The pharmacokinetics and pharmacodynamics of adinazolam: multi-ethnic comparisons

The pharmacokinetics and pharmacodynamics of adinazolam and N-demethyladinazolam (NDMAD), its major active metabolite, were compared in 39 healthy male volunteers (13 Asian, 12 Caucasian and 14 African-American). In a four-way, double-blind crossover design, subjects were administered (1) 30 mg oral adinazolam mesylate SR tablets, (2) 10 mg parenteral (IV) adinazolam mesylate, (3) 30 mg IV NDMAD and (4) placebo. Venous blood samples were collected at specific time intervals after drug administration and assayed for adinazolam and NDMAD concentrations. Sedation was rated at the time of each blood draw according to the Nurse-Rated Sedation Scale, and the digit-symbol substitution test was administered to evaluate psychomotor performance. After IV administration of adinazolam, Asians manifested significantly higher C_max, larger AUC and lower CL of both adinazolam and NDMAD than their Caucasian and African-American counterparts. Likewise, after IV NDMAD Asians had significantly higher NDMAD C_max and AUC than Caucasians and African-Americans. Most of these differences remained statistically significant after controlling for body surface area. With PO adinazolam, Asians also manifested substantially higher C_max, larger AUC and lower CL for both adinazolam and NDMAD; however, with the exception of C_max, these differences did not reach statistical significance. These results are in accordance with previous observations for ethnic-related differences in drug pharmacokinetics. In contrast, pharmacodynamic differences were not noted among the three study groups. Received: 19 June 1996/Final version: 17 September 1996     

Multiple-Dose Pharmacokinetics and Pharmacodynamics of Adinazolam in Elderly Subjects

The pharmacokinetics and pharmacodynamics of adinazolam (AD) were evaluated in 21 elderly subjects (mean age, 69 ± 4 years) at four dose levels during a placebo-controlled, double-blind, dose escalation regimen in which the oral dose was varied from 10 to 60 mg daily, in divided doses. Fifteen subjects received adinazolam mesylate; six received placebo. Plasma samples collected during a single dosing interval in each dosing period (3 days) were assayed for adinazolam and monodesmethyl adinazolam (NDMAD) by high-performance liquid chromatography (HPLC). Urine samples were collected during a single interval during the 20- and 40-mg daily dose periods and assayed for NDMAD by HPLC. Pharmacologic effects of adinazolam were assessed using psychomotor performance tests and sedation ratings. Adinazolam pharmacokinetics were linear over the dosage range studied. Daily dose had no significant effect on dose-normalized AUC and C _max for AD. Dose-normalized NDMAD AUC values as well as values were not significantly affected by the daily dose of adinazolam. The ratio NDMAD/AD was not substantially affected by the dose. Renal clearance of NDMAD for the 20-and 40-mg daily doses were 5.6 ± 2.1 and 5.5 ± 2.2 liters/hr, respectively, and did not correlate with creatinine clearance. Adinazolam and NDMAD did not substantially accumulate in elderly subjects, even upon multiple dosing at 8-hr intervals. The dosing regimens in this experiment appeared to be well tolerated in the elderly, as performance tests and sedation scores indicated no substantial dose-related effects of adinazolam on psychomotor performance.     

Comparison of enantioselective disposition of rabeprazole versus lansoprazole in renal-transplant recipients who are CYP2C19 extensive metabolizers

The purpose of this study was to investigate the comparative pharmacokinetics of rabeprazole and lansoprazole enantiomers in renal-transplant recipients on tacrolimus who were CYP2C19 extensive metabolizers. Sixteen Japanese patients were randomly assigned after renal transplantation to receive repeated doses of one of the following two regimens for 28 days; tacrolimus, mycophenolate mofetil and prednisolone together with either 20?mg of racemic rabeprazole (n?=?8) or 30?mg of racemic lansoprazole (n?=?8). The mean C_max and AUC_0–24 of (R)-lansoprazole compared to (S)-lansoprazole in renal transplant recipients were 12-fold (954?±?522 vs. 167?±?137?ng?ml^?1, respectively) and 6.9-fold (4787?±?3454 vs. 451?±?354?ng?h?ml^?1, respectively) greater, and its elimination half-life was 2.1-fold (2.3?±?1.0 vs. 1.2?±?0.6?h, respectively) longer. In contrast, although the elimination half-life of (R)-rabeprazole was significantly longer than that of the (S)-enantiomer (2.1?±?0.5 vs. 1.3?±?0.9?h, respectively; P?C_max between the (R)- and (S)-enantiomer (186?±?40 vs. 200?±?92?ng?ml^?1, respectively). In conclusion, in renal-transplant recipients who are CYP2C19 extensive metabolizers, there is less stereoselective difference in the pharmacokinetic disposition between the (R)- and (S)-enantiomers of rabeprazole than those of lansoprazole.     

Disposition and bioavailability of the β1-adrenoceptor antagonist talinolol in man

In an open randomized crossover study, the pharmacokinetics and bioavailability of the selective β₁-adrenoceptor antagonist talinolol (Cordanum®—Arzneimittelwerk Dresden GmbH, Germany) were investigated in twelve healthy volunteers (five female, seven male; three poor and nine extensive metabolizers of the debrisoquine hydroxylation phenotype) after intravenous infusion (30 mg) and oral administration (50 mg), respectively. Concentrations of talinolol and its metabolites were measured in serum and urine by HPLC or GC-MS. At the end of infusion a peak serum concentration (C_max) of 631 ± 95 ng mL^?1 (mean ± SD) was observed. The area under the serum concentration-time curve from zero to infinity (AUC_0-∞) was 1433 ± 153 ng h mL^?1. The following parameters were estimated: terminal elimination half life (t_1/2), 10.6 ± 3.3 h; mean residence time, 11.6 ± 3.1 h; volume of distribution, 3.3 ± 0.5 L kg^?1; and total body clearance, 4.9 ± 0.6 mL min^?1 kg^?1. Within 36 h 52.8 ± 10.6% of the administered dose was recovered as unchanged talinolol and 0.33 ± 0.18% as hydroxylated talinolol metabolites in urine. After oral administration a C_max of 168 ± 67 ng mL^?1 was reached after 3.2 ± 0.8h. The AUC_0-∞ was 1321 ± 382 ng h mL^?1. The t_1/2 was 11.9 ± 2.4 h. 28.1 ± 6.8% of the dose or 55.0 ± 11.0% of the bioavailable talinolol was eliminated as unchanged talinolol and 0.26 ± 0.17% of the dose as hydroxylated metabolites by kidney. The absolute bioavailability of talinolol was 55 ± 15% (95% confidence interval, 36–69%). Talinolol does not undergo a relevant first-pass metabolism, and its reduced bioavailability results from incomplete absorption. Talinolol disposition is not found to be altered in poor metabolizers of debrisoquine type.     

Pharmacokinetic study of a tripeptide HIV-1 protease inhibitor,KNI-174, in rats after intravenous and intraduodenal administrations

Recently, as a new type of anti-AIDS drug, an HIV-1 protease inhibitor, KNI-174, has been synthesized; it shows a potent and selective HIV-1 protease inhibitory activity in vitro. In this study, we developed an HPLC assay system for KNI-174 in rat plasma and examined the pharmacokinetics of KNI-174 in rats using this assay method after both intravenous (i.v.) and intraduodenal (i.d.) administrations to obtain the disposition characteristics and bioavailability of this new anti-AIDS drug. This HPLC assay method is specific to KNI-174 and the standard curve was linear from 0.02 to 30 μg ml^?1 plasma. After i.v. administration, 10.0 mg kg^?1, KNI-174 disappeared from the rats' plasma in a three-exponential decay. The mean terminal elimination half-life, t_1/2ÀZ, was 3.97 ± 0.19 (S.E.)h, the total body clearance, CL_tot, was 9.53 ± 1.08 ml min^?1 and the distribution volume at steady state, V_{d, ss}′ was 7070 ± 960 ml kg^?1. In the case of the i.d. administration, 10.0 mg kg^?1, the mean peak plasma concentration, C_max, and the peak time, t_max, were 0.196 ± 0.076 μg ml^?1 and 0.444 ± 0.193 h, respectively. The bioavailability of KNI-174 till infinity, BA^(0-infinity), was 5.37 per cent. Because the IC₅₀ of KNI-174 against HIV-1 in PHA-PBM was 138 ng ml^?1, the time needed for maintaining the concentrations above IC₅₀ after a single i.d. administration of KNI-174 is estimated to be 0.350 ± 0.184 h.     

The pharmacokinetics and absolute bioavailability of selegiline in the dog

Selegiline is beneficial to Parkinsonian patients as an adjunct to levodopa therapy. Currently no pharmacokinetic data are available for selegiline in the literature, mainly due to lack of analytical methods that can measure concentrations below 10 ng mL^?1 in plasma. A sensitive fluorimetric assay based on inhibition of rat brain monoamine oxidase-B (MAO-B) in vitro has been developed to measure selegiline in plasma as low as 0.25 ng mL^?1. The pharmacokinetics of selegiline were investigated following intravenous and oral administration to four female mongrel dogs. Each dog received 1 mg kg^?1 selegiline in solution via gavage or by an intravenous route separated by one week. The mean terminal half-life, volume of distribution of the central compartment, and systemic clearance of selegiline were 60.24 ± 9.56 min, 6.56 ± 0.56 L kg^?1, and 159.91 ± 19.28 mL min^?1 kg^?1, respectively. After oral administration selegiline appeared to be absorbed rapidly with a t_max and C_max of 25 ± 5.8 min and 5.2 ± 1.36 ng mL^?1, respectively. The absolute bioavailability of selegiline in the dog was 8.51 ± 3.31%.     

Clinical pharmacology of adinazolam and N-desmethyladinazolam mesylate following single intravenous infusions of each compound in healthy volunteers

Summary The tolerability, pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam (NDMAD) were assessed following intravenous infusions of 5, 10, 15, and 20 mg adinazolam mesylate, 10, 20, 30 and 40 mg NDMAD mesylate, and placebo. Six subjects per dose level received treatments in a double-blind crossover design.No clinically significant changes were seen in blood pressure, pulse, respiration, or clinical laboratory parameters. Untoward effects typical of benzodiazepines were observed almost exclusively after NDMAD administration. Adinazolam and NDMAD pharmacokinetics were dose-independent. NDMAD clearance was 50% of the value for adinazolam. Adinazolam and NDMAD administrations increased uric acid clearance and decreased plasma uric acid. Adinazolam administration had no significant effect on psychomotor performance. NDMAD administration produced dose related decreases in performance; 286 ng/ml NDMAD produced a 50% decrease in DSST.These results confirm that adinazolam and NDMAD both produce uricosuria and definitively show that adinazolam is devoid of benzodiazepine-like effects at therapeutic concentrations; NDMAD mediates these effects. Uricosuric activity is present for both compounds, but the relative potencies are still unknown.Presented in part at the Nineteenth Annual Meeting of the American College of Clinical Pharmacology, Las Vegas, NV, November 4–8, 1990     

Adinazolam pharmacokinetics and behavioral effects following administration of 20–60 mg oral doses of its mesylate salt in healthy volunteers

The pharmacokinetics and pharmacodynamics of adinazolam were studied in 15 normal, healthy, non-obse volunteers. Placebo capsules and capsules containing 20, 40, and 60 mg adinazolam mesylate were administered as single oral doses in a randomized, 4-way crossover design. Plasma concentrations of adinazolam and mono-N-desmethyladinazolam (NDMAD) were determined by HPLC. Psychomotor performance and memory tests were performed and the degree of sedation assessed at designated times following drug administration. Adinazolam and NDMAD pharmacokinetics were linear throughout the dosage range studied. The ratio of NDMAD to adinazolam area under the curve was approximately 4:1. Dose-related decrements in psychomotor performance and memory were observed up to 8h after dosing (P<0.025 in all cases). Psychomotor performance decrements correlated more closely with NDMAD plasma concentrations than with adinazolam concentrations. These results suggest that NDMAD is responsible for a significant degree of the sedative and psychomotor effects observed after the administration of adinazolam.     

Pharmacokinetics of a novel retinoid AGN 190168 and its metabolite AGN 190299 after intravenous administration of AGN 190168 to rats

The pharmacokinetics of AGN 190168, a novel synthetic retinoid, and its major metabolite, AGN 190299, in rat blood after intravenous administration was investigated. Approximately 4.4 mg kg^?1 (high dose) or 0.49 mg kg^?1 (low dose) of AGN 190168 was administered to rats via the femoral vein. Blood was collected from the femoral artery at various time points during an 8 h period. Blood concentrations of AGN 190168 and AGN 190299 were determined by a specific and sensitive high-pressure liquid chromatographic (HPLC) method. AGN 190168 was rapidly metabolized in rats. The only detectable drug-related species in the blood was AGN 190299. Therefore, only pharmacokinetics of AGN 190299 were calculated. Elimination of AGN 190299 appeared to be non-linear after administration of the high dose, and linear after administration of the low dose. The maximum elimination rate (V_max) and the concentration at half of the V_max (k_m), as estimated by a Michaelis—Menten one-compartment model, were 7.58 ± 2.42 μg min^?1 (mean ± SD) and 6.10 ± 1.58 μg mL^?1, respectively. The value of the area under the blood concentration time curve (AUC) was 9.54 ± 1.68 μg h mL^?1 after administration of the high dose and 0.594 ± 0.095 μg h mL^?1 after administration of the low dose. The clearance value was 7.79 ± 1.20 mL min^?1 kg^?1 after the high dose, statistically significantly different from that after the low dose (p < 0.05), 14.0 ± 2.2 mL min^?1 kg^?1. The terminal half-life (t_1/2) was 1.25 ± 0.74 h for the high-dose group and 0.95 ± 0.16 h for the low-dose group. Study results demonstrate rapid systemic metabolism of AGN 190168 to AGN 190299, non-linear pharmacokinetics of AGN 190299 after the 4.4 mg kg^?1 dose, and the lack of difference in disposition profiles between sexes after intravenous administration of AGN 190168 to rats.     

The acetylcholinesterase oxime reactivator HI-6 in man: Pharmacokinetics and tolerability in combination with atropine

In a double-blind, placebo-controlled, single-dose ascending pharmacokinetics and tolerance study, we evaluated the bispyridinium oxime HI-6 dichloride monohydrate (62.5, 125, 250, and 500 mg), administered intramuscularly with atropine sulphate, 2 mg, in 24 healthy male volunteers. The plasma HI-6 peak concentration (C_max) and area under the concentration—time curve (AUC) demonstrated linear pharmacokinetics with low intradose variability, suggestive of uniformity of effect among subjects. HI-6 (500 mg) attained plasma drug concentrations that appeared adequate for practical use as an antidote. The mean ± SD time to maximum plasma HI-6 concentration (t_max = 0.69 ± 0.21 h, n = 16), and absorption half-life (t/2_a = 0.17 ± 0.05 h) indicated rapid onset of effect. The volume of distribution (V_d = 0.25 ± 0.04 L kg^?1 TBW) approximated the extracellular fluid volume. A high total body clearance (CL = 252 ± 52 mL min^?1) and short apparent elimination half-life (t/2_e = 1.15 ± 0.19 h) were expected for this polar quaternary ammonium drug. The renal clearance (CL_r = 137 ± 33 mL min^?1), which approximated the expected glomerular filtration rate, and 24 h urinary excretion of unchanged drug (55 ± 10%) indicated substantial non-renal elimination. Blood pressure, heart rate, respiratory rate, electrocardiographic parameters, mental acuity, and vision were not altered. Adverse events and changes in serum, urine and semen laboratory tests were mild. The pharmacokinetics, safety, and apparent efficacy of HI-6 suggest it may be a superior oxime antidote against nerve agent poisoning.     

Kinetic Characterization and Identification of the Enzymes Responsible for the Hepatic Biotransformation of Adinazolam and N-Desmethyladinazolam in Man

The kinetics of the N-demethylation of adinazolam to N-desmethyladinazolam (NDMAD), and of NDMAD to didesmethyladinazolam (DDMAD), were studied with human liver microsomes using substrate concentrations in the range 10–1000 μm . The specific cytochrome P450 (CYP) isoforms mediating the biotransformations were identified using microsomes containing specific recombinant CYP isozymes expressed in human lympho-blastoid cells, and by the use of CYP isoform-selective chemical inhibitors. Adinazolam was demethylated by human liver microsomes to NDMAD, and NDMAD was demethylated to DDMAD; the substrate concentrations, K_m, at which the reaction velocities were 50% of the maximum were 92 and 259 μm , respectively. Another metabolite of yet undetermined identity (U) was also formed from NDMAD (K_m 498 μm ). Adinazolam was demethylated by cDNA-expressed CYP 2C19 (K_m 39 μm ) and CYP 3A4 (K_m 83 μm ); no detectable activity was observed for CYPs 1A2, 2C9, 2D6 and 2E1. Ketoconazole, a relatively specific CYP 3A4 inhibitor, inhibited the reaction; the concentration resulting in 50% of maximum inhibition, IC50, was 0·15 μm and the inhibition constant, K_i, was < 0·04 μm in five of six livers tested. Troleandomycin, a specific inhibitor of CYP 3A4, inhibited adinazolam N-demethylation with an IC50 of 1·96 μm . The CYP 2C19-inhibitor omeprazole resulted in only partial inhibition (IC50 21 μm ) and sulphaphenazole, α-naphthoflavone, quinidine and diethyldithiocarbamate did not inhibit the reaction. NDMAD was demethylated by cDNA-expressed CYP 3A4 (K_m 220 μm , Hill number A 1·21), CYP 2C19 (K_m 187 μm , Hill number A 1·29) and CYP 2C9 (K_m 1068 μm ). Formation of U was catalysed by CYP 3A4 alone. Ketoconazole strongly inhibited NDMAD demethylation (IC50 0·14 μm ) and formation of U (IC50 < 0·1 μm ) whereas omeprazole and sulphaphenazole had no effect on reaction rates. These results show that CYP 3A4 is the primary hepatic CYP isoform mediating the N-demethylation of adinazolam and NDMAD. Co-administration of adinazolam with CYP 3A4 inhibitors such as ketoconazole or erythromycin might lead to reduced efficacy, since adinazolam by itself has relatively weak benzodiazepine agonist activity, with much of the pharmacological activity of adinazolam being attributable to its active metabolite NDMAD.     

Effects of glycyrrhizin on the pharmacokinetics of puerarin in rats

1. Puerarin has been reported to possess a wide range of pharmacological activities. This study investigated the effects of glycyrrhizin on the pharmacokinetics of puerarin in rats.

2. The pharmacokinetics of orally administered puerarin (50?mg/kg) with or without glycyrrhizin pretreatment (100?mg/kg/day for 7?days) were investigated. The plasma concentration of puerarin was determined using a sensitive and reliable LC-MS/MS method. The pharmacokinetics profiles were calculated and compared. Additionally, a Caco-2 cell transwell model was used to investigate the potential mechanism of glycyrrhizin’s effects on the pharmacokinetics of puerarin.

3. The results showed that when the rats were pretreated with glycyrrhizin, the maximum concentration (C_max) of puerarin decreased from 761.25?±?52.34 to 456.32?±?34.75?ng/mL, and the area under the concentration–time curve from zero to infinity (AUC_0–inf) also decreased from 4142.15?±?558.51 to 2503.74?±?447.57?μg·h/L. The oral clearance of puerarin increased significantly from 12.20?±?1.53 to 20.47?±?3.25?L/h/kg (p?4. In conclusion, these results indicated that glycyrrhizin could affect the pharmacokinetics of puerarin, possibly by decreasing the systemic exposure of puerarin by inducing the activity of P-gp.     

Pharmacokinetic study of two acetylcholinesterase reactivators, trimedoxime and newly synthesized oxime K027, in rat plasma

K027 [1‐(4‐hydroxyiminomethylpyridinium)‐3‐(4‐carbamoylpyridinium)–propane dibromide] is a promising new reactivator of organophosphate‐ or organophosphonate‐inhibited acetylcholinesterase (AChE) with low acute toxicity and broad spectrum efficacy. The aim of the present study was to compare the pharmacokinetics of both compounds. Male Wistar rats (body weight = 320 ± 10 g) were administered a single intramuscular dose of K027 (22.07 mg kg^?1) and an equimolar dose of trimedoxime. Blood was collected at various time intervals until 180 min. Plasma samples were analyzed by reversed‐phase HPLC with ultraviolet (UV) detection. The recovery of both oximes from the plasma was approximately 90% and a linear relationship (R² > 0.998) was observed between the peak areas and concentrations of calibrated standards in the range 1–100 µg ml^?1. Near‐identical plasma profiles were obtained for both compounds. No differences were found in the mean ± SD values of C_max (18.6 ± 2.5 vs 20.0 ± 6.3 µg ml^?1, P = 0.72) and AUC_0–180min (2290 ± 304 vs 2269 ± 197 min µg ml^?1, P = 0.84). However, the percentage coefficient of variation of the first‐order rate constant of absorption (k_a) was 3‐fold higher (P < 0.01) providing evidence for more erratic absorption of intramuscular trimedoxime as compared with K027. In conclusion, oxime K027 might have superior pK properties that may be translated in its faster absorption and subsequent tissue distribution. Copyright © 2011 John Wiley & Sons, Ltd.     

Disposition of LY333531, a selective protein kinase C β inhibitor,in the Fischer 344 rat and beagle dog

1. Studies were conducted in the Fischer 344 rat and beagle dog to determine the disposition of LY333531 and its equipotent active des-methyl metabolite, LY338522, both potent and selective inhibitors of the β-isozyme of protein kinase C. 2. Male Fischer 344 rats and female beagle dogs received a single 5-mgkg^?1 oral dose of ¹⁴C-LY333531. Urine, faeces, bile and plasma were collected and analysed for ¹⁴C, LY333531 and LY338522. 3. LY333531 was eliminated primarily in the faeces (91% by 120 h in rat, 90% by 96h in dog). Bile contributed the majority of the radioactivity excreted in the faeces in rat (66% in the cannulated bile duct study) and a variable but significant proportion in dog. 4. Pharmacokinetics following a single 5?mg kg^?1 oral dose of ¹⁴C-LY333531 to the male rat produced C_max and AUC_0-∞ for LY333531 of 14.7 ng ml^?1 and 60.8ng h ml^?1, respectively, with a half-life of 2.5 h. LY338522 and total radioactivity showed similar profiles. 5. In the female dog at the same dose, C_max and AUC_0-∞ of LY333531 were higher, producing 245 ± 94 ng ml^?1 and 1419 ± 463ng h ml^?1, respectively, with a half-life of 5.7 h. 6. The data indicate that the disposition of LY333531 is similar in rat and dog.     

Pharmacokinetics and Cardiovascular Effects of YM-21095, a Novel Renin Inhibitor,in Dogs and Monkeys

Abstract— The pharmacokinetics and cardiovascular effects of YM-21095 ((2 RS), (3S)-3-[N^α-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)-butyl]-l-histidylamino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thio]-2-butanol), a potent renin inhibitor, have been studied in beagle dogs and squirrel monkeys. Plasma levels of YM-21095 after 3 mg kg^?1 intravenous dosing to dogs declined biphasically and fitted a two-compartment model. Kinetics were as follows: t½α = 4·9±0·2 min, t½β = 2·76±0·79 h, Vd_ss = 3·86±1·04 L kg^?1, plasma clearance = 2·22 ± 0·39 L kg^?1, and AUC= 1445 ± 266 ng h mL^?1. After 30 mg kg^?1 oral dose, maximum plasma concentration, t_max and AUC of YM-21095 were 28·8 ± 9·6 ng mL^?1, 0·25 h and 23·6 ± 7·7 ng h mL^?1, respectively. Systemic bioavailability as determined on the basis of the ratio of AUC after intravenous and oral dose was 0·16 ± 0·04%. In conscious, sodium-depleted monkeys, YM-21095 at an oral dose of 30 mg kg^?1 lowered systolic blood pressure and inhibited plasma renin activity without affecting heart rate and plasma aldosterone concentration. Maximum plasma concentration of YM-21095 after 30 mg kg^?1 oral dose to monkeys was 71·8 ± 41·5 ng mL^?1, which was reached 0·5 h after the dose. At equihypotensive doses, captopril and nicardipine increased plasma renin activity markedly and slightly, respectively. These results suggest that oral absorption of YM-21095 is low in dogs and monkeys, and YM-21095 shows a blood pressure lowering effect by inhibiting plasma renin activity in sodium-depleted monkeys.     

Repeated dose pharmacokinetics of pancopride in human volunteers

The aim of this study was to assess the pharmacokinetic profile of pancopride after repeated oral dose administration of 20 mg pancopride in tablet form once a day for 5 d in 12 healthy male volunteers. Plasma levels were measured by HPLC using a solid phase extraction method and automated injection. The minimum quantification limit of pancopride in plasma was 2 ng mL^?1. The maximum plasma concentration (mean ± SD) after the first dose was 92.5 ± 41.5 ng mL^?1 and t_max was 1.7 ± 0.9 h. The elimination half-life (t_1/2) was 14.3 ± 6.9 h. The area under the concentration-time curve from zero to infinity (AUC) was 997 ± 396 ng h mL^?1. The maximum plasma concentration (mean ± SD) at steady state (day 5) was 101.8 ± 36.9 ng mL^?1 and t_max was 2.2 ± 1.2 h. The elimination half-life (t_1/2) was 16.3 ± 2.7 h and the minimum plasma concentration (C) was 16.6 ± 6.9 ng mL^?1. The area under the concentration-time curve during the dosing interval (AUC) was 995 ± 389 ng h mL^?1. The average plasma concentration at steady state (C) was 43.3 ± 16.1 ng mL^?1 and the experimental accumulation ratio (R_AUC) was 1.34 ± 0.19, whereas the mean theoretical value (R) was 1.40 ± 0.29. The results obtained showed a good correlation between the experimental plasma levels and the expected values calculated using a repeated dose two-compartment model assessed by means of the Akaike value. It is concluded that the pharmacokinetics of pancopride are not modified after repeated dose administration. The safety parameters showed no clinically relevant alterations.     

Nonlinear elimination and hepatic concentration of conjugation- metabolite of valproate in guinea-pigs

The plasma clearance and metabolic rate characteristics of valproic acid (VPA) were studied using guinea-pigs placed on various (0.08-9 μmol ml^?1 = 11–1303 μg ml^?1) steady-state plasma concentrations (C_ss) by constant intravenous (i.v.) infusion. The total clearance (CL) was significantly decreased at plasma concentration of 0.61 μmol ml^?1 (88 μg ml^?1). The metabolic clearance of VPA was apparently biphasic. The maximum metabolic rate (V_max) and the Michaelis-Menten constant (K_m) for the primary (V_maxl, K_ml) and the secondary (V_max2, K_m2) pathways were V_maxl = 1.52 μmol min ^?1kg^?1, K_ml = 0.15 μmol ml^?1, V_max2 = 24.98 μmol min ^?1 kg^?1 and K_m2 = 11.70 μmol ml^?1, respectively. The K_ml value was within clinical therapeutic concentration range. The formation of conjugated VPA (cjVPA) metabolite in liver was shown to be saturable. Plasma protein binding of VPA was also nonlinear. The dose-dependent decrease in metabolic clearance was counterbalanced by the increased unbound fraction (f_u), resulting in a relatively constant apparent clearance of VPA over a wide concentration range. The hepatic concentration of VPA was not significantly different from the plasma unbound concentration, again over a wide concentration range. The biliary and hepatic concentrations of VPA were not significantly different; but the concentration ratio of cjVPA in bile compared with that of VPA in liver decreased against hepatic concentration of VPA, which suggests a saturable conjugation rate. The K_m value estimated from hepatic cjVPA production as a function of plasma VPA concentration was comparable with the K_ml value. These results implied that the primary metabolic parameters may describe the conjugation pathway which is nonlinear within the clinical therapeutic concentration range.     

Pharmacokinetics and pharmacodynamics of morphine-3-glucuronide in rats and its influence on the antinociceptive effect of morphine

In this study the pharmacokinetics and pharmacodynamics of morphine-3-glucuronide (M3G) were investigated in rats after i.v. administration as a bolus dose (86.7 μmol kg^?1) and as a constant rate infusion (2.9 μmol h^?1) over 5 days. After the bolus dose, the clearance (Cl) was 12.1 ± 0.6 ml min ^?1* kg, the volume of distribution at steady state (V_ss) 1.68 ± 0.89 1 kg^?1, the half-life of the first phase 13.2 ± 1.8 min and the halflife of the second phase 11.6 ± 7.7 h. After the constant rate infusion, Cl was 10.5 ± 1.7 ml min^?1*kg. The antagonistic effect of M3G on the antinociceptive effect of a bolus dose of morphine (35 μmol kg^?1) was tested during steady state concentrations of M3G on day 4 and to M3G naïve rats. No antinociceptive, hyperalgesic or withdrawal effects were observed as a result of M3G administration, but a significantly lower antinociceptive effect of morphine was found in the M3G infusion group compared to the control group. Systemically administered M3G antagonized the antinociceptive effect of morphine, but this cannot be the only explanation to the tolerance development observed after morphine administration.     

In-vivo Distribution and Erythrocyte Binding Characteristics of Cyclosporin in Renal Transplant Patients

The pharmacokinetic parameters of cyclosporin, a potent immunosuppressive agent, show large intra-and inter-individual variability, possibly because of the different analytical methods used. A recently developed cyclosporin-specific radioimmunoassay has been used to study the in-vivo distribution and binding characteristics of cyclosporin in whole blood, plasma and erythrocytes of fifteen renal transplant patients. The profiles of cyclosporin concentration-time curves after an oral dose of cyclosporin had either one peak (ten patients, group A) or two (five patients, group B). Essentially no difference was observed between the two groups in the relationship between equilibrium cyclosporin concentrations in erythrocyte and plasma as a function of whole-blood concentration. The equilibrium in-vivo cyclosporin concentrations in erythrocytes and plasma were, however, markedly lower than those previously observed under in-vitro conditions. The ratio of cyclosporin concentration in erythrocytes (C_E) to that in plasma (C_P) changed with time, in inverse proportion to the change in cyclosporin concentration in blood, over the range 0.63-2.80 in individual patients with an average of 1.36 ± 007 (mean ± s.e.m.) for group A and 1.42 ± 0.23 for group B. The apparent cyclosporin binding affinity (K_d) to erythrocytes under in-vivo conditions averaged 452.2 ± 47.6 nm (543.5 ± 57.2 ng mL^?1) for group A and 419.4 ± 41.2 nm (504.1 ± 49.5 ng mL^?1) for group B, whereas apparent cyclosporin binding capacity (B_max) of the blood cell averaged 0.83 ± 0.07 nmol mL^?1 for group A and 0.78 ± 0.07 nmol mL^?1 for group B. Significantly reduced average K_d (262.7 ± 40.2 nm or 315.8 ± 48.9 ng mL^?1, P < 001) and B_max (0.56 ± 008 nmol mL^?1, P < 005) values were observed during the period after T_max (4–12 h after the drug ingestion) in group A patients. Apparent K_d and B_max, determined by a nonlinear regression technique, were 131.6 ± 29.4 and 1088.0 ± 114.7 nm (158.2 ± 35.4 and 1307.8 ± 137.9 ng mL^?1) and 0.178 ± 0.024 and 0.814 ± 0.078 nmol mL^?1, respectively, during the 4–12 h period in group A patients. These findings reveal distinct differences in in-vivo distribution of cyclosporin and the binding characteristics of the compound to erythrocytes from those previously observed under in-vitro conditions. The significantly lower K_d of cyclosporin binding to erythrocytes during the elimination phase suggests a potential effect of cyclosporin-containing erythrocytes or of cyclosporin contained in erythrocytes during cyclosporin treatment.     

Bioavailability of nifedipine: A comparison between two preparations

In a random cross-over study, eight healthy volunteers received single 10 mg doses of either nifedipine capsule (Adalat, Bayer) or nifedipine tablets (Taro) after an overnight fast. The areas under the serum concentration time curves were not significantly different (AUC^{0→ ∞} 319·8 ± 28·0 (SEM) ng ml^?1 h^?1 for capsules, 260·8 ± 15·3 ng ml^?1 h^?1 for tablets). The peak serum levels and the time of their occurrence were 162·4 ± 23·4 ng ml^?1 at 30 min for capsules and 43·0 ± 3·0 ng ml^?1 at 1–2 h for tablets, indicating that the absorption of nifedipine from the capsule is faster than from the tablet form. Clinical symptoms of vasodilation corresponded with the nifedipine peak levels. We conclude that although the bioavailability in general of the two preparations is similar, the therapeutic equivalence may differ. Depending on the therapeutic indication each preparation may have its merits.