Brain, plasma and tissue pharmacokinetics of risperidone and 9-hydroxyrisperidone after separate oral administration to rats

RATIONALE: Following an oral dose of risperidone (RSP), concentrations of its major metabolite 9-hydroxyrisperidone (9-OHRSP) were high in plasma and tissues but disproportionately lower in the brain compared to RSP, indicating that 9-OHRSP may have different pharmacokinetic properties. OBJECTIVES: To investigate non-compartmental pharmacokinetics of RSP and 9-OHRSP in plasma, brain and other tissues after separate administration of a single oral dose of 6 mg/kg RSP and 9-OHRSP to rats. METHODS: Plasma, brain, liver, lung, kidney and spleen tissues were collected at pre-dose and at 0.5, 1, 2, 5, 6, 12, 24, 36 and 48 h post-dose, homogenized in saline and assayed for RSP and 9-OHRSP using a sensitive and specific liquid chromatography tandem mass spectrometry method. RESULTS: The concentration-time curve of RSP and 9-OHRSP showed that they were readily absorbed and followed a multiphase elimination pattern. The terminal elimination half-life (t(1/2) ) of RSP after the RSP dose was longest in the liver (17.6 h) and shortest in the spleen (1.2 h). The t(1/2)of 9-OHRSP after the RSP dose was shorter in plasma (3.4 h) and other tissues (approximately 8-11 h) than that for RSP but it was longer in the spleen. However, the t(1/2) of 9-OHRSP after the 9-OHRSP dose was shorter in most tissues as compared to the t(1/2) of 9-OHRSP after the RSP dose. The area under the concentration-time curve (AUC) of RSP and 9-OHRSP was 6-67 times higher in the plasma and tissues than in the brain. AUCs of 9-OHRSP in tissues after the RSP dose were 2-5 times higher than those for RSP, except in the brain, where AUCs of RSP and 9-OHRSP were similar. CONCLUSION: Pharmacokinetics of 9-OHRSP in many tissues were different after RSP and 9-OHRSP doses. The reason for disproportionate brain levels of 9-OHRSP is not clear. The overall exposure to active drug in the brain as represented by AUC was similar after the RSP and 9-OHRSP doses and the 9-OHRSP is probably an equal contributor to the pharmacological actions of RSP.     

Pharmacokinetics and tissue distribution of olanzapine in rats

The single dose pharmacokinetics of olanzapine in rats, following an oral dose and its distribution in the brain and other tissues after repeated oral and intra-peritoneal (i.p.) administration, were studied. Olanzapine in plasma, brain, liver, lung, kidney, spleen and fat was assayed at predose, 0.25, 0.5, 1, 2, 5, 12, 24, 36, 48 h postoral dose of 6 mg/kg and after daily oral and i.p. doses of 0.25, 1, 3, and 6 mg/kg/day of olanzapine for 15 consecutive days by a sensitive and specific HPLC method with electrochemical detection. Olanzapine was readily absorbed and distributed in plasma and tissues as the peak concentrations were reached within approximately 45 min after the oral dose. The terminal half-life of olanzapine in plasma was 2.5 h and in tissues it ranged from 3 to 5.2 h. The area under the concentration-time curve (AUC(last)) was lowest in plasma and largest in liver and lung. The AUC(last) of olanzapine was eight times larger in brain and three to 32 times larger in other tissues than that in plasma. After repeated oral doses, the plasma and tissue concentrations of olanzapine were generally higher than those after repeated i.p. doses. The liver and spleen had the highest concentrations after oral and i.p doses, respectively. In both cases, the tissue concentrations were four- to 46-fold higher than that in plasma and correlated with administered doses. Likewise, plasma concentrations strongly correlated with the simultaneous brain and tissue concentrations (r(2)>0.908, p<0.0001). On average, the brain levels were 6.3-13.1 and 5.4-17.6 times higher than the corresponding plasma level after oral and i.p. doses, respectively. The tissue to plasma level ratio of olanzapine was higher in other tissues. The data indicated that olanzapine is rapidly absorbed and widely distributed in the tissues of rats after oral and i.p. administration. The plasma concentration appears to predict the simultaneous concentration in brain and other tissues. There was no marked localized accumulation of olanzapine in any of the regions of the rat brain.     

The pharmacokinetics of pirtenidine in the rat and dog

1. Pharmacokinetic studies on the topical antimicrobial agent, pirtenidine, have been conducted in male Sprague-Dawley rats and beagle dogs, using a validated h.p.l.c. method with u.v. detection to measure the drug in plasma.

2. Following a single i.v. bolus dose to the rat (equivalent to 1.35 mg base/kg) or dog (equivalent to 0.23 mg base/kg), the drug was extensively distributed with an apparent volume of distribution of 8.61/kg in rat and 3.31/kg in dog. Clearance was high (rat 2.71/h/kg; dog 1.51/h/kg) which resulted in a short terminal half-life in both species (2.2 and 1.5 h respectively).

3. Following a single oral dose to rats (equivalent to 4.5 mg base/kg) plasma pirtenidine concentrations were generally below the minimum quantifiable level of the analytical method (1 ng/ml). A maximum possible bioavailability of 0.3% was estimated.

4. After administering the same oral dose to dogs plasma concentrations rose slowly (t1/2abs=1.2 h) to a peak (49.7 ng/ml) at 5.0 h post-dose. The terminal elimination half-life was 2.1 h. The absolute bioavailability was 10%.     

The pharmacokinetics of the antimigraine compound zolmitriptan in Japanese and Caucasian subjects

BACKGROUND: Zolmitriptan is a 5HT(1B/1D) receptor agonist effective in the acute treatment of migraine. Clinical trials in the USA and Europe have demonstrated the optimal oral therapeutic dose to be 2.5 mg. The 2.5-mg oral tablet has recently been licensed in Japan. OBJECTIVE: To compare the pharmacokinetics of zolmitriptan and its metabolites in Japanese and Caucasian subjects and evaluate the effect of gender on these pharmacokinetics in Japanese volunteers. METHODS: In this open, parallel-group study, 30 Japanese and 30 Caucasian volunteers (20-45 years) received a single 2.5-mg zolmitriptan tablet in the fasting state. Blood samples were taken up to 15 h post-dose to determine plasma concentrations of zolmitriptan and its active metabolite, 183C91. Urinary excretion of zolmitriptan, 183C91 and the inactive N-oxide and indole acetic acid metabolites were measured over 24 h. RESULTS: Japanese volunteers were, on average, smaller and lighter than Caucasian volunteers. Plasma-concentration profiles of zolmitriptan and 183C91 were similar in the two groups. Although geometric mean zolmitriptan and 183C91 area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C(max)) were slightly higher in Japanese subjects (up to 20%), these differences were not considered to be of clinical relevance as the 90% confidence interval for the ratio of AUCs fell within pre-specified limits (0.67 to 1.5). Mean zolmitriptan and 183C91 half-lives were around 2.5 h for both populations. Urinary excretion of the four analytes was similar in Japanese and Caucasians. Plasma concentrations of zolmitriptan were higher in Japanese females than males (AUC 40% and C(max) 29% higher), consistent with the results previously obtained in Caucasians. CONCLUSION: Pharmacokinetic parameters of zolmitriptan were similar between Caucasian and Japanese volunteers.     

Pharmacodynamic behaviour of the selective cyclooxygenase-2 inhibitor lumiracoxib in the lipopolysaccharide-stimulated rat air pouch model.

PURPOSE: To investigate the pharmacodynamic behaviour of the selective cyclooxygenase-2 inhibitor, lumiracoxib, in the rat air pouch. METHODS: Air pouches were injected with lipopolysaccharide to stimulate prostaglandin E2 (PGE2) production 1h after lumiracoxib treatment. Pouch fluid samples were collected 6 or 24 h after lumiracoxib administration to measure PGE2 levels. Lumiracoxib concentrations in pouch fluid and plasma were measured by mass spectrometry. RESULTS: Oral administration of lumiracoxib resulted in dose-dependent inhibition of PGE2 production 6 and 24 h post-dose. The estimated ED50 values for inhibition of PGE2 production were 0.1 and 2.0 mg/kg at 6 and 24 h, respectively. Lumiracoxib concentrations in plasma and pouch fluid increased in proportion to dose. There was a strong positive correlation between lumiracoxib concentrations in plasma and pouch fluid compartments. Lumiracoxib concentrations were higher in plasma than in pouch fluid 6 h post-dose, but at 24 h post-dose, pouch fluid concentrations were > or =4-fold greater than plasma concentrations. CONCLUSIONS: Lumiracoxib readily enters the air pouch and persists in this extravascular compartment for a longer period of time than in plasma. This distribution profile may contribute to the ability of lumiracoxib to inhibit PGE2 production up to 24 h after dosing.     

Pharmacokinetics and safety of oral almotriptan in healthy male volunteers

Almotriptan (LAS 31416) is a new, oral, specific 5-hydroxytryptamine(1B/1D) receptor agonist for the treatment of migraine. The pharmacokinetics and safety of a range of oral doses were assessed in 23 healthy male volunteers. Peak plasma concentrations were reached between 1.5 and 4 h after dosing. The maximum plasma concentration and area under the curve showed dose proportionality over the dose range 5-200 mg. The elimination half-life was constant at approximately 3 h across all dose levels. A substantial proportion of the initial dose was excreted in urine (27%-39%) during 12 h post-dose and the main excretory product was unchanged drug. Three major urinary metabolites were detected, all of which were pharmacologically inactive. The most common events following almotriptan administration were headache, tiredness and mild nausea. Nine events (18%) were classed as probably related to almotriptan and these were all at the highest dose level of 200 mg. The maximum tolerated dose of almotriptan was, therefore, determined as 150 mg. In conclusion, almotriptan is well tolerated following single, oral doses up to 150 mg and has predictable pharmacokinetics.     

Pharmacokinetics of lurasidone, a novel atypical anti-psychotic drug, in rats

This study aimed to characterise the pharmacokinetics of lurasidone, a new atypical anti-psychotic drug, in rats after intravenous and oral administration at dose range 0.5-2.5 and 2.5-10?mg/kg, respectively. Moreover, tissue distribution, liver microsomal stability and plasma protein binding were estimated. After intravenous injection, systemic clearance, steady-state volumes of distribution and half-life remained unaltered as a function of dose with values in the range 22.1-27.0?mL/min/kg, 2,380-2,850?mL/kg and 229-267?min, respectively. Following oral administration, absolute oral bioavailability was not dose dependent with approximately 23%. The recoveries of lurasidone in urine and bile were 0.286% and 0.0606%, respectively. Lurasidone was primarily distributed to nine tissues (brain, liver, kidneys, heart, spleen, lungs, gut, muscle and adipose) and tissue-to-plasma ratios of lurasidone were ranged from 1.06 (brain) to 9.16 (adipose). Further, lurasidone was unstable in rat liver microsome and the plasma protein binding of lurasidone was concentration independent with approximately 99.6%. In conclusion, lurasidone showed dose-independent pharmacokinetics at an intravenous dose of 0.5-2.5?mg/kg and an oral dose of 2.5-10?mg/kg. Lurasidone was primarily distributed to nine tissues and appeared to be primarily eliminated by its metabolism.     

Plasma pharmacokinetics and tissue distribution of [6]‐gingerol in rats

[6]‐Gingerol is one of the pungent components in ginger which has been found to possess various pharmacological effects. However, there is insufficient information on the properties of [6]‐gingerol based on controlled pharmacokinetic studies. The aim of this study was to clarify distribution profiles of [6]‐gingerol in blood and biological tissues of experimental rats. Rats were administered a 240 mg/kg dose of Gs (a ginger extract, containing 53% [6]‐gingerol) by oral ingestion. Plasma samples were collected at 2.5, 5, 7.5, 10, 15, 20, 30, 45 min, and 1, 1.5, 2, 3, 4 h after dosing (eight samples per time point), and brain, heart, lung, spleen, liver, kidney, stomach and small intestine tissues were collected at 5, 15, 30 min and 1, 2, 4 h after dosing (five animals per time point). Samples were prepared by a liquid‐liquid extraction procedure and the extracts were assayed by HPLC‐UV. After per oral application, [6]‐gingerol was absorbed rapidly into the plasma, and the maximal concentration (4.23 µg/ml) was reached after 10 min post dosing. [6]‐Gingerol plasma concentrations declined with time in a biexponential pattern. The elimination half‐time at the terminal phase was 1.77 h and the apparent total body clearance was 40.8 l/h. When administered orally, [6]‐gingerol was well distributed to the tissues examined, with the highest concentrations found in the gastrointestinal tract. Maximal concentrations of [6]‐gingerol were reached in most tissues at 0.5 h post‐dosing. The concentrations of [6]‐gingerol in tissues all were higher than in plasma with corresponding tissue to plasma ratios greater than 1 after 0.25 h post‐dose, showing high tissue partitioning and extensive distribution. Copyright © 2008 John Wiley & Sons, Ltd.     

大鼠口服东莨菪素后的组织分布和排泄特征研究(英文)

研究东莨菪素在大鼠体内的组织分布和排泄特征,SD大鼠灌胃东莨菪素(50mg/kg),分别于给药后5,15,30,60,120,240分钟取大鼠心、肝、脾、肺、肾、肌肉、脂肪、脑、睾丸、子宫、胃、小肠等组织器官测定其原形药物浓度。结果表明,东莨菪素广泛分布于各组织器官且于给药后15分钟浓度即达峰值,其中肝、肾、胃和小肠含量较高。此外,东莨菪素在胆汁、尿液、粪便的排泄研究显示,胆汁、尿液、粪便的累积排泄量分别为0.032%,3.752%和0.784%。表明东莨菪素在大鼠体内主要以代谢物的形式消除。     

Pharmacokinetics and distribution of recombinant erythropoietin in rats.

Pharmacokinetics and distribution of recombinant human erythropoietin (rh-EPO, Epoch, CAS 11096-26-7) were studied in rats. After intravenous administration, concentrations of rh-EPO in the plasma declined biexponentially. AUC increased proportionally with the dose. The half-life of a-phase was prolonged with increasing doses. The low volume (Vss) of the distribution of rh-EPO was 65-79 ml/kg, which indicate a mainly extracellular distribution of this drug. The half-life of beta-phase was 1.98-2.7 h. The total body clearance was 18-21 ml/h/kg, and was independent of the dose. The renal clearance was much lower than total body clearance, suggesting that extrarenal clearance, presumably metabolism, plays a role in elimination. rh-EPO was eliminated by metabolism. The profiles of times vs concentration of radioactivity in the bone marrow and spleen, which are considered to be target tissues, were different from that of the plasma; namely bone marrow and spleen showed Cmax at 30 min after dosing, and this time, radioactivity in these tissues showed almost intact rh-EPO. At the dose of 0.1 micrograms/kg, the concentration in the bone marrow was about 2-fold higher than that of plasma, the concentration in the spleen was lower than that in the plasma 30 min after dosing of rh-EPO. The distributions of rh-EPO in both tissues were saturable.     

Metabolism, pharmacokinetics and excretion of a potent tachykinin NK1 receptor antagonist (CP-122,721) in rat: characterization of a novel oxidative pathway

The metabolism, pharmacokinetics and excretion of a potent and selective substance P receptor antagonist, (+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzlamino)-2-phenylpiperidine, CP-122,721, have been studied in rat following oral administration of a single dose of [14C]CP-122,721. Total recovery of the administered dose was 84.1+/-1.1% for male rat and 80.9+/-2.7% for female rat. Approximately 81% of the administered radioactivity recovered in urine and faeces were excreted in the first 72 h. Absorption of CP-122,721 was rapid in both male and female rat, as indicated by the rapid appearance of radioactivity in plasma. The plasma concentrations of total radioactivity were always much greater than unchanged drug, indicating early formation of metabolites. CP-122,721 t1/2 was 3.1 and 2.2 h for male and female rat, respectively. The plasma concentrations of CP-122,721 reached a peak of 941 and 476 ng ml-1 for male and female rat, respectively, at 0.5 h post-dose. Based on AUC0-tlast, only 1.5% of the circulating radioactivity was attributable to unchanged drug (average of male and female rats) and the balance, approximately 98.5% of the plasma radioactivity was due to metabolites. The major metabolic pathways of CP-122,721 were due to O-demethylation, aromatic hydroxylation and indirect glucuronidation. The minor metabolic pathways included aliphatic oxidation at the piperidine moiety and aliphatic oxidation at the benzylic position of the trifluoromethoxy anisole moiety. In addition, a novel oxidative metabolite resulting from ipso substitution by the oxygen atom and trifluoromethoxy elimination followed by glucuronide conjugation was also identified.     

Daily variations in steady-state plasma concentrations of carbamazepine and its metabolites in epileptic children

Total plasma carbamazepine, carbamazepine-10,11-epoxide (CBZ-EP) and 10,11-dihydro-10,11-trans-dihydroxy-carbamazepine (CBZ-DIOL) concentrations were measured during a 24h period in 21 patients receiving carbamazepine monotherapy, in equally divided doses, every 12h. Interdose and diurnal variations in plasma concentrations of parent drug and metabolites were assessed. Carbamazepine and both metabolites showed significant differences in mean 4h post-dose plasma concentrations between day and night dosing (p less than 0.001). Significant linear correlations were obtained between carbamazepine dose and plasma concentrations of carbamazepine, CBZ-EP and CBZ-DIOL when sampling times were standardised (p less than 0.01). Comparisons of plasma concentrations of the parent compound with those of its 2 main metabolites revealed significant linear correlations in all cases (p less than 0.01). The effects of daily fluctuations in plasma concentrations of all 3 compounds on their relative concentrations (CBZ-EP:carbamazepine, CBZ-DIOL:carbamazepine and CBZ-DIOL:CBZ-EP) during the 24h period were also determined: the plasma concentration ratios CBZ-EP:carbamazepine and CBZ-DIOL:carbamazepine were significantly related to the dose of carbamazepine at fixed sampling times (p less than 0.05, with 1 exception). The large interdose and diurnal variation in plasma carbamazepine concentrations observed in this study (approximately 40% decrease from peak to trough) has important implications both clinically and in relation to therapeutic drug monitoring.     

The effect of end-stage renal failure and haemodialysis on the elimination kinetics of sotalol.

A single oral dose of sotalol (160 mg) was administered to control subjects with normal renal function and patients with chronic renal failure in the interdialysis period to estimate the elimination kinetics of the drug. Sotalol concentrations in body fluids were measured fluorimetrically using a modified Garrett and Schnelle (1971) method. Mean plasma half-life (T 1/2) was approximately 5 h in normals, 42 h in patients off-dialysis. During haemodialysis the mean plasma half-time was on the average 7 hours. Comulative urinary excretion of the drug was considerably lower in the patient group: 9% of the dose in 48 h as opposed to 61% in normals. Comparison of sotalol concentrations in plasma versus ultrafiltrate from the coil kidney indicates that the drug in vivo is negligible bound to plasma proteins in remal patients. The net-lowering effect of a 6 to 7 h haemodialysis on the plasma concentration decay line was by 20%. Post-dialysis plasma concentration data suggest that the rate at which sotalol returns to plasma from body tissues appears to be the rate-controlling factor in the elimination of sotalol by haemodialysis.     

Bioavailability of isradipine in young and old rats: effect of mode of administration

The bioavailability of isradipine has been examined in 7- and 52-week-old rats after oral (12.5 mg kg-1) or intravenous (2.5 mg kg-1) doses as a solution and administration of various doses (1.8-85.5 mg kg-1) in the diet. Serial plasma samples were obtained from each rat and the drug concentration was determined by radioimmunoassay. Absorption from the dose given by gavage was rapid but when administered in a drug diet mixture, isradipine appeared in the plasma slowly and in a manner reflecting the feeding pattern. Its absolute bioavailability from the drug-diet mixture averaged 3% over the dose range tested. By gavage its bioavailability was enhanced to 5% of dose with peak plasma values approximately 7 times higher than from a comparable dose in the diet. The low oral bioavailability of isradipine in the rat was most likely due to extensive first-pass metabolism. The decline in plasma concentrations was biexponential, with a mean terminal half-life of 3.6-3.7 h after oral or intravenous dosing. The pharmacokinetic characteristics of isradipine examined were independent of the age of the rat, except that its volume of distribution decreased with age. The older rats also showed a greater inter-animal variability in isradipine bioavailability from the drug-diet mixture.     

Absorption,distribution and excretion of lacidipine,a dihydropyridine calcium antagonist,in rat and dog

1. The absorption, distribution and excretion of lacidipine have been studied in rat and dog after i.v. (0.05 mg/kg for rat; 0.5 mg/kg for dog) and oral dosage (2.5 mg/kg for rat; 2.0 mg/kg for dog).

2. Lacidipine was rapidly and extensively absorbed after oral dosing, in both species. Oral bioavailability was up to 26% in rat and up to 32% in dog, due to extensive first-pass metabolism.

3. After oral administration, peak levels of radioactivity were reached at 4-8 h in rat and 1-2 h in dog. Unchanged lacidipine peaked at 1-2 h in both species. Plasma levels of radioactivity were higher in female rats than in males but there was no difference in levels of unchanged drug.

4. After i.v. dosing the terminal half-life of unchanged drug was 2.9 h in rat and 8.2 h in dog. The half-life of radioactivity in plasma was longer in both species.

5. After both routes of administration, radioactivity was rapidly distributed in rat tissues with the highest concentration in liver, fat and gastrointestinal tract. Only traces of radioactivity were detected in the CNS and in rat foetuses.

6. Extensive biliary elimination occurred, and most of the radioactivity (73-95%) was excreted in the faeces after i.v. or oral administration.

7. The compound was extensively metabolized, no significant amount of unchanged drug was excreted in bile or urine.     

Absorption, distribution and excretion of lacidipine, a dihydropyridine calcium antagonist, in rat and dog

1. The absorption, distribution and excretion of lacidipine have been studied in rat and dog after i.v. (0.05 mg/kg for rat; 0.5 mg/kg for dog) and oral dosage (2.5 mg/kg for rat; 2.0 mg/kg for dog). 2. Lacidipine was rapidly and extensively absorbed after oral dosing, in both species. Oral bioavailability was up to 26% in rat and up to 32% in dog, due to extensive first-pass metabolism. 3. After oral administration, peak levels of radioactivity were reached at 4-8 h in rat and 1-2 h in dog. Unchanged lacidipine peaked at 1-2 h in both species. Plasma levels of radioactivity were higher in female rats than in males but there was no difference in levels of unchanged drug. 4. After i.v. dosing the terminal half-life of unchanged drug was 2.9 h in rat and 8.2 h in dog. The half-life of radioactivity in plasma was longer in both species. 5. After both routes of administration, radioactivity was rapidly distributed in rat tissues with the highest concentration in liver, fat and gastrointestinal tract. Only traces of radioactivity were detected in the CNS and in rat foetuses. 6. Extensive biliary elimination occurred, and most of the radioactivity (73-95%) was excreted in the faeces after i.v. or oral administration. 7. The compound was extensively metabolized, no significant amount of unchanged drug was excreted in bile or urine.     

Pharmacokinetics of ciprofloxacin. 1st communication: absorption, concentrations in plasma, metabolism and excretion after a single administration of [14C]ciprofloxacin in albino rats and rhesus monkeys

The absorption, disposition, metabolism and excretion of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-[U-14C]piperazinyl)-3- quinoline carboxylic acid (ciprofloxacin, Bay o 9867; designated tradename: Ciprobay) were studied following a single intraduodenal (rat), oral and intravenous (rat, monkey) administration, respectively, in the dose range 5 to 30 mg/kg body weight. Ciprofloxacin was absorbed partially (30 to 40%) in both species. Peak plasma concentrations of radioactivity were measured approximately 1 h (rat) or 2 h (monkey) after oral dosing. Terminal half-lives ranging from 26 to 44 h were determined for the elimination of radioactivity from the plasma (observation time up to 48 h after dosing). Nearly identical concentrations of the unchanged drug and total radioactivity were found during the first 7 or 8 h for the monkey after intravenous injection and for the rat also after oral administration, respectively. After reaching maximum concentration of 0.25 microgram/ml after administration of 5 mg/kg to rats and 0.88 microgram/ml after dosing with 30 mg/kg to a rhesus monkey, the unchanged drug was eliminated from plasma corresponding to half-lives ranging from 3 h (rat) and 4.4 h (monkey). The radioactivity was rapidly and completely excreted in both species. After intravenous administration about 51% (rat) and 61% (monkey), respectively, was excreted via the kidney. After oral dosing renal excretion amounted to 6-14% (rat) and 30% (monkey), respectively. Maximum residues in the body (exclusive gastrointestinal tract) of 1% of dose occurred in both species. In urine and feces of rats predominantly the unchanged drug and a conjugate were detected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ivermectin distribution in the plasma and tissues of patients infected with Onchocerca volvulus

Objective: To determine the distribution of ivermectin in plasma and tissues of onchocerciasis patients following a single oral dose of 150?μg?kg^?1. Setting: Medical Department at Soba University Hospital, Khartoum. Patients: Twenty five patients and fourteen healthy volunteers. Methods: Serial blood samples were obtained from both groups. Tissue samples were removed from various patients as full thickness skin punch biopsies or during nodulectomy. Ivermectin concentration was determined by radioimmunoassay. Results: The plasma pharmacokinetic variables for patients were; maximum plasma concentration 52.0?ng?ml^?1; time to achieve maximum concentration, 5.2?h.; elimination half life, 35.0?h; and the area under the plasma concentration curve versus time, 2852 ng?h?ml^?1. In healthy volunteers, the plasma ivermectin distribution was similar to that in patients, and both groups showed a tendency for a second rise in plasma concentration of the drug suggestive of enterohepatic recirculation. Ivermectin was detected in tissues obtained from patients. Fat showed the highest and most persistent levels, whilst values for skin, nodular tissues, and worms were comparable. Subcutaneous fascia contained the lowest concentrations. Conclusion: Infection with O. volvulus does not affect the pharmacokinetics of ivermectin, and filarial infected tissues and parasites themselves do take up the drug. There may be prolonged retention of ivermectin because of depot formation in fat tissue.     

Antiarrhythmic effects of Org 6001 in rats: correlation with plasma and tissue drug concentrations.

The antiarrhythmic effects of Org 6001 following oral administration in the rat have been assessed and correlated with plasma, myocardial and skeletal muscle drug concentrations. Arrythmias were induced by coronary artery ligation in anaesthetized rats. Org 6001 (10, 20, 50 and 100 mg/kg given 1 h before ligation) significantly reduced mortality and the incidence of ventricular fibrillation in the 0-30 min post ligation period. Only the highest dose of drug also significantly reduced the number of ventricular ectopic beats following ligation. A linear relationship was observed between the oral dose and the Org 6001 concentrations in plasma and skeletal muscle determined 90 min after drug administration. The Org 6001 concentration in the myocardium was not linearly related to the administered dose and Org 6001 appeared to be concentrated to a higher extent in cardiac than in skeletal muscle at that time. No statistically significant difference in drug levels in the ischaemic left ventricle and normal right ventricle plus septum was observed. The antiarrythmic effect of Org 6001, as measured by changes in the incidence of ventricular fibrillation, correlated with myocardial concentrations of the drug.     

Pharmacokinetic properties of rithmidazole upon single intravenous introduction

The kinetics of rithmidazole (an imidazobenzimiodazole derivative possessing the properties of I, III, and IV class antiarrhythmics) was studied upon a single intravenous introduction in rats (in a dose of 10 mg/kg) and in healthy male volunteers (300 mg/kg). The drug pharmacokinetics in rat blood plasma was characterized by rapid elimination from the systemic blood flow (drug detected by HPLC only within 6 h); the total plasma clearance was 1.43 liter/(h kg), the terminal half-elimination time was 1.76 h, and the equilibrium distribution volume (2.42 liter/kg) exceeded the total volume of water in the animal organism, which is indicative of a high level of absorption in tissues. The drug is characterized by a low level of binding to blood proteins and erythrocytes. Investigation of the drug distribution between tissues showed evidence of extensive, blood-flow-dependent penetration, with the drug concentration in most tissues exceeding that in the blood plasma. The maximum amounts of rithmidazole were found in the lungs, spleen, liver, and kidneys. The major excretion route for the unchanged drug is via urine and bile, amounting to 10% and approximately 1% of the dose introduced, respectively, determined within 72 h. The results are indicative of a low probability of the hepatoduodenal circulation of the unchanged substance: about 90% of the drug undergo metabolic transformation. The pharmacokinetics of rithmidazole in volunteers was also characterized by rapid elimination from the systemic blood flow; the total plasma clearance was 0.89 liter/(h kg), the terminal half-elimination time was 2.12 h, and the equilibrium distribution volume was 1.66 liter/kg. The obtained results show that the pharmacokinetic profiles of rithmidazole in rats and humans exhibit a similar character, with a high intensity of distribution and elimination processes.