Preparation of ketamine tablets for treatment of patients with neuropathic pain

Ketamine is known to have distinguished analgesic effects without anesthetic when administered in a low dose. Since ketamine is not commercially available except injection forms, we prepared ketamine tablets for the home-care medication of patients with neuropathic pain. The direct compression or wet granulation method was employed to form 150 mg of tablets containing 50 mg of ketamine. The latter method was superior to the former one in terms of content uniformity, weight variation and disintegration tests of the tablets. Ketamine contents in the tablet prepared by the wet granulation method were unchanged for 12 weeks under the conditions of 25 degrees C and 75% relative humidity (RH). The Cmax and AUC0-3 h values for ketamine after administration of the tablet were slightly smaller than those of the syrup in a healthy volunteer. However, analgesic effects of the tablet was similar to that of the syrup in a patient with neuropathic pain. And the tablet was also effective for another four patients with neuropathic pain. These results indicate that ketamine tablets are useful for the home-care medication of patients with neuropathic pain.     

Comparative bioavailability of a cisapride suppository and tablet formulation in healthy volunteers

Summary The comparative bioavailability of cisapride as a 30 mg suppository and three 5 mg oral tablets was investigated in 12 non-smoking, healthy male volunteers. The two formulations were administered on two separate occasions following an overnight fast, according to a randomized cross-over design. The plasma concentration of cisapride was measured over 48 h after drug administration. The 30 mg suppository exhibited a mean time to the peak plasma concentration of 3.8 h, while the tablets showed a significantly earlier peak time of 1.5 h. The maximum plasma concentration of cisapride after the 30 mg suppository (50.3 ng · ml^–1) was significantly lower than after the tablets (74.3 ng · ml^–1). The AUCs following the two treatments did not differ significantly from each other.The comparative bioavailability of the 30 mg cisapride suppository in relation to the three 5 mg oral tablets was 85%, with a 95%-confidence interval of 67% to 102% (not adjusted for dose). Normalizing the mean AUC by dose, the relative bioavailability of the suppository was 43% of that of the tablet. The elimination half-life of cisapride was not significantly different following the administration of the two formulations (9.3 h for the suppository and 9.8 h for the tablet).     

The absolute bioavailability of racemic ketamine from a novel sublingual formulation

Aim

The principal study objective was to investigate the pharmacokinetic characteristics of a new sublingual ketamine wafer and to establish its absolute bioavailability and local tolerability.

Methods

The study was of open label, two way randomized crossover design in eight healthy male volunteers. Each participant received either a single 10 mg intravenous dose as a constant rate 30 min infusion or a 25 mg sublingual dose of ketamine wafer in two treatment periods with a 7 day wash out. Pharmacokinetic blood sampling and local tolerability and safety assessments were carried out during 24 h following both dosing occasions. Plasma concentrations were analyzed by non-compartmental methods and local tolerability was assessed using modified Likert scales.

Results

The median (90% CI lower, upper limit) absolute bioavailability of sublingual ketamine was 29% (27, 31%). The first quantifiable plasma ketamine concentration was observed within 5 min for all eight participants for both routes of administration and the median (min–max) time of the peak plasma concentration was 0.75 h (0.25–1.0 h) after sublingual administration. The ketamine wafer had very good local tolerability.

Conclusion

Sublingual administration of the ketamine wafer resulted in rapid absorption. The ketamine wafer has comparable bioavailability with other oral transmucosal formulations of ketamine but with markedly reduced inter-subject variability, warranting further evaluation as an analgesic adjunct.     

Pharmacokinetics and pharmacodynamics of human chorionic gonadotropin (hCG) after rectal administration of hollow-type suppositories containing hCG

To determine the effectiveness of human chorionic gonadotropin (hCG) administered rectally, we studied the pharmacokinetics and pharmacodynamics of hCG using a hollow-type suppository. HCG was not detected in plasma when only hCG was administered rectally, even at a higher dose (4,000 IU/kg body weight) than intravenous injection, because of its low bioavailability due to high molecular weight or degradation by proteolytic activity. To enhance the rectal absorption of hCG, the effectiveness of its coadministration with alpha-cyclodextrin (alpha-CyD), an absorption-enhancing agent, was investigated in male rabbits. HCG was detected in plasma following coadministration of hCG and alpha-CyD (10 mg/kg body weight) into the rectum. The plasma hCG concentration increased with increasing dose of alpha-CyD. The AUC(0-48) observed after coadministration of hCG and alpha-CyD at 30 mg/kg body weight was approximately four times higher than that of hCG and alpha-CyD at 10mg/kg body weight. HCG at a high concentration induced a rapid increase in the plasma testosterone concentration (74.2 +/- 3.4 ng/ml) 2 h after intravenous administration. However, the testosterone concentration 24 h after intravenous administration decreased to the physiological level (approximately 20 ng/ml) which had been observed before such administration. On the other hand, the maximum level of testosterone concentration (40.0 +/- 12.6 ng/ml) was observed 24 h after rectal administration of hCG (400 IU/kg body weight) in combination with alpha-CyD (30 mg/kg body weight). Moreover, the plasma testosterone concentration (31.0 +/- 11.4 ng/ml) obtained 72 h after rectal administration tended to be maintained at a higher level than that (14.4 +/- 0.9ng/ml) observed before the administration. These results suggest that the hollow-type suppository as a rectal delivery system of hCG is promising as a new mode of hCG therapy.     

盐酸纳洛酮舌下含片在犬体内的药代动力学及绝对生物利用度

本文采用高效液相色谱－电化学检测法研究了盐酸纳洛酮舌下含片在犬体内的药代动力学及绝对生物利用度。雄性犬８只，ｉｖ５ｍｇ盐酸纳洛酮后，血浆药物浓度的经时过程符合二室开放模型，分布半衰期（ｔ１／２α）为１２．０ｍｉｎ，消除半衰期（ｔ１／２β）为１４３．４ｍｉｎ，ＡＵＣ为７．９２ｍｇ（ｍｉｎ／Ｌ。犬给予５ｍｇ盐酸纳洛酮舌下含片后，血浆药物浓度的经时过程符合一级吸收二室开放模型，吸收较快，吸收半衰期（ｔ１／２Ｋａ）为１１．０ｍｉｎ，分布半衰期（ｔ１／２α）为１５．４ｍｉｎ，消除半衰期（ｔ１／２β）为１６４．１ｍｉｎ，达峰时间（Ｔｍａｘ）为２７．７ｍｉｎ，高峰浓度（Ｃｍａｘ）为３４．２ｎｇ／ｍｌ，ＡＵＣ为６．７９ｍｇ．ｍｉｎ／Ｌ，盐酸纳洛酮舌下含片的绝对生物利用度为８６．８（１０．９％。经统计学检验，两种途径给药后的ｔ１／２α、ｔ１／２β、（和（均无显著性差异（Ｐ＞０．０５）。上述结果表明，盐酸纳洛酮舌下含片在犬体内的处置过程与ｉｖ途径是相似的，生物利用度较高，预计在临床能产生较好的疗效     

Effects of enzyme induction, renal and cardiac function on ketamine plasma kinetics in patients with ketamine long-term analgosedation

Steady-state plasma levels of ketamine and its metabolites norketamine and dehydronorketamine were determined in 4 different groups of a total of 27 patients with ketamine long-term analgosedation (1.1 - 1.3 mg/kg/h). In 9 of the patients who had normal liver and kidney function (group 1), steady-state levels after 3 days of continuous infusion were 1.2 +/- 0.3 micrograms/ml ketamine, 1.0 +/- 0.6 micrograms/ml norketamine, and 2.6 +/- 1.0 micrograms/ml dehydronorketamine. The measured ketamine levels in group 1 were in agreement with the expected value, which may be calculated from published pharmacokinetic data after bolus injection. In 8 patients with acute renal failure (group 2), a tendency to about 20% higher ketamine steady-state plasma levels compared to group 1 was observed, but this difference was not significant. However, dehydronorketamine plasma levels were significantly higher in this group. Only a minor fraction of the ketamine dose (10% and 4%) was eliminated during hemodialysis or hemofiltration treatment, respectively. Steady-state plasma levels in 5 patients with cardiogenic shock (group 3) did not differ significantly from those of group 1. In 5 patients with long-term use of barbiturates (group 4), steady-state plasma levels of ketamine were significantly lower compared to groups 1 and 3, most likely due to barbiturate-induced enzyme induction. Hyperdynamic circulatory reactions were not observed in any of the patients. Psychomimetic effects could be excluded in 16 of the patients and were unlikely in 6 patients. In 5 further patients, psychomimetic effects could not definitely be excluded due to difficulties in non-verbal communication.     

Bioavailability and pharmacokinetics of ketanserin in elderly subjects

Summary The bioavailability of ketanserin has been examined in a cross-over experiment in 21 elderly subjects (aged 59–72 years) by administration of tablets (40 mg), solution (40 mg) and injectable solution (10 mg). After two weeks of treatment with 40 mg ketanserin tablets further 18 blood samples for analysis were collected under steady-state conditions. Plasma levels were measured by HPLC. The absolute bioavailability of ketanserin tablets was 52.7%; their relative bioavailability compared to a solution containing an equal quantity of active compound was 85.5%. Therefore, the low absolute bioavailability of ketanserin cannot be attributed to the formulation.The active compound was rapidly liberated from the tablet, reaching a peak of 103.8 ng/ml after 0.97 h. Individual plasma level-time curves were fitted to an open three compartment model and a half-life of 17.7±7.26 h was calculated for the terminal elimination phase. An average terminal elimination half-life of 15.4±4.2 ng/ml was found after administration of the ketanserin solution.Multiple dosing with 40 mg tablets b.d.s. resulted in an AUC over one dosing interval at steady-state of 666±201 ng × h/ml. The AUC extrapolated to infinity was 1200±405 ng × h/ml for the last tablet. This is 1.8-times the AUC in one dosing interval, and 2.3-times the AUC of a single dose. Under steady-state conditions, the mean peak plasma level was 155.1 ng/ml (1.08 h after dosing) and the terminal half-life was 19.1±5.1 h.For the metabolite ketanserinol terminal half-lives of 21.4 h after a single tablet and 31.0 h after discontinuation of multiple dosing were calculated. Compared to the parent compound there was much more marked accumulation of ketanserinol.Despite moderate accumulation and prolongation of the terminal half-life of ketanserin under steady-state conditions, dosage adjustment is not required in elderly people. First-pass metabolism and bioavailability remained in the range found in previous studies of ketanserin in young subjects.     

The pharmacokinetics of ketamine following intramuscular injection to F344 rats

Ketamine is a glutamate N‐methyl‐D‐aspartate receptor antagonist that is a rapid‐acting dissociative anesthetic. It has been proposed as an adjuvant treatment along with other drugs (atropine, midazolam, pralidoxime) used in the current standard of care (SOC) for organophosphate and nerve agent exposures. Ketamine is a pharmaceutical agent that is readily available to most clinicians in emergency departments and possesses a broad therapeutic index with well‐characterized effects in humans. The objective of this study was to determine the pharmacokinetic profile of ketamine and its active metabolite, norketamine, in F344 rats following single or repeated intramuscular administrations of subanesthetic levels (7.5 mg/kg or 30 mg/kg) of ketamine with or without the SOC. Following administration, plasma and brain tissues were collected and analyzed using a liquid chromatography–mass spectrometry method to quantitate ketamine and norketamine. Following sample analysis, the pharmacokinetics were determined using non‐compartmental analysis. The addition of the current SOC had a minimal impact on the pharmacokinetics of ketamine following intramuscular administration and repeated dosing at 7.5 mg/kg every 90 minutes allows for sustained plasma concentrations above 100 ng/mL. The pharmacokinetics of ketamine with and without the SOC in rats supports further investigation of the efficacy of ketamine co‐administration with the SOC following nerve agent exposure in animal models.     

Determination of ketamine and norketamine in plasma by micro-liquid chromatography-mass spectrometry

A sensitive method of determination of ketamine and norketamine by micro-liquid chromatography/mass spectrometry was developed as part of a clinical trial in a pediatric population. Compounds were extracted from 100mul plasma samples using solid-phase extraction on Oasis((R)) MCX cartridges. Separation was achieved on a C18 micro-column with a mobile phase composed of formic acid 0.1% and acetonitrile (90/10, v/v). Detection of ketamine, norketamine and their internal standard norketamine D4 was performed using selected ion monitoring at m/z 238.2, 224.2 and 228.2, respectively. Under these conditions, no loss of signal due to matrix effect was found and time of analysis did not exceed 10min. Extracted calibration curves were linear from 5 to 500ng/ml for each analyte, with correlation coefficients over 0.999. Intra- and inter-day validation studies showed mean recoveries between 98.1 and 101.7% and a relative standard deviation below 1.9%. Extraction recoveries ranged from 84.8 to 89.8% for both ketamine and norketamine. Limit of quantification was 4ng/ml for each analyte.     

Isosorbide dinitrate plasma concentrations and bioavailability in human subjects after administration of standard oral and sublingual formulations

The bioavailability of isosorbide dinitrate from formulations containing 5, 10, and 20 mg in tablets and 10 mg in solution for oral use and 5 mg in tablets for sublingual use, has been compared. When adjusted for dose, the peak mean plasma drug concentrations after oral administration were similar (e.g., 9.2 ng/mL after a 10-mg tablet) and about one-half that obtained after sublingual administration. Drug concentrations declined monoexponentially with mean half-lives ranging from 25-36 min. The relative bioavailability of isosorbide dinitrate from the oral formulations was not significantly different (p greater than 0.05) over the dose range studied, whereas the relative bioavailability after sublingual administration was about twice as great (p less than 0.01) as that after oral administration. The plasma drug concentration-time profile after administering the 5-mg sublingual tablet was similar to that obtained after administering orally a solution containing 10 mg, indicating that the latter should be as clinically effective as the former.     

Increased bioavailability of clomipramine after sublingual administration in rats

This study examined the absorption and disposition of clomipramine in rats after sublingual (5 and 50 mg/kg), oral (50 mg/kg), and iv (5 mg/kg) administration. The mean oral bioavailability of clomipramine was 24.8% and 29.7%, respectively, in conscious rats and in rats anesthetized with ketamine/xylazine (30/3 mg/kg). When given sublingually in isotonic saline at a dose of 50 mg/kg, clomipramine was rapidly absorbed, and the mean absolute bioavailability (36.2%) was increased over oral dosing. The mean AUC values of clomipramine were 2258 +/- 1762 ng.h/mL and 1891 +/- 867 ng.h/mL after oral administration to conscious and anesthetized rats, respectively, and 3303 +/- 1576 ng.h/mL after sublingual administration to anesthetized rats. Sublingual administration (5 mg/kg doses) of clomipramine formulated with a permeation enhancer, 2-hydroxypropyl beta-cyclodextrin, further increased the sublingual bioavailability to 57.1%. The sublingual route may be an alternative route of administration of clomipramine, providing enhanced bioavailability.     

The bioavailability of doxycycline

The bioavailability of doxycycline (Doxy-Diolan 100 tablets, test, active substances: 100 mg doxycyclin per tablet) was compared with that of another commercially available tablet-formulation containing the same active substance (reference). In a cross-over study, 16 young healthy male volunteers were administered in fasting state orally by one tablet containing 100 mg active substance. The concentrations of doxycycline were determined in plasma and saliva by a high-performance liquid chromatographic assay. Mean maximum plasma concentration (cmax +/- standard deviation) of doxycycline were 1.57 +/- 0.40 micrograms/ml (test) and 1.59 +/- 0.38 micrograms/ml (reference), respectively, and were reached 1.47 +/- 0.55 h and 1.66 +/- 0.57 h after administration. Plasma half-lives were 16.6 +/- 2.9 h and 16.8 +/- 3.0 h, the areas under the plasma concentration-time curves (AUC0-00) 29.3 +/- 4.5 mg/l.h and 29.7 +/- 4.4 mg/l.h. The concentration of doxycycline in saliva were low, median maximum concentrations of 50 ng/ml were measured 1-2 h after administration. The statistical evaluation revealed bioequivalence between both drugs.     

The systemic availability of meptazinol in man after oral and rectal doses

Summary We have studied the pharmacokinetics of the centrally-acting analgesic meptazinol after oral and rectal administration to 15 healthy men. Each subject took a standard 200 mg tablet orally and Witepsol H12 suppositories containing 75, 100, and 150 mg of the drug in a cross-over design.Meptazinol plasma concentrations were measured by HPLC using fluorescence detection and the pharmacokinetics determined.The t_max values for the 100 mg and 150 mg suppositories (median =0.5 h) were statistically significantly shorter than for the tablet (median =1.13 h), suggesting that meptazinol was more rapidly absorbed via the rectal route.Despite substantial intersubject variation in C_max the plasma concentrations after rectal dosage were higher than after oral administration. There was a statistically significant (p<0.001) improvement in systemic availability for each of the suppository doses (mean approximately 15.5% compared with the oral tablet (mean approximately 4.5%).     

Urinary excretion rates of ketamine and norketamine following therapeutic ketamine administration: method and detection window considerations

Ketamine is widely used in veterinary medicine. Its medical application in humans is limited to children because in adults it induces severe psychedelic episodes. In recent years, teenagers have abused ketamine as a recreational and "club drug" because of its hallucinogenic and stimulant effects. Ketamine is also misused as a "date-rape" drug (to induce amnesia in unsuspecting victims). Sensitive gas chromatography-mass spectrometry-negative chemical ionization (GC-MS-NCI) and liquid chromatography-mass spectrometry-atmospheric pressure chemical ionization (LC-MS-APCI) methods were applied for the simultaneous quantification of ketamine and its major metabolite, norketamine, in urine. Urine samples were collected from hospitalized children who had received ketamine as an anesthetic. Individual urine samples were collected up to 16 days after drug administration. Using the GC-MS-NCI method, ketamine was detected in the urine of the children from only the day of drug administration up to 2 days after drug administration. Its concentrations ranged from 29 to 1410 ng/mL. Norketamine (measured in concentrations of 0.1-1442 ng/mL) was detected up to 14 days. Using the LC-MS-APCI method, norketamine was detected up to 6 days after drug administration, ranging in concentrations of 2-1559 ng/mL, while ketamine was detected up to 11 days (2-1204 ng/mL). In the urine taken from one child, ketamine was not detected through the entire 16-day period using both methods. The detection window for the analytes is highly dependent on the method used for determination and varies between individuals.     

The pharmacokinetics of tranylcypromine enantiomers in healthy subjects after oral administration of racemic drug and the single enantiomers

The pharmacokinetics of the two enantiomers of tranylcypromine were evaluated in six healthy subjects after oral dosage of the racemate (20 mg of the sulphate) and the single enantiomers (10 mg of the sulphate) using an enantiospecific assay. Significant differences in AUC, Cmax, lambda(z), and CLR of the two enantiomers were observed both on administration of the racemate and of the individual enantiomers. The plasma concentrations and urinary excretion rates of (-)-tranylcypromine exceeded those of (+)-tranylcypromine. AUCs of the (-)-enantiomer [arithmetical means 197 ng ml(-1) h after the racemate, 130 ng ml(-1) h after the enantiomer] were greater than those of the (+)-enantiomer [26 ng ml(-1) h after the racemate, 28 ng ml(-1) h after the enantiomer] (P = 0.0001). No in vivo racemisation was detected. The power of the study was insufficient to establish any enantiomer-enantiomer interaction except for a possible interaction at the level of renal clearance (P = 0.013 for both enantiomers).     

Pharmacokinetic investigation of a nicotine sublingual tablet

OBJECTIVE: To evaluate the pharmacokinetics of a new 2-mg nicotine sublingual tablet under varying conditions of use. METHODS: The pharmacokinetics of the 2-mg nicotine sublingual tablet were investigated in four separate studies involving healthy adult volunteer smokers: (1) a multiple-dose comparison with 2-mg nicotine chewing gum (n=24; 13 males, 11 females), (2) a dose-proportionality study comparing single doses of 2, 4 and 6 mg (n=21, 10 males, 11 females), (3) an evaluation of the effect of incorrect tablet use, i.e. chewing the tablet followed by either immediate or delayed swallowing (n = 19, 10 males, 9 females), and (4) the effect of oral and gastric pH on nicotine absorption from the tablet (n=20; 11 males, 9 females). Study parameters were maximal plasma concentration (Cmax), time to Cmax (tmax), and area under the plasma concentration-time curve (AUC). RESULTS: The plasma nicotine profiles were similar following repeated administration of the sublingual tablet and the 2-mg nicotine chewing gum (mean Cmax 13.2 versus 14.4 ng/ml, median tmax 20 versus 20 min, mean AUC11-12 12.4 versus 13.5 ng/ml per hour) with no statistically significant difference between the two treatments. The pharmacokinetics of the 4- and 6-mg doses were non-linear compared to the 2-mg dose, probably as a result of more of the dose being swallowed and undergoing first-pass metabolism in the liver. The mean Cmax for the 2-, 4- and 6-mg dose was 3.8 +/- 1.0, 6.8 +/- 2. 1, and 9.0 +/- 3.3 ng/ml, respectively, and in terms of dose proportionality the relative bioavailability of the 4- and 6-mg dose was 0.82 and 0.71, respectively. Incorrect tablet use, i.e. chewing the tablet and immediate swallowing decreased nicotine bioavailability both in terms of rate and extent. Mean Cmax was 12.1 ng/ml (correct use), 10.3 ng/ml (chewing and immediate swallowing), and 12.1 ng/ml (chewing and delayed swallowing). Corresponding mean values for AUC9-10 were 11.6, 9.6 and 11.2 ng/ml per hour. There were no significant differences between 'alkaline mouth' versus control, 'acidic mouth' versus control or 'alkaline stomach' versus control, but the rate of nicotine absorption was increased at alkaline compared to acidic oral pH (mean Cmax 6.1 versus 4.9 ng/l ml, P = 0.003; median tmax 60 versus 90 min, P= 0.0002). CONCLUSION: The pharmacokinetic profile of the nicotine 2-mg tablet was similar to that of the 2-mg nicotine chewing gum. Absorption of nicotine from the tablet was nonlinear at higher doses (two or three tablets). Chewing the tablet and keeping the remains in the mouth or concurrent use of acidic beverages or antacids are equivalent to recommended sublingual use during normal oral pH conditions.     

Pharmacokinetic profile of a new controlled-release isosorbide-5-mononitrate 60 mg scored tablet (Monoket Multitab).

The influences of food, tablet splitting, and fractional dosing on the pharmacokinetics of a new controlled-release double-scored tablet containing 60 mg isosorbide-5-mononitrate (Monoket Multitab) were investigated in healthy male volunteers. Food interaction was evaluated after single dose administration under fasted conditions and after a standard high-fat breakfast. The effect of tablet splitting was assessed at steady-state, after 5 days of once daily dosing with the tablet taken intact or trisected. The influence of fractional dosing was assessed after 1 and 6 days of daily regimen of 40 mg in the morning (2/3 of a tablet) and 20 mg in the evening (1/3 of a tablet). The pharmacokinetics of isosorbide-5-mononitrate after taking the tablet intact or in three fragments were very similar with a mere 10% increase of maximum plasma concentration (C(max)) for the latter, while the time to peak (T(max)) decreased from 5 to 4 h and areas under the concentration vs. time curves (AUCs) were virtually unchanged. Morning trough concentration reached 53 and 46 ng/ml, respectively. Administration of the intact tablet after a high-fat breakfast increased C(max) by 18% and AUC by 21%, and slightly delayed T(max) from 5 to 6h. During fractional dosing, morning and evening C(max) reached 364 and 315 ng/ml on the first day, and 373 and 300 ng/ml on the 6th day, respectively. The ratio of AUC(0-24 h) on the last day to AUC(infinity) on the first day, was 82.1% (confidence limits 71.7-94.1%) possibly resulting from peripheral volume expansion. The release characteristics of Monoket Multitab are thus moderately influenced by concomitant intake of food and to a very minor extent by tablet breaking. Fractional dosing allows to achieve lower peak and higher morning trough levels, while total exposure is comparable to that during once daily dosing (AUC(0-24 h, s.s.) of 5.55+/-1.78 and 5.71+/-1.08 microg h/ml).     

Pharmacokinetics of two lorazepam formulations, oral and sublingual, after multiple doses

The pharmacokinetic profiles of a sublingual and a conventional oral lorazepam tablet formulation were established following chronic administration to twelve healthy male volunteers. Fitting a multi-dose equation based on a one-compartment model to the observed data, the average elimination half-lives for the sublingual and oral doses are estimated to be 11 and 8 h, respectively, while the corresponding absorption half-lives are 15 and 55 min; this confirms earlier reports that the sublingual formulation is more rapidly absorbed. The observed time to steady-state for both formulations was approximately 3 days, which agrees well with that predicted from previous single dosing studies. Although the sublingual formulation yields a higher average steady-state minimum plasma concentration than the oral formulation (41.6 versus 38.1 ng ml-1), the maximum lorazepam concentration achieved during steady state was approximately 83 ng ml-1 for both formulations. The average steady-state plasma concentration is estimated to be 63 ng ml-1, independent of the formulation used.     

A critical point in chiral chromatography–mass spectrometry analysis of ketamine metabolites

Ketamine is a widely used dissociative drug, whose quantification in plasma and urine can be of pharmacological, toxicological, and clinical interest. Although tandem mass spectrometry allows the reliable determination of ketamine and its metabolites in biological matrices, the structural similarity between norketamine (main active metabolite) and dehydronorketamine (a less relevant metabolite) can represent a critical aspect. These compounds differ exclusively in two hydrogen atoms, but the consequent two-unit difference in their mass/charge ratio is partially nullified by the isotopic abundance of the chlorine atom present in their structure. This, along with their similar fragmentation pattern, can result in the incorrect identification of the enantiomers of these ketamine metabolites even with triple quadrupole instruments, if shared transitions are monitored after chiral chromatography. The key to prevent norketamine overestimation is therefore observing analyte-specific MS/MS transitions. Here, we describe in detail how we investigated this issue, during the development of an analytical method for ketamine and norketamine enantiomer determination in plasma.     

Rifampicin has a Profound Effect on the Pharmacokinetics of Oral S‐Ketamine and Less on Intravenous S‐Ketamine

Low‐dose ketamine is currently used in several acute and chronic pain conditions as an analgesic. Ketamine undergoes extensive metabolism and is thus susceptible to drug–drug interactions. We examined the effect rifampicin, a well‐known inducer of many cytochrome P450 (CYP) enzymes and transporters, on the pharmacokinetics of intravenous and oral S‐ketamine in healthy volunteers. Eleven healthy volunteers were administered in randomized order 600 mg rifampicin or placebo orally for 6 days in a four‐session paired cross‐over study. On day 6, S‐ketamine was administered intravenously (0.1 mg/kg) in the first part of the study and orally (0.3 mg/kg) in the second part. Plasma concentrations of ketamine and norketamine were measured up to 24 hr and behavioural and analgesic effects up to 12 hr. Rifampicin treatment decreased the mean area under the plasma ketamine concentration–time curve extrapolated to infinity (AUC _0–∞) of intravenous and oral S‐ketamine by 14% (p = 0.005) and 86% (p < 0.001), respectively. Rifampicin decreased greatly the peak plasma concentration of oral S‐ketamine by 81% (p < 0.001), but shortened only moderately the elimination half‐life of intravenous and oral S‐ketamine. Rifampicin decreased the ratio of norketamine AUC _0–∞ to ketamine AUC _0–∞ after intravenous S‐ketamine by 66%, (p < 0.001) but increased the ratio by 147% (p < 0.001) after the oral administration of S‐ketamine. Rifampicin profoundly reduces the plasma concentrations of ketamine and norketamine after oral administration of S‐ketamine, by inducing mainly its first‐pass metabolism.