dose and concomitant saturation of elimination kinetics at the higher dose (20 mg/kg). The apparent eliminationt _1/2 of FL markedly increased and the metabolite-to-parent drug ratio declined with the higher dose, this also being consistent with saturable elimination. Brain concentrations reflected the plasma kinetics of FL and NFL and the metabolite-to-parent drug ratio varied with dose and time of administration and was modified at the highest dose tested. FL and its metabolite NFL distributed almost evenly in discrete brain areas and subcellular distribution was similar for both compounds. Neurochemical studies of FL should consider the formation of the active metabolite NFL and extrapolation of data across animal species requires consideration of dose dependence in the rat.     

Pharmacokinetics of Ketorolac and p-Hydroxyketorolac Following Oral and Intramuscular Administration of Ketorolac Tromethamine

Ketorolac tromethamine (KT), a potent analgesic with cyclooxygenase inhibitory activity, was administered in an open, randomized, single-dose study of Latin-square design to 12 healthy male volunteers. Doses of 30 mg oral (po) and 30, 60, and 90 mg intramuscular (im) KT were administered in solution. Plasma samples were analyzed for ketorolac (K) and its inactive metabolite, p-hydroxyketorolac (PHK), by reversed-phase high-performance liquid chromatography (HPLC). The 30-mg im dose was found to be similar to the 30-mg po dose with respect to total AUC values for both K and PHK. The amount of PHK circulating in plasma was very low as judged by AUC ratios (PHK/K × 100) of 1.9 and 1.5% for the 30-mg po and im doses, respectively. The rate of absorption of K and formation of PHK, as determined by C _max and T _max values, was significantly slower following the im doses. Total AUC and C _max for K and PHK increased linearly with dose after im administration of 30, 60, and 90 mg of KT. The mean plasma half-life of K was remarkably consistent between po and im administration and was independent of dose, ranging from 5.21 to 5.56 hr. The plasma metabolic profile was similar following both routes of administration and graded im doses.     

An interaction study with cimetidine and the new angiotensin II antagonist valsartan

Objective: This was a randomised, open, three-way crossover study in 12 healthy male volunteers to determine the effect of a single oral dose of cimetidine on the pharmacokinetics of a single oral dose of the angiotensin II receptor antagonist valsartan – and vice versa. The volunteers received either valsartan alone (160 mg), or cimetidine alone (800 mg), or valsartan 1 h after cimetidine. The study was designed primarily to detect a possible influence of cimetidine on the rate and extent of absorption of valsartan. Methods: Plasma concentrations of valsartan and cimetidine, measured by means of high-performance liquid chromatography, were used to calculate pharmacokinetic parameters. The rate of absorption of valsartan and the fraction of the dose absorbed and systemically available after oral administration were calculated using data from an i.v. study with valsartan in healthy young volunteers. Results: The pharmacokinetics of cimetidine – area under curve (AUC_{0–48 h}), maximum concentration (C_max), time to reach C_max (t_max) and apparent terminal plasma half-life (t_1/2) – was not changed by co-administration of valsartan. For valsartan, the AUC_{0–48 h} increased by 7% and the C_max by 51% (ratio of geometric means) with co-administration of cimetidine. The higher value for C_max was attributed to the initial increase in the rate of absorption of valsartan: k_a was increased 2.7-fold and another indicator for the rate of absorption, C_max/t_max, 2.2-fold. This effect was ascribed to inhibition of acid secretion by cimetidine, which leads to a higher gastric pH, thereby increasing the solubility of valsartan; the t_1/2 of valsartan was not changed. After valsartan alone, 19% of the dose was absorbed, 23% with co-administration of cimetidine. It was estimated that only 2.2% of the possible change in AUC might be missed by giving a single high dose of cimetidine instead of multiple doses, with the aim to optimally inhibit formation of the inactive metabolite of valsartan. Cimetidine-related changes in the rate of elimination of valsartan were not anticipated, since the clearance from plasma occurs mainly by biliary excretion of unchanged valsartan; metabolism and renal excretion are only minor contributors. Therefore, even in the clinically relevant situation with multiple doses of valsartan and cimetidine, notable changes in the pharmacokinetics of valsartan, except for an increase in C_max, are not to be expected. This increase in C_max appears to be of no clinical significance. Valsartan alone and in combination with cimetidine was well tolerated by healthy subjects. Received: 16 October 1996 / Accepted in revised form: 25 September 1997