Spinal biopharmaceutics of bupivacaine and lidocaine by microdialysis after their simultaneous administration in rabbits

The aim of the present study was to determine the intrathecal bioavailability of a mixture of lidocaine and bupivacaine in a rabbit model of spinal anesthesia by using the microdialysis technique. Catheter and microdialysis probe were inserted under control of the view either in the epidural or in the intrathecal space. First, the epidural disposition of the mixture of bupivacaine and lidocaine was studied after epidural administration. Then, the intrathecal and plasma dispositions of bupivacaine and lidocaine were investigated following intrathecal or epidural administration. The epidural clearance of bupivacaine was higher than that of lidocaine, suggesting a more significant uptake of bupivacaine into the systemic circulation and/or into the CSF. The intrathecal bioavailability of bupivacaine and lidocaine was 12.3 and 17.9%, respectively, while it was 5.5 and 17.7% following the separate administration of each agent [Clément, R., Malinovsky, J.M., Le Corre, P., Dollo, G., Chevanne, F., Le Verge, R., 1999. Cerebrospinal fluid bioavailability and pharmacokinetics of bupivacaine and lidocaine following intrathecal and epidural administrations in rabbits using microdialysis. J. Pharmacol. Exp. Ther. 289, 1015-21]. After intrathecal administration, a decrease in C(max) and AUC values was observed for bupivacaine in comparison with the separate administration. Moreover, after epidural administration, the systemic resorption was slower and lower, especially for bupivacaine. Such a reduction in the systemic absorption of bupivacaine might increase its intrathecal bioavailability, resulting from a vasoconstrictor effect of lidocaine reducing the systemic absorption of bupivacaine from the epidural space leading to an increase of its extent of absorption through meninges into CSF although its absorption rate was not modified.     

CSF and plasma pharmacokinetics of pethidine and norpethidine in man after epidural and intrathecal administration of pethidine

Summary The disposition of pethidine and its main metabolite, norpethidine, in cerebrospinal fluid (CSF) and plasma was studied in 11 thoracic surgery patients after lumbar epidural (100 mg;n=6) or lumbar intrathecal (25 mg;n=5) administration of pethidine. Pethidine appeared more slowly in plasma after intrathecal than after epidural administration (t_max 2.3 h and 14 min, respectively), but systemic bioavailability was similar. The CSF concentrations of pethidine were higher than those in plasma after both routes of administration. The maximal CSF/plasma concentration ratio was 6000 to 45000 after intrathecal administration but was only 26 to 97 after the epidural route. Pethidine was rapidly distributed in CSF; nine to ten h after the intrathecal and epidural injections the CSF/plasma concentration ratios were 12 to 89 and 2 to 33, respectively. The calculated bioavailability in CSF of epidural pethidine was 10.3%. The terminal elimination half-life of pethidine was 6.0 h (CSF) and 5.4 h (plasma) after intrathecal administration and 8.6 h (CSF) and 8.8 h (plasma) after epidural injection. The volume of distribution of unchanged pethidine in the subarachnoid space was 13 ml·kg^–1 and clearance from the CSF was 15 µl·kg^–1·min^–1. In all patients receiving intrathecal pethidine and in some patients after epidural pethidine, CSF norpethidine concentrations were higher than those in plasma; the maximum CSF norpethidine was 102 to 1211 ng·ml^–1 and 14 to 210 ng·ml^–1 and the maximum CSF/plasma norpethidine concentration ratios were 21 to 652 and 0.6 to 14 times after intrathecal and epidural administration, respectively. Norpethidine was rapidly distributed and its level in CSF was about the same or lower than in plasma during the terminal elimination phase. The maximum CSF norpethidine level was 1.2±1.0% of that of pethidine after intrathecal injection. Thus, epidural pethidine enters the CSF more rapidly and to a greater extent than has been previously shown for epidural morphine, but pethidine is more rapidly redistributed from CSF. The terminal elimination half-life of pethidine was found to be long in relation to the reported duration of analgesia after a single spinal dose of pethidine, which suggests a potential risk of accumulation within the CSF on multiple spinal injections of pethidine. Pethidine is partly metabolised within the subarachnoid space by N-dealkylating enzymes in the CNS. After intrathecal injection of more than 25 mg pethidine, the concentration of the principle metabolite, norpethidine, in CSF may be higher than that associated with CNS toxicity in man.Presented at the III World Conference on Clinical Pharmacology and Therapeutics, Stockholm, Sweden 1986     

Plasma and CSF morphine concentrations after i.m. and epidural administration

Morphine concentrations in plasma and CSF after i.m. and epidural morphine administration were assayed in patients undergoing surgery of the low abdomen. Morphine concentration in CSF after i.m. administration of this drug is remarkably lower than morphine concentration in plasma. The highest value is attained in CSF after about 90' and is followed by a slow downsloping to lowest values, which were observed 4 hours after drug administration. Kinetics of morphine passage into plasma after epidural administration is similar to that found after i.m. administration. In the latter experimental condition (epidural administration), concentrations of morphine in CSF 30' after administration are markedly lower than those found in plasma. However, 60 min. after epidural administration plasma and CSF morphine concentrations are similar, in particular CSF concentrations are 4 to 8 times higher than those obtained after i.m. administration. Such high levels persist for a long time.     

Pharmacokinetics of epidural morphine in man

Summary Cerebrospinal fluid (CSF) and plasma morphine concentrations were determined in 5 patients after epidural administration of 6 mg morphine; plasma samples were collected frequently during the initial 6 h and 6–7 CSF samples were obtained from each patient over a 24 h period. Morphine was analysed using gas chromatography and electron capture detection. Individual morphine concentration-time curves were plotted for plasma and CSF and various pharmacokinetic variables were calculated. Plasma morphine concentrations after epidural injection were similar to those found after intramuscular administration; C_max (66±8 mg/ml: mean±SEM) appeared within 12±3 min, and the terminal elimination half-life in plasma was 213±24 min. In CSF, morphine reached a peak (1575±359 ng/ml) after 135±40 min. The terminal elimination half-life for morphine in CSF was 239±10 min. The CSF bioavailability of morphine after epidural administration was calculated to be 1.9±0.5%.The study showed that epidural administration of morphine resulted in CSF concentrations many times higher than those in plasma, but still only 2% of the dose administered was available to the CSF compartment. Morphine was eliminated with similar speed from CSF and plasma.     

Intranasal administration of milnacipran in rats: evaluation of the transport of drugs to the systemic circulation and central nervous system and the pharmacological effect

Recently, transnasal drug delivery has attracted a great deal of attention as an administration route to deliver drugs directly to the central nervous systems (CNS) and drug targeting of the CNS is expected to increase. In the present study, we investigated the possibility of using a transnasal delivery system for milnacipran, a serotonin-noradrenaline reuptake inhibitor (SNRI), by evaluating the transport to the systemic circulation and cerebrospinal fluid (CSF) and the pharmacological effect after intranasal (i.n.) administration. Moreover, the effect of chitosan as a bioadhesive material on the transport to the systemic circulation and CSF and the pharmacological effect after i.n. administration were evaluated. As a result, i.n. administration of milnacipran was found to produce a higher direct delivery to the CNS as well as to the systemic circulation, suggesting that this is a promising route of administration and an alternative to peroral (p.o.) administration. Furthermore, the i.n. co-administration with chitosan led to increased plasma and CSF concentrations and an enhanced pharmacological effect, evaluated by means of the forced swimming test. The results suggested that chitosan produced a long residence time of milnacipran in the nasal cavity due to its bioadhesive effect, leading to the enhanced transport of milnacipran from the systemic circulation to the CNS via the blood-brain barrier by an increase in systemic absorption as well as direct transport to the CNS, resulting in a higher antidepressant effect compared to that with p.o. administration.     

Logic and inference in clinical trials.

1 Epidural administration of opiates for analgesia has recently generated widespread interest and would theoretically be advantageous as a method for relief of pain in labour. 2 Plasma pethidine concentrations were measured after intravenous, intramuscular and epidural administration of pethidine to women in labour and after epidural administration to non-pregnant female surgical patients. 3 Kinetic parameters were derived from the plasma concentration data in each group of subjects and the relationship between plasma kinetics and analgesia in labour were examined. 4 Absorption of pethidine from the epidural space in pregnant women in rapid and excepting the lower initial values, the average plasma concentration and area under the plasma concentration v time curve did not differ significantly (P less than 0.01) from those obtained with intravenous dosage, but were significantly higher (P less than 0.01) during the first 2 h after dosage than the results after intramuscular administration. The analgesia provided by the epidural route of administration was greater than with intravenous or intramuscular administration. 5 It is postulated that the analgesic efficacy of epidural pethidine in women in labour is due to a combination of systemic and local effects and that the local effect is attributable to the local anaesthetic properties of pethidine rather than a selective anti-nociceptive action on the spinal cord.     

Nasal administration of a physostigmine analogue (NXX-066) for Alzheimer's disease to rats

The nasal route has been receiving attention for the administration of systemically active drugs because delivery is convenient, reliable and rapid. The aims of this study were to investigate the systemic absorption of nasally administered (3aS)-cis-1, 2, 3, 3a, 8, 8a-hexahydro-1, 3a, 8-trimethyl-pyrrolo-[2,3b]-indol-5-yl 3, 4 dihydro-2-isoquinolincarboxylate (NXX-066), a physostigmine analogue, in rats and to compare the uptake of the drug into the cerebrospinal fluid (CSF) after nasal and intravenous administration. NXX-066 (3 micromol/kg) was administered to both nostrils or into the vena jugularis of male Sprague-Dawley rats. Blood and CSF samples were obtained at regular intervals from the arteria carotis and by cisternal puncture, respectively. The concentrations of NXX-066 in the blood and CSF samples were measured using HPLC with fluorescence detection. NXX-066 was absorbed rapidly after nasal administration with the peak concentration occurring within 1.5 min. The nasal bioavailability of NXX-066 was 100+/-30% and the elimination from plasma was as rapid as that following intravenous administration. Low concentrations of NXX-066 were detected in the CSF after both intravenous and nasal administration. In conclusion, NXX-066 was rapidly and totally absorbed into the systemic circulation and uptake into the CSF was not enhanced by nasal administration in rats.     

Clinical pharmacokinetics of epidural and spinal anaesthesia

Epidural and spinal anaesthesia results from the interaction of local anaesthetics with nerve structures, primarily those located within the subarachnoid space. Local anaesthetics can reach the sites of action along various distribution pathways. Uptake into extraneural tissues (in particular epidural fat) and systemic absorption compete with neural tissue distribution and thereby affect the clinical potency and duration of action. Consequently, epidural doses must be much higher than spinal doses. The systemic absorption of lignocaine (lidocaine), bupivacaine and etidocaine following lumbar epidural administration has been shown to be biphasic, with a rapid initial absorption phase followed by a much slower absorption phase. Initial absorption rates of lignocaine and bupivacaine following subarachnoid injection are much slower, but the late absorption rates are similar to those after epidural administration. The tissue distribution characteristics of various amide-type agents are similar, because more extensive plasma binding offsets the greater tissue affinity of the more lipophilic compounds bupivacaine and etidocaine. The amide-type agents are predominantly eliminated by hepatic metabolism, except prilocaine, which is also metabolised elsewhere in the body. Ester-type agents are rapidly hydrolysed in blood and liver and are eliminated much faster than amide-type agents. The blood concentrations attained depend primarily upon the dose administered. The addition of adrenaline (epinephrine) reduces the peak plasma drug concentrations; similarly, the age of the patient, disease states and drug interactions may alter the pharmacokinetics to various extents. Because of the low dose requirements, systemic toxicity is not a problem during spinal anaesthesia. During epidural anaesthesia, however, the safety margin is relatively small, and systemic toxicity is very likely to occur after inadvertent intravascular injection of an epidural dose.     

Pharmacokinetics of lignocaine and bupivacaine in surgical patients following epidural administration. Simultaneous investigation of absorption and disposition kinetics using stable isotopes

The pharmacokinetics of lignocaine (lidocaine) and bupivacaine following epidural administration were studied in 12 surgical patients using a stable isotope method. Shortly after epidural administration of the agent to be evaluated, a deuterium-labelled analogue was administered intravenously. Plasma concentrations of the unlabelled and the deuterium-labelled local anaesthetics were determined using gas chromatography and mass fragmentography. The pharmacokinetic behaviour of both agents was consistent with a 2-compartment open model and two parallel first-order absorption processes. The mean distribution and elimination half-lives were 12 minutes and 100 minutes for lignocaine, and 22 minutes and 143 minutes for bupivacaine. The mean volumes of the central compartment and the mean steady-state volumes of distribution were: lignocaine, 43L and 99L; bupivacaine, 33L and 68L. Total plasma clearances averaged 0.95 L/min (57 L/h) for lignocaine and 0.52 L/min (31.2 L/h) for bupivacaine. The half-lives, characterising the fast and slow absorption processes, were 9.3 and 82 minutes for lignocaine, and 7.0 minutes and 362 minutes for bupivacaine; the fractions of the doses absorbed in the fast and slow processes were lignocaine 0.38 and 0.58, bupivacaine 0.28 and 0.66, respectively. The results indicate that the local anaesthetics are completely absorbed from the epidural space into the general circulation. The initial absorption rates of both local anaesthetics appear to be similar, but, later, the absorption of bupivacaine proceeds much more slowly than the absorption of lignocaine.     

Nasal absorption of (S)-UH-301 and its transport into the cerebrospinal fluid of rats

Targeting the brain via nasal administration of drugs has been studied frequently over the last few years. In this study, the serotonin-1a receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropyl-amino) tetralin ((S)-UH-301) hydrochloride was used as a model substance. The systemic absorption and transport of (S)-UH-301 into male Sprague-Dawley rat cerebrospinal fluid (CSF) were investigated after nasal and intravenous administration. Blood and CSF samples were obtained at regular time intervals from the arteria carotis and by cisternal puncture, respectively, after administration to both nostrils (total 12 micromol/kg) or into the vena jugularis (6 micromol/kg). The concentrations of (S)-UH-301 in plasma and CSF were measured by HPLC with electrochemical detection. The maximum plasma concentration of intranasal (S)-UH-301 occurred in about 7 min and the absolute bioavailability seemed to be complete (F=1.2+/-0.4). Initially, no increased concentrations of (S)-UH-301 were seen in CSF after nasal compared to intravenous administration i.e. it appeared that no direct transport of (S)-UH-301 from the nasal cavity, along the olfactory neurons and into the CSF occurred. However, a prolonged duration of the concentration was seen after nasal administration of (S)-UH-301 and after about 20 min the CSF(na):CSF(iv) concentration ratio (corrected for different dosage) exceeded 1.     

The pharmacokinetics of isoniazid and hydrazine metabolite in plasma and cerebrospinal fluid of rabbits

The pharmacokinetics of isoniazid (INH) and hydrazine metabolite (HYD) in plasma and cerebrospinal fluid (CSF) of ten rabbits was studied after separate intravenous (i.v.) and oral (p.o.) administration in a crossover study. The concentrations of INH and HYD in the biological fluids were determined by high performance liquid chromatography (HPLC). There was no difference in the area under plasma concentration-time curves, indicating that oral absorption was complete. The mean apparent volume of distribution after i.v. (3.02 +/- 0.55 L) was smaller (p less than 0.01) than that after p.o. (4.29 +/- 1.25 L) dosing. The elimination t1/2 of INH in CSF was longer (p less than 0.005) than that in plasma after either route of administration. There was no significant barrier to the penetration of INH into the CSF from the general circulation. The HYD plasma concentrations were similar after either route. HYD was eliminated at a slower rate (Ke = 0.17 h-1) than INH (Ke = 0.59 h-1). There was prolonged exposure of the body to HYD (greater than 6 h - above 0.1 micrograms/ml).     

Pharmacokinetics of pyrazinamide in plasma and CSF of rabbits following intravenous and oral administration

The pharmacokinetics of pyrazinamide (PZA) in cerebrospinal fluid (CSF) and plasma of 10 rabbits were studied after separate intravenous (i.v.) and oral (p.o.) administration, in a cross-over study. Concentrations of PZA in biological fluids were determined by high performance liquid chromatography (HPLC). After p.o. dose PZA was absorbed rapidly and peak plasma concentration was attained at 0.5 h post administration. After i.v. dose, the plasma PZA concentrations declined rapidly within 10 min and subsequently more slowly following a bi-exponential manner. No difference was observed in the area under plasma concentration-time curves indicating oral absorption was complete and no apparent first-pass metabolism occurred. The (mean +/- S.D.) elimination t1/2 after i.v. (1.04 +/- 0.18 h) was significantly shorter (P less than 0.0005) than that after oral (1.95 +/- 0.63 h) dose and the apparent volume of distribution was also significantly smaller (P less than 0.005) after i.v. (3.211 +/- 0.412 l) than after oral (5.936 +/- 1.607 l) administration. The elimination t1/2 of PZA in CSF was nearly identical to that in plasma after either i.v. (1.07 +/- 0.20 h) or p.o. (1.84 +/- 0.56 h) administration. There is no apparent barrier in rabbits for the penetration of PZA into CSF from the general circulation.     

鼻腔给药促进盐酸美普他酚在大鼠体内的吸收及脑转运

目的考察大鼠鼻腔给药后血和脑脊液中盐酸美普他酚 (MEP)的浓度，并与口服比较。方法采用连续采集法收集脑脊液样品，用HPLC-荧光检测器测定各生物样品中MEP的浓度。结果鼻腔给药后药物迅速吸收入血，并在血和脑脊液中达到高浓度，而MEP口服后体内药浓很低。鼻腔给药后血和CSF的AUC值分别为口服的7.375和15.6倍。结论MEP鼻腔给药具有起效快、生物利用度高的特点，有望成为口服的替代途径。     

DISTRIBUTION OF ANTIHISTAMINES INTO THE CSF FOLLOWING INTRANASAL DELIVERY

The preferential absorption of certain drug compounds from the nasal cavity into the cerebrospinal fluid (CSF) raises questions regarding the transport processes controlling drug disposition following intranasal delivery. The disposition characteristics of several structurally similar antihistamine compounds, hydroxyzine, chlorpheniramine, triprolidine, and chlorcyclizine, into the CSF following nasal administration were studied using the rat as an animal model. The antihistamines were administered either intranasally or intra-arterially, and serial CSF and plasma samples were collected from the cisterna magna and the femoral artery, respectively. The drug levels in CSF and plasma were assayed by HPLC. Hydroxyzine concentrations in plasma and CSF were found to be significantly greater than most of the other compounds tested. In addition, hydroxyzine also showed the most rapid systemic absorption following nasal administration. Interestingly, the hydroxyzine levels in CSF following intranasal administration were significantly higher than those following intra-arterial administration. The AUC ratios between CSF and plasma for hydroxyzine after intranasal and intra-arterial administration were 4·0 and 0·4, respectively. The AUC ratios for triprolidine, the other antihistamine with measurable CSF concentrations, were 0·5 and 0·7, respectively. The distribution of antihistamines from the nasal membrane into the CSF appears to be controlled by a combination of their molecular properties. It also appears that the intranasal delivery of drugs with optimal physicochemical characteristics can result in an improved CNS bioavailability compared to those achieved from an equivalent parenteral dose. ©1997 by John Wiley & Sons, Ltd.     

A comparison of the pharmacokinetics of metronidazole in man after oral administration of single doses of benzoylmetronidazole and metronidazole

1 Three healthy male volunteers were treated with benzoylmetronidazole suspension (3.2 g equivalent to 2 g metronidazole) in a pilot study to investigate the absorption of benzoylmetronidazole into the systemic circulation. A further ten healthy male volunteers took part in a crossover study to compare the pharmacokinetics of metronidazole and its principal oxidative metabolites after administration of benzoylmetronidazole (equivalent to 2 g or 400 mg of metronidazole) or metronidazole (400 mg).

2 The plasma pharmacokinetics of metronidazole and metabolite I[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole] and plasma and urinary concentrations of these, plus benzoylmetronidazole and metabolite II [2-methyl-5-nitroimidazole-1-acetic acid], were determined using specific and sensitive high performance liquid chromatographic assay procedures.

3 No benzoylmetronidazole was observed in any plasma or urine sample assayed. The values for and times of the highest observed plasma metronidazole concentrations after a single oral dose of benzoylmetronidazole, equivalent to 2 g and 400 mg metronidazole, were 17 μg/ml at 5.1 h after dosing and 4.6 μg/ml at 3.2 h after dosing, respectively. Following oral administration of metronidazole (400 mg), the comparable values were 8.5 μg/ml at 0.8 h after dosing. Peak plasma concentrations of metabolite I after each dose were comparable with each other when corrected for the amount of metronidazole reaching the systemic circulation. The peak concentrations of this metabolite were markedly lower than the peak metronidazole concentrations in the same volunteer. Metabolite II was observed in low concentrations (0.8 μg/ml or less) in plasma at a few time intervals after administration of the higher dose of benzoylmetrinidazole and was not detected at any time interval after administration of benzoylmetronidazole (640 mg, equivalent to 400 mg metronidazole) or metronidazole (400 mg).

4 Pharmacokinetic parameters of metronidazole absorption are markedly different after administration of benzoylmetronidazole than after dosing with metronidazole, but the pharmacokinetic parameters of metronidazole and metabolite I elimination are essentially identical after equimolar doses of each form of the drug. The systemic availability of metronidazole derived from benzoylmetronidazole is approximately 80% of that from metronidazole and is independent of dose over the range studied.

5 The mean value for minimum plasma metronidazole concentration at steady-state during the o.d. administration of benzoylmetronidazole (3.2 g equivalent to 2 g metronidazole) was predicted (from these single dose data) to be 6.2 μg/ml. Thus, these predictions suggest that the majority of patients will maintain therapeutic plasma metronidazole concentrations for the whole of the dosing interval during a once-daily dosing regimen. This oral liquid formulation of metronidazole may thus be regarded as a suitable alternative to other presentations of the drug.

     

Analysis of enterohepatic circulation of cefixime in rat by fast inverse Laplace transform (FILT)

The enterohepatic circulation of cefixime in rat was evaluated by a nonlinear least square analysis program, MULTI(FILT), into which the fast inverse Laplace transform (FILT) was incorporated. The plasma time course in the bile duct-cannulated rat exhibited a biexponential curve after the rapid iv administration of cefixime. Several pharmacokinetic models for the enterohepatic circulation were constructed based on the recirculatory concept and the Laplace-transformed equations corresponding to these models were derived by means of the method of transfer function. The transformed equations were simultaneously fitted to the time courses of plasma concentration in rats with laparotomy and with bile duct cannula. The optimum model was selected based on the Akaike's information criterion (AIC). The local moment characteristics for a single pass through enterohepatic circulation were further calculated from the time courses of both the plasma concentration and the amount excreted into the bile. The recovery ratio (Fc) and the mean circulatory time (-tc) through a single pass of enterohepatic circulation were estimated 27.9% and 1.07 hr, respectively. The recovery ratio (Fa) and the mean absorption time (-tc) for the absorption process from the intestinal tract into the systemic circulation were 68.3% and 0.0234 hr, respectively. The recovery ratio (Fb) and the mean transit time (-tb) for the disposition process through the systemic circulation into the bile were 40.8% and 1.05 hr, respectively.     

Stereoselective pharmacokinetics of BOF-4272 racemate after oral administration to rats and dogs

The stereoselective pharmacokinetics of BOF-4272 enantiomers in rats and dogs was investigated by simultaneously measuring concentrations in arterial, portal, and venous plasma, the liver, and the kidney at 2 h after the oral administration of the racemic drug. The concentrations of BOF-4272 enantiomers were measured using high-performance liquid chromatography. The concentrations of the S(-) enantiomer in arterial, portal, and venous plasma were higher than those of the R(+) enantiomer in rats, but the opposite was found in dogs. In rats, absorption from the intestinal tract into the portal system was almost the same for the two enantiomers, whereas the hepatic uptake of the R(+) enantiomer was greater than that of the S(-) enantiomer. In dogs, absorption from the intestinal tract into the portal system was greater for the R(+) enantiomer than for the S(-) enantiomer, whereas hepatic uptake was comparable for the two enantiomers. The stereoselectivity of the renal uptake of BOF-4272 enantiomers had little effect on the stereoselectivity of enantiomers in the systemic circulation in both rats and dogs. The stereoselectivity in the systemic circulation of BOF-4272 enantiomers is therefore related to hepatic uptake in rats, and to absorption from the intestinal tract into the portal system in dogs.     

Huperzine A in rat plasma and CSF following intranasal administration

This paper presents to investigate the levels of Huperzine A in plasma and CSF of rats after three different kinds of administrations and to find out whether intranasal administration is the best route to transfer the drug into the CNS. The drugs of two doses (167 and 500 microg/kg) were administered to male Sprague-Dawley rats intravenously, intranasally and intragastricly, respectively. Series plasma and cerebrospinal fluid (CSF) samples were collected from femoral artery and cisterna magna for 6h. The drug concentrations were determined by HPLC-fluorescence method. The AUC(plasma) and the AUC(CSF) of intranasal administration were 90.3% and 127.7% in low dose group (167 microg/kg) and 91.3% and 69.4% in high dose group (500 microg/kg) compared with intravenous administration. The AUC(plasma) and the AUC(CSF) of intragastric administration were 98.9% and 52.1% in high dose group (500 microg/kg) compared with intravenous administration.     

Disposition of ethmozine in cerebrospinal fluid and plasma of rabbits

The concentration-time profiles of ethmozine, a newly introduced anti-arrhythmic drug, in the cerebrospinal fluid (CSF) and plasma of six rabbits (New Zealand white rabbits of both sexes, 4.0-5.0 Kg) were studied after intravenous bolus administration. CSF samples at various intervals were obtained while the animal was lightly anaesthetized with intravenous thiopentone (40 mg Kg-1) and blood samples at other intervals were taken while the animal was conscious. Blood samples (1 ml) were collected from the implanted cannula of the ear artery while CSF samples (0.3 ml) were obtained from the cisterna magna. The plasma concentrations of ethmozine in six rabbits declined rapidly after intravenous injection for up to 30 min. then slowly over 12 h. Using non-compartmental analysis, the mean (+/- S.E.M.) elimination half-life, mean residence time, plasma clearance and volume of distribution at steady state were 13.9 +/- 9.2 h, 19.9 +/- 13.4 h, 2.3 Lh-1 and 26.8 +/- 7.9 L respectively. The mean CSF-plasma concentration ratios for ethmozine at 0.5, 1.0, 2.0, 4.0, 8.0 and 12.0 h were 0.17, 0.14, 0.16, 0.16, 0.23 and 0.22 respectively. The results suggest that ethmozine is able to penetrate into the CSF from the general circulation and this may be related to its adverse effects on the central nervous system.     

Hydroxocobalamin uptake into the cerebrospinal fluid after nasal and intravenous delivery in rats and humans

The possibility of direct transport of hydroxocobalamin from the nasal cavity into the cerebrospinal fluid (CSF) after nasal administration in rats was investigated and the results were compared with a human study. Hydroxocobalamin was given to rats (n=8) both intranasally (214 microg/rat) and intravenously (49.5 microg/rat) into the jugular vein using a Vascular Access Port (VAP). Prior to and after drug administration, blood and CSF samples were taken and analysed by radioimmunoassay. The AUCCSF/AUCplasma ratio after nasal delivery does not differ from the ratio after intravenous infusion, indicating that hydroxocobalamin enters the CSF via the blood circulation across the blood-brain barrier (BBB). This same transport route is confirmed by the cumulative AUC-time profiles in CSF and plasma, demonstrating a 30 min delay between plasma absorption and CSF uptake of hydroxocobalamin in rats and in a comparative human study. The present results in rats show that there is no additional uptake of hydroxocobalamin in the CSF after nasal delivery compared to intravenous administration, which is in accordance with the results found in humans. This indicates a predictive value of the used rat model for the human situation when studying the nose to CSF transport of drugs.