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%.     

Pharmacokinetics and urinary excretion of DMXBA (GTS-21), a compound enhancing cognition

DMXBA (3-(2, 4-dimethoxybenzylidene)-anabaseine, also known as GTS-21) is currently being tested as a possible pharmacological treatment of cognitive dysfunction in Alzheimer's disease. In this study, plasma and brain pharmacokinetics as well as urinary excretion of this compound have been evaluated in adult rats. DMXBA concentrations were determined by HPLC. Following a 5 mg kg⁻¹ iv dose, DMXBA plasma concentration declined bi-exponentially with mean (±SE) absorption and elimination half-lives of 0.71±0.28 and 3.71±1.12 h, respectively. The apparent steady state volume of distribution was 2150±433 mL kg⁻¹, total body clearance was 1480±273 mL h⁻¹ kg⁻¹, and AUC_0–∞ was 3790±630 ng h mL⁻¹. Orally administered DMXBA was rapidly absorbed. After oral administration of 10 mg kg⁻¹, a peak plasma concentration of 1010±212 ng mL⁻¹ was observed at 10 min after dosing. Elimination half-life was 1.740±0.34 h, and AUC_0–∞ was 1440±358 ng h mL⁻¹. DMXBA peak brain concentration after oral administration was 664±103 ng g⁻¹ tissue, with an essentially constant brain–plasma concentration ratio of 2.61±0.34, which indicates that the drug readily passes across the blood–brain barrier. Serum protein binding was 80.3±1.1%. Apparent oral bioavailability was 19%. Renal clearance (21.8 mL h⁻¹ kg⁻¹) was less than 2% of the total clearance (1480±273 mL h⁻¹ kg⁻¹); urinary excretion of unchanged DMXBA over a 96 h period accounted for only 0.28±0.03% of the total orally administered dose. Our data indicates that DMXBA oral bioavailability is primarily limited by hepatic metabolism. © 1998 John Wiley & Sons, Ltd.     

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.     

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.     

Bioavailability Study of Glycyrrhetic Acid after Oral Administration of Glycyrrhizin in Rats; Relevance to the Intestinal Bacterial Hydrolysis

To clarify the metabolic fate of glycyrrhizin when orally ingested, we investigated the bioavailability of glycyrrhetic acid, the aglycone of glycyrrhizin, after intravenous or oral administration of glycyrrhetic acid (5.7 mg kg^?1, equimolar to glycyrrhizin) or glycyrrhizin (10 mg kg^?1) at a therapeutic dose in rat. Plasma concentration of glycyrrhetic acid rapidly decreased after its intravenous administration, with AUC of 9200 ± 1050 ng h mL^?1 and MRT of 1.1 ±0.2 h. The AUC and MRT values after oral administration were 10600± 1090 ng h mL^?1 and 9.3 ±0.6 h, respectively. After oral administration of glycyrrhizin, the parent compound was not detectable in plasma at any time, but glycyrrhetic acid was detected at a considerable concentration with AUC of 11700 ± 1580 ng h mL^?1 and MRT of 19.9 ± 1.3 h, while glycyrrhetic acid was not detected in plasma of germ-free rats at 12 h after oral administration of glycyrrhizin. The AUC value of glycyrrhetic acid after oral administration of glycyrrhizin was comparable with those after intravenous and oral administration of glycyrrhetic acid, indicating a complete biotransformation of glycyrrhizin to glycyrrhetic acid by intestinal bacteria and a complete absorption of the resulting glycyrrhetic acid from intestine. Plasma glycyrrhizin rapidly decreased and disappeared in 2 h after intravenous administration. AUC and MRT values were 2410 ± 125 μg min mL^?1 and 29.8 ± 0.5 min, respectively. Plasma concentration of glycyrrhetic acid showed two peaks, a small peak at 30 min and a large peak at 11.4 h, after intravenous administration of glycyrrhizin, with an AUC of 15400±2620 ng h L^?1 and an MRT of 18.8 ± 1.0 h. The plasma concentration profile of the latter large peak was similar to that of glycyrrhetic acid after oral administration of glycyrrhizin, which slowly appeared and declined. The difference of MRT values (19.9 and 9.3 h) for plasma glycyrrhetic acid after oral administration of glycyrrhizin and glycyrrhetic acid suggests the slow conversion of glycyrrhizin into glycyrrhetic acid in the intestine.     

Pharmacokinetics and Tissue Distribution of (±)-3′-Azido-2′,3′-dideoxy-5′-O-(2-bromomyristoyl)thymidine,a Prodrug of 3′-Azido-2′,3′-dideoxythymidine (AZT) in Mice

The in-vivo biodistribution and pharmacokinetics in mice of 3′-azido-2′,3′-dideoxythymidine ( 1 , AZT), 2-bromomyristic acid ( 2 ) and their common prodrug, (±)-3′-azido-2′,3′-dideoxy-5′-O-(2-bromomyristoyl)thymidine ( 3 ) are reported. The objectives of the work were to enhance the anti-human immunodeficiency virus and anti-fungal effects of 1 and 2 by improving their delivery to the brain and liver. The pharmacokinetics of AZT (βt1/2 (elimination, or beta-phase, half-life) = 112.5 min; AUC (area under the plot of concentration against time) = 29.1 ± 2.9 μmol g^?1 min; CL (blood clearance) = 10.5 ± 1.1 mL min^?1 kg^?1) and its ester prodrug ( 3 , βt1/2 = 428.5 min; AUC = 17.3 ± 4.7 μmol g^?1 min; CL = 17.6 ± 4.8 mL min^?1 kg^?1) were compared after intravenous injection of equimolar doses (0.3 mmol kg^?1) via the tail vein of Balb/c mice (25.30 g). The prodrug was rapidly converted to AZT in-vivo, but plasma levels of AZT (peak concentration 0.17 μmol g^?1) and AUC (12.3 μmol min g^?1) were lower than observed after AZT administration (peak concentration 0.36 μmol g^?1; AUC 29.1 μmol min g^?1). The prodrug also accumulated rapidly in the liver immediately after injection, resulting in higher concentrations of AZT than observed after administration of AZT itself (respective peak concentrations 1.11 and 0.81 μmol g^?1; respective AUCs 42.5 and 12.7 μmol min g^?1). Compared with doses of AZT itself, 3 also led to significantly higher brain concentration of AZT (25.7 compared with 9.8 nmol g^?1) and AUCs (2.8 compared with 1.4 μmol min g^?1). At the doses used in this study the antifungal agent 2-bromomyristic acid was measurable in plasma and brain within only 2 min of injection. Hepatic concentrations of 2-bromomyristic acid were higher for at least 2 h after dosing with 3 than after dosing with the acid itself. In summary, comparative biodistribution studies of AZT and its prodrug showed that the prodrug led to higher concentrations of AZT in the brain and liver. Although the prodrug did not result in measurably different concentrations of 2-bromomyristic acid in the blood and brain, it did lead to levels in the liver which were higher than those achieved by dosing with the acid itself.     

Pharmacokinetics and brain distribution of zolpidem in the rat after acute and chronic administration

Abstract— The pharmacokinetics of zolpidem were studied after single dose, administered for either 7 or 28 days to rats. Thirty minutes after the last dose, animals were killed and the brain removed. The highest concentrations in plasma, which were observed at the first sampling time (0·5 h) were 2341±540 (day 0), 1956 ± 325 (day 7) and 2908 ± 1369 ng mL^?1 (day 28). Corresponding AUC values of 1742 ± 488, 1583 ± 422 and 2683 ± 1249 ng mL^?1 h were found. MRT increased significantly from 0·46 ± 0·06 h on day 0 to 0·67 ± 0·02 h on day 28. The cerebral levels showed no significant change during the chronic administration (766 ± 285, 685 ± 171 and 887 ± 264 ng g^?1, respectively). No modification of the principal kinetic parameters was detected up to the 28th day of treatment.     

Pharmacokinetic and Pharmacodynamic Studies of the Histamine H1-Receptor Antagonist Ebastine in Dogs

Abstract— The pharmacokinetics and pharmacodynamics of ebastine at single oral doses of 10 and 20 mg were studied in six healthy beagle dogs. Plasma concentrations of the active metabolite of ebastine were measured at predetermined times after the dose. At these times an intradermal injection of 0·01 mL of a 0·2 mg mL^?1 histamine diphosphate solution was given, and wheal areas were computed. The plasma elimination half-life of ebastine was 4·38 ± 1·01 h after 10 mg ebastine and 4·09 ± 0·74 h after 20 mg ebastine; the distribution volume was 3·99 ± 0·88 and 3·65 ± 0·75 L kg^?1 after 10 and 20 mg of ebastine, respectively; the clearance after the 10 mg dose of ebastine was 0·67 ± 0·24 L h^?1 kg^?1 and after 20 mg ebastine was 0·63 ± 0·17 L h^?1 kg^?1. The mean histamine-induced wheal areas were significantly suppressed from 1 to 25 h after the 10 mg dose ebastine and from 1 to 32 h after the 20 mg dose ebastine, compared with the mean predose wheal areas (P < 0·001). Maximum suppression of the wheals was 75 and 82% from 10 and 20 mg ebastine, respectively. A combined pharmacokinetic-pharmacodynamic model was used to analyse the relationship between inhibition of wheal skin reaction and changes in the active metabolite of plasma concentration after ebastine administration. A significant delay of 3–4 h was present between the maximum effect and the peak plasma concentration. Calculated from mean data, the rate constant for equilibration of the drug between plasma and effect site was 0·17 and 0·22 h^?1 after 10 and 20 mg ebastine with a half-life of 4·13 and 3·56 h, respectively, and the steady-state plasma concentration resulting in 50% of maximal effect was 18·9 ± 4.8 ng mL^?1 after 10 mg and 18·2 ± 5.7 ng mL^?1 after 20 mg ebastine.     

The influence of pyruvic acid on the pharmacokinetics of sulphadiazine in rabbits

During the past few years, acetylation polymorphism has been shown to be a proven, established fact, and N-acetyltransferase, an enzyme that transfers an acetyl group to the substrate, has been recognized as the main factor in acetylation polymorphism. In a recent study, a significant difference between the acetylation phenotype and plasma pyruvic acid (PA) concentration in rabbits was found. In this report, the influence of PA on the pharmacokinetics of sulphadiazine (SDZ), a drug that has been used in pharmacogenetic studies of acetylation, was studied. By using a loading dose of 300 mg kg^?1, and an infusion rate of 7.5 mg min^?1 of kg^?1 of PA, the concentration of PA reached a steady state (C_ss∽100 μg mL^?1) in 30 min. During PA infusion in rapid-acetylation rabbits, no significant changes were found in any of the pharmacokinetic parameters for SDZ. However, differences were found in the β half-life, AUC, clearance, and k₁₀ of SDZ in slow acetylators: the β half-life decreased from 115.74 ± 12.47 min to 62.96 ± 4.36 min (p < 0.001); AUC decreased from 10 617.38 ± 1179.81 μg mL^?1 to 6217.14 ± 391.32 μg min mL^?1 (p < 0.001); clearance increased from 0.0044 ± 0.0008 L min^?1 kg^?1to 0.0068 ± 0.0007 L min^?1 kg^?1 (p < 0.001); and k₁₀ increased from 0.0090 ± 0.0009 min^?1 to 0.0193 ± 0.0028 min^?1 (p < 0.005). The reason for this may be that PA influences the elimination of SDZ in slow-acetylation rabbits.     

Neuropharmacology: Amitriptyline and Clomipramine Increase the Concentration of Administered L-Tryptophan in the Rat Brain

The tricyclic antidepressant amitriptyline has been shown to reduce concentrations of large neutral amino acids (LNAA) in rat plasma. Compounds with that property might interact with such amino acids used as therapeutic agents with a central site of action by causing a change in the relationship between the administered LNAA and its endogenous LNAA competitors for carrier-mediated transport through the blood–brain barrier into the brain. This study was performed to investigate if the antidepressant agents amitriptyline and clomipramine could, by such a mechanism, increase brain concentrations of administered tryptophan. Intraperitoneal administration of L-tryptophan alone (100 mg kg^?1) resulted in an increase in the concentration of tryptophan in the rat brain from 14 ±0.7 to 100 ± 4.3 nmol g^?1 compared with rats given saline only. When rats were given tryptophan with amitriptyline (25 mg kg^?1, i.p.) or clomipramine (25 mg kg^?1, i.p.) brain concentrations of tryptophan were increased even further, to 150 ±4.5 and 157 ± 10.2 nmol g^?1, respectively. Administration of L-tryptophan alone resulted in an increase in the rat plasma tryptophan ratio [(concentration of tryptophan)/(total concentration of LNAAs)] from 0.14±0.003 to 0.42±0.011 compared with rats given saline only. When rats were given tryptophan with amitriptyline or clomipramine the plasma tryptophan ratios were increased even further to 0.52 ±0.017 and 0.54 ±0.025, respectively. All these effects were statistically significant (P < 0.001). These findings support the hypothesis that tricyclic antidepressants could interact with administered tryptophan by changing the relationship in plasma between tryptophan and its endogenous LNAA competitors for transport into the brain, resulting in higher concentrations of tryptophan in the brain. It is possible that this could be the mechanism of the previously reported finding that clomipramine and tryptophan potentiate each other in the treatment of depression.     

Delivery of atovaquone and proguanil across sublingual membranes,in vitro

Malarone^?, a combination of atovaquone (AT) and proguanil (PR), is indicated for the prophylaxis and treatment of uncomplicated Plasmodium falciparum malaria. This study aimed to determine in vitro the feasibility of delivering the combination of AT and PR as a spray formulation via the sublingual route, using Franz diffusion cells incorporating porcine sublingual mucosa. Firstly, 1?mg mL^?1 of each drug in 20% 1,8-Cineole in ethanol was used; and secondly, 5?mg mL^?1 AT and 1?mg mL^?1 PR in 20% 1-methyl-2-pyrrolidone in ethanol was examined, dosed every 2?h over a 12-h period and receptor phase samples were analyzed by HPLC. From the first study, mean fluxes for AT and PR were 12.89?±?1.2 and 5.88?±?0.9 µg cm^?2 h^?1 respectively; pharmacokinetic calculations indicated that these fluxes were insufficient to achieve the target plasma concentrations for AT and PR of 1.4 µg mL^?1 and 200?ng mL^?1 respectively, in the treatment of falciparum malaria. However, in the second study, the fluxes of AT and PR increased to 50.92?±?20.8 and 12.01?±?1.5 µg cm^?2 h^?1 respectively, and pharmacokinetic calculations indicated that therapeutic plasma concentrations are attainable for pediatric application.     

The Disposition of Thioperamide,a Histamine H3-Receptor Antagonist,in Rats

Abstract— An HPLC method using an ovomucoid-conjugated column has been developed for measurement of thioperamide, a histamine H₃ antagonist, with a minimum quantitation limit of 0·05 μg mL^?1 The assay was used to study the disposition of thioperamide in rats. After bolus intravenous administration of thioperamide (10 mg kg^?1), the plasma concentration decreased monoexponentially with a half-life of 26·9 min. The apparent total body clearance of thioperamide from rat plasma was 74·6 mL min^?1 kg^?1. Although thioperamide was quickly transferred to various tissues, its concentrations in peripheral tissues were higher than that in the brain. However, the brain regional tissue/plasma ratios of thioperamide increased continuously after its injection.     

Dose Regimen Adjustment for Milrinone in Congestive Heart Failure Patients with Moderate and Severe Renal Failure

This study was designed to test a proposed dose modification for intravenous milrinone in congestive heart failure patients (CHF, NYHA I-II) with either moderate or severe renal impairment. All the patients were administered an intravenous loading dose of drug at 50 μg kg-1 over 10 min. This was followed by an 18 h maintenance infusion of milrinone at 0·45 or 0·35 μg kg^?1 min^?1 for the moderate (chromium-EDTA clearance of 31–75 mL min^?1, n = 10) and severe renally impaired subjects (chromium-EDTA of clearance 10–30 mL min^?1, n = 11), respectively. Plasma and urine samples were collected for up to 34 h and analysed for parent drug by validated HPLC methods. The mean (± s.d.) steady-state plasma concentrations of milrinone were within the therapeutic range (100–300 ng mL^?1) for both groups, with values of 239 ± 71 ng mL^?1 and 269 ± 32 ng mL^?1 for the moderate and severe patients, respectively. No statistical differences were observed between the steady-state values for the two groups. With the exception of two patients per group, individual steady-state levels were also within the therapeutic range. Those outside the nominal range showed steady-state levels, ranging between 308 and 353 ng mL^?1, that were not associated with any serious adverse events. As predicted for this highly renally cleared drug, there were differences (P < 0·001) in the total plasma clearance (CL_P), renal clearance (CL_r), and plasma terminal half-life (t1/2) of drug, with values in the severe group being 44% lower, 75% lower, and about 134% longer respectively, when compared with the moderate group. High (correlation coefficient > 0·8) and significant correlations (P < 0·001) were observed between CL_P and CL_r and the degree of renal impairment (chromium-EDTA clearance). The apparent volume of distribution was approximately 40% higher (P < 0·01) in the severe group compared with that for the moderate group (moderates were 0·443 ± 0·155 L kg^?1). This volume difference suggests a decrease in the plasma protein-binding of milrinone because of the renal disease. The fraction of drug excreted in the urine was 0·705 ± 0·100 for the moderate group and 0·320 ± 0·089 for the severe group (P < 0·001). These results may suggest an increase in non-renal clearance of the compound, representing a partial compensation mechanism for the reduced renal function. In conclusion, this study has confirmed that the current dose reductions recommended for the use of intravenous milrinone in CHF patients with impaired renal function will yield plasma concentrations of the drug within the therapeutic range.     

Pharmacokinetics and haemodynamic effect of deacetyl diltiazem (M1) in rabbits after a single intravenous administration

Deacetyl diltiazem (M₁) is a major metabolite of the widely used calcium antagonist diltiazem (DTZ). In order to study the pharmacokinetic and haemodynamic effects of this metabolite, M₁ was administered as a single 5 mg kg⁻¹ dose intravenously (iv) to New Zealand white rabbits (n = 5) via a marginal ear vein. Blood samples, blood pressure (SBP and DBP), and heart rate (HR) recordings were obtained from each rabbit up to 8 h, and urine samples for 48 h post-dose. Plasma concentrations of M₁ and its metabolites were determined by HPLC. The results showed that the only quantifiable basic metabolite in the plasma was deacetyl N-monodesmethyl DTZ (M₂). The t_1/2 and AUC of M₁ and M₂ were 2.1±0.5 and 3.0±1.1 h, and 1300±200 and 240±37 ng h mL⁻¹, respectively. The Cl and Cl_r of M₁ were 60±10 and 0.81±0.63 mL min⁻¹ kg⁻¹, respectively. M₁ significantly decreased blood pressure (SBP and DBP) for up to 1 h post-dose (p <0.05), but had no significant effect on the heart rate (p >0.05). The E_max and EC₅₀ as estimated by the inhibitory sigmoidal E_max model were 20±18% 620±310 ng mL⁻¹, respectively for SBP; 20±8.3% and 420±160 ng mL⁻¹ for DBP. © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetics of Chlorimipramine,Chlorpromazine and their N-Dealkylated Metabolites in Plasma of Healthy Volunteers After a Single Oral Dose of the Parent Compounds

Abstract— A single oral dose of 0·7 mg kg^?1 clorimipramine (n= 18) and chlorpromazine (n= 16) was given to each subject 45 days apart and plasma concentrations of parent drugs and their monodesmethyl and didesmethyl metabolites were measured by GC. Ingestion of chlorimipramine resulted in an area under the plasma concentration-time curve (AUC _0–24) for parent drug plus metabolites 5-fold higher than that observed in the same subjects following chlorpromazine intake (600 ± 87 and 124 ± 14 ng mL^?1, respectively). Plasma chlorimipramine levels reached a mean peak value of 43·8 ng mL^?1, an average of 3·4 h after dosage, whereas the mean peak chlorpromazine level was 15·1 ng mL^?1, which occurred 2 h after administration. Desmethyl metabolite kinetics of chlorimipramine appeared to be elimination rate-limited and those of chlorpromazine appeared to be formation-rate-limited. The response to single doses of these two drugs in healthy subjects highlights the two distinct dispositional processes involved, thus offering pharmacokinetic explanation of the hitherto empirical discrepancy in dosage levels in chronic treatment.     

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.     

Plasma pharmacokinetics and urinary and biliary excretion of a new potent tripeptide HIV-1 protease inhibitor,KNI-272, in rats after intravenous administration

The pharmacokinetic (PK) characteristics of KNI-272, a potent and selective HIV-1 protease inhibitor, were evaluated in rats after intravenous (IV) administration. The effect of dose on KNI-272 plasma kinetics, and the urinary and biliary elimination kinetics of KNI-272, were examined. After IV administration of 10.0 mg kg^?1 KNI-272, the mean terminal elimination half-life, t_1/2λz, was 3.49 ± 0.19 (SE) h, the total plasma clearance, CL_tot, was 15.1 ± 1.2 mL min^?1 and the distribution volume at steady state, V_d,ss, was 3790±280 mL kg^?1. On the other hand, after 1.0mg kg^?1 IV administration, t_d,ss, was 3.04±0.11 h, CL_tot was 15.9±0.2mL min^?1, and V_d,ss was 6950±600 mL kg^?1. The PK parameters of KNI-272 after IV administration showed that the disposition of KNI-272 in the rat plasma is linear within the dose range from 1.0 to 10.0mg kg^?1. Using an equilibrium dialysis method, the plasma binding of KNI-272 was measured in vitro. The free fractions were 17.7 ± 0.6%, 12.1±1.5%, and 13.8 ± 1.4% at the total concentration ranges of 9.898 ± 0.097 μg mL^?1, 0.888 ± 0.008 μg mL^?1, and 0.470±0.55 μg mL^?1, respectively. The percentages of the dose excreted into the urine and bile as the unchanged form were 1.20 ± 1.06% and 1.61 ± 0.32% at 1.0mg kg^?1 dose, and 0.164 ± 0.083% and 1.42 ± 0.26% at 10.0 mg kg^?1 dose, respectively. The renal clearance (CL_R) and the biliary clearance (CL_B) were calculated to be 0.191 and 0.256mL min^?1 for 1.0mg kg^?1, and 0.0248 and 0.215 mL min^?1 for 10.0 mg kg^?1, respectively. When comparing these values with the CL_tot values, the urinary and biliary excretion of KNI-272 are minor disposition routes.     

Pharmacokinetics and tissue disposition of danofloxacin in sheep

The plasma pharmacokinetics of danofloxacin administered at 1.25 mg kg⁻¹ body weight by the intravenous and intramuscular routes were determined in sheep. Tissue distribution was also determined following administration by the intramuscular route at 1.25 mg kg⁻¹ body weight. Danofloxacin had a large volume of distribution at steady state (V_ss) of 2.76±0.16 h (mean±S.E.M.) L kg⁻¹, an elimination half-life (t_1/2β) of 3.35±0.23 h, and a body clearance (C1) of 0.63±0.04 L kg⁻¹ h⁻¹. Following intramuscular administration it achieved a maximum concentration (C_max) of 0.32±0.02 μg mL⁻¹ at 1.23±0.34 h (t_max) and had a mean residence time (MRT) of 5.45±0.19 h. Danofloxacin had an absolute bioavailability (F) of 95.71±4.41% and a mean absorption time (MAT) of 0.81±0.20 h following intramuscular administration. Mean plasma concentrations of >0.06 μg mL⁻¹ were maintained for more than 8 h following intravenous and intramuscular administration. Following intramuscular administration highest concentrations were measured in plasma (0.43±0.04 μg mL⁻¹), lung (1.51±0.18 μg g⁻¹), and interdigital skin (0.64±0.18 μg g⁻¹) at 1 h, duodenal contents (0.81±0.40 μg mL⁻¹), lymph nodes (4.61±0.35 μg g⁻¹), and brain (0.06±0.00 μg mL⁻¹) at 2 h, jejunal (10.50±4.31 μg mL⁻¹) and ileal (5.25±1.67 μg mL⁻¹) contents at 4 h, and colonic contents (8.94±0.65 μg mL⁻¹) at 8 h. © 1998 John Wiley & Sons, Ltd.     

Natural Products: Anti-hyperalgesic Effect of an Ethanolic Extract of Propolis in Mice and Rats

Propolis, or bee glue, which contains a complex mixture of secondary metabolites, has long been used in many countries for the management of several diseases. The purpose of this study was to evaluate, by means of several pharmacological models, the anti-hyperalgesic effect of propolis collected in the south of Brazil. The abdominal constrictions induced in mice by intraperitoneal injection of acetic acid (0.6%), kaolin (50 mg kg^?1) or zymosan (40 mg kg^?1) were inhibited to different extents by an extract of propolis (1–60 mg kg^?1) administered intraperitoneally 30 min earlier; mean ID50 (concentrations resulting in 50% inhibition) values were 2.7, 10.8 and 10.7 mg kg^?1, respectively, and maximum inhibition was 58 ± 5, 57 ± 10 and 51 ± 5%, respectively. Given orally (25–200 mg kg^?1, 1 h previously) propolis also inhibited the abdominal constrictions induced by acetic acid (maximum inhibition 43 ±5%). When injected intraperitoneally (3–60 mg kg^?1, 30 min previously), propolis attenuated both the neurogenic (first phase) and inflammatory (second phase) pain responses and paw oedema caused by intraplantar injection of formalin (2.5%); maximum inhibition was 32 ±5, 43 ±6 and 19 ±2%, respectively. Oral administration of propolis (25–200 mg kg^?1, 1 h previously) inhibited both phases and reduced the oedema formation associated with the second phase of the formalin test (maximum inhibition 22±5, 33 ±6 and 26±3%) and extract of propolis (3–30 mg kg^?1 i.p. or 25–100 mg kg^?1 p.o., respectively 30 min and 1 h previously) significantly inhibited capsaicin-induced pain with maximum inhibition of 39±8 and 41 ±8%, respectively. When assessed in the Randall–Sellito test of pain, the extract of propolis (3–30 mg kg^?1, i.p., 30 min previously) significantly reversed the hyperalgesia induced by intraplantar injection of bradykinin (3 nmol per paw) in rats (P < 0.01). In contrast with morphine the extract of propolis (. 100 mg kg^?1, 30 min previously) was ineffective when assessed in the tail-flick and hot-plate thermal assays. Naloxone (5 mg kg^?1 i.p.) reversed (P < 0.01) the effect of morphine (5 mg kg^?1 s.c.) by 70 and 94% respectively in the first and second phases of the formalin test, but did not interfere with the analgesic effect of propolis (10 mg kg^?1 i.p., 30 min previously). These results show that ethanolic extract of propolis, given systemically, has significant anti-hyperalgesic action when assessed in chemical, but not thermal, models of nociception in mice and rats. Its analgesic action seems to be unrelated to release or activation of the opioid system.     

Pharmacokinetics of the novel anticonvulsant hepp after single intravenous administration of three different doses in dogs

HEPP (D, L-3-hydroxy-3-ethyl-3-phenylpropanamide) is a novel compound with a wide spectrum of anticonvulsant activity and relatively low toxicity. The aim of this investigation was to study the pharmacokinetics of HEPP in mongrel dogs and to assess its linearity after intravenous administration of 8, 15, and 30 mg kg^?1. A biphasic disappearance pattern with a rapid distribution phase was observed in the plasma concentration versus time curve. The mean terminal half-life (t_1/2β) was the same after the three doses (3.4±0.15h) and the mean half-lives of the distribution phase (t_1/2α) were not significantly different after the three doses (0.09±0.02, 0.08±0.07, and 0.11±0.03 h for 8, 15, and 30 mg kg^?1 respectively). The mean AUC_0-∞ values were 44.1±10.8, 72.1±8.8, and 127.4±23.2 μg h mL^?1, respectively, showing a linear increase. The individual values of AUC_0-∞ corrected for the administered dose (AUC_0-∞/D) were 0.29±0.04, 0.23±0.05, and 0.22±0.06 h mL^?1. These values were not statistically different. Neither the mean residence time (MRT=4.55±1.50, 4.90±1.32, and 5.07±1.95 h), the steady state volume of distribution (V_ss=0.86±0.11, 1.01±0.17, and 1.20±0.40 L kg^?1) nor the systemic clearance (Cl=3.36±0.82, 3.53±0.44, and 4.02±0.68 mL min^?1 kg^?1) showed significant differences between doses. The values of V_ss suggest that HEPP is distributed in the whole body fluid. The invariant pharmacokinetic parameters and the direct correlation between AUC_0-∞ and the dose suggest that the kinetics of HEPP in dogs are linear over the range of doses studied.