Pharmacokinetics of 450 mg ropivacaine with and without epinephrine for combined femoral and sciatic nerve block in lower extremity surgery. A pilot study.

AIMS: No pharmacokinetic data exist on doses of ropivacaine larger than 300 mg for peripheral nerve block in man, although in clinical practice higher doses are frequently used. The purpose of the present study was to describe the pharmacokinetic profile in serum of 450 mg ropivacaine with and without epinephrine in patients undergoing anterior cruciate ligament reconstruction. METHODS: Twelve patients were randomly allocated to receive a single shot combined sciatic/femoral nerve block with 60 ml of either ropivacaine 0.75% alone (group R, n = 6) or ropivacaine 0.75% plus epinephrine 5 µg ml(-1) (group RE, n = 6). Venous blood samples for total and free ropivacaine serum concentrations were obtained during 48 h following block placement. Pharmacokinetic parameters were calculated using a non-compartmental approach. RESULTS: Results are given as mean (SD) for group R vs. group RE (95% CI of the difference). Total Cmax was 2.81 (0.94) µg ml(-1) vs. 2.16 (0.21) µg ml(-1) (95% CI -0.23, 1.53). tmax was 1.17 (0.30) h vs. 1.67 (0.94) h (95% CI -1.40, 0.40). The highest free ropivacaine concentration per patient was 0.16 (0.08) µg ml(-1) vs. 0.12 (0.04) µg ml(-1) (95% CI -0.04, 0.12). t(1/2) was 6.82 (2.26) h vs. 5.48 (1.69) h (95% CI -1.23, 3.91). AUC was 28.35 (5.92) µg ml(-1) h vs. 29.12 (7.34) µg ml(-1) h (95% CI -9.35, 7.81). CONCLUSIONS: Free serum concentrations of ropivacaine with and without epinephrine remained well below the assumed threshold of 0.56 µg ml(-1) for systemic toxicity. Changes in pharmacokinetics with epinephrine co-administration did not reach statistical significance.

Variable absorption of clavulanic acid after an oral dose of 25 mg/kg of Clavubactin and Synulox in healthy cats.

The aims of this investigation were to calculate the pharmacokinetic parameters and to identify parameters, based on individual plasma concentration-time curves of amoxicillin and clavulanic acid in cats, that may govern the observed differences in absorption of both drugs. The evaluation was based on the data from plasma concentration-time curves obtained following a single-dose, open, randomised, two-way crossover phase-I study, each involving 24 female cats treated with two Amoxi-Clav formulations (formulation A was Clavubactin and formulation was B Synulox; 80/20 mg, 24 animals, 48 drug administrations). Plasma amoxicillin and clavulanic acid concentrations were determined using validated bioassay methods. The half-life of elimination of amoxicillin is 1.2 h (t1/2 = 1.24 +/- 0.28 h, Cmax = 12.8 +/- 2.12 microg/ml), and that of clavulanic acid 0.6 h (t1/2 = 0.63 +/- 0.16 h, Cmax = 4.60 +/- 1.68 microg/ml). There is a ninefold variation in the AUCt of clavulanic acid for both formulations, while the AUCt of amoxicillin varies by a factor of two. The highest clavulanic acid AUCt values indicate the best absorption; all other data indicate less absorption. Taking into account that the amoxicillin-to-clavulanic acid dose ratio in the two products tested was 4:1, the blood concentration ratios may actually vary much more, apparently without compromising the products" high efficacy against susceptible microorganisms.

Differences between lovastatin and simvastatin hydrolysis in healthy male and female volunteers:gut hydrolysis of lovastatin is twice that of simvastatin.

The aim of this pharmacokinetic evaluation was to show the effect of the extra methyl group in simvastatin on esterase hydrolysis between lovastatin and simvastatin in male and female volunteers. This study was based on the plasma concentration-time curves and the pharmacokinetics of lovastatin and simvastatin with its respective active metabolite statin-beta-hydroxy acid obtained from two different bioequivalence studies, each with 18 females and 18 males. Results were: The group of female volunteers showed a higher yield of the active metabolite beta-hydroxy acid than the group of males (p < 0.002) for both lovastatin and simvastatin. This difference was not related to the body weight of both groups. In the male/female groups, subject-dependent yield of active metabolite beta-hydroxy acid was demonstrated, which was independent of the formulation. The variation in plasma/liver hydrolysis resulted in a fan-shaped distribution of data points when the AUCt lovastatin was plotted vs. that of the beta-hydroxy acid metabolite. In the fan of data points, subgroups could be distinguished, each showing a different regression line and with a different Y-intercept (AUCtbeta-hydroxy acid). Lovastatin hydrolysis was higher than simvastatin hydrolysis. It was possible to discriminate between hydrolysis of both lovastatin and simvastatin by plasma/liver or tissue esterase activity. The three subgroups of subjects (males/females) showing different but high yield of statin beta-hydroxy acid can be explained by variable hydrolysis of plasma and hepatic microsomal and cytosolic carboxyesterase activity. This study showed clearly that despite the subject-dependent hydrolysis of lovastatin/simvastatin to the active metabolite, males tend to hydrolyse less than females. The extra methyl group in simvastatin results in less hydrolysis due to steric hindrance.

Lack of male-female differences in disposition and esterase hydrolysis of ramipril to ramiprilat in healthy volunteers after a single oral dose.

The objective of this study was to identify differences in disposition and esterase hydrolysis of ramipril between male and female volunteers. Plasma concentration and area under the concentration-time curve until the last measured concentration (AUCt) data of ramipril and its active metabolite ramiprilat (-diacid) were obtained from a randomised, cross-over bioequivalence study in 36 subjects (18 females and 18 males). Participants received a single 5-mg oral dose of two different formulations of ramipril (Formulation I and II). Plasma ramipril and ramiprilat concentrations were determined according to validated methods involving liquid chromatography-mass spectrometry. A total number of 2 x 34 available plasma concentration-time curves of both the parent drug and the metabolite could be analysed, and variations (50-100% coefficient of variation [CV]) in plasma concentrations of both parent drug and metabolite were found. With both the formulations, the mean plasma concentrations-time curves of males and females were identical. The groups of female and male volunteers showed similar yields (AUCt = microg x h/L) of the metabolite ramiprilat (p = 0.37); however, females showed a higher AUCt/kg than males (p = 0.046). This difference was solely attributed to the difference in body weight between males and females (p = 0.00049). In both male and female groups, a subject-dependent yield of active metabolite ramiprilat was demonstrated, which was independent of the formulation. There is a large variation in the ramiprilat t1/2beta (50-60% CV). There is a group of subjects who showed a t1/2beta of approximately 80 h (15% CV), and two apparent groups with a longer t1/2beta for each formulation (124 h, 22.5% CV; 166 h, 21.6% CV, respectively, p = 0.0013). This variation in the terminal half-life of ramiprilat is not sex related. In all three groups of half-lives, the corresponding Cmax values (mean +/- SD) of ramiprilat in males and females were identical. Thus, with identical Cmax and half-lives, the difference found in the AUCt/kg of ramiprilat must be due to the difference in dose, as the consequence of the difference in body weight, following a standard dose of 5 mg in both males and females. This study showed clearly that despite subject-dependent hydrolysis of ramipril to the active metabolite ramiprilat, the variability in the rate of hydrolysis between males and females is similar. With a fixed dose (5 mg), females received a higher dose/kg than males and consequently showed a higher AUCt/kg of the active metabolite ramiprilat.

Lack of Male-Female Differences in Disposition and Esterase Hydrolysis of Ramipril to Ramiprilat in Healthy Volunteers after a Single Oral Dose.

The objective of this study was to identify differences in disposition and esterase hydrolysis of ramipril between male and female volunteers. Plasma concentration and area under the concentration-time curve until the last measured concentration (AUCt) data of ramipril and its active metabolite ramiprilat (-diacid) were obtained from a randomised, cross-over bioequivalence study in 36 subjects (18 females and 18 males). Participants received a single 5-mg oral dose of two different formulations of ramipril (Formulation I and II). Plasma ramipril and ramiprilat concentrations were determined according to validated methods involving liquid chromatography-mass spectrometry. A total number of 2 × 34 available plasma concentration-time curves of both the parent drug and the metabolite could be analysed, and variations (50-100% coefficient of variation [CV]) in plasma concentrations of both parent drug and metabolite were found. With both the formulations, the mean plasma concentrations-time curves of males and females were identical. The groups of female and male volunteers showed similar yields (AUCt = mg.h/L) of the metabolite ramiprilat (p = 0.37); however, females showed a higher AUCt/kg than males (p = 0.046). This difference was solely attributed to the difference in body weight between males and females (p = 0.00049). In both male and female groups, a subject-dependent yield of active metabolite ramiprilat was demonstrated, which was independent of the formulation.There is a large variation in the ramiprilat t1/2ß (50-60% CV). There is a group of subjects who showed a t1/2ß of approximately 80 h (15% CV), and two apparent groups with a longer t1/2ßfor each formulation (124 h, 22.5% CV; 166 h, 21.6% CV, respectively, p = 0.0013). This variation in the terminal half-life of ramiprilat is not sex related. In all three groups of half-lives, the corresponding Cmax values (mean ± SD) of ramiprilat in males and females were identical. Thus, with identical Cmax and half-lives, the difference found in the AUCt /kg of ramiprilat must be due to the difference in dose, as the consequence of the difference in body weight, following a standard dose of 5 mg in both males and females.This study showed clearly that despite subject-dependent hydrolysis of ramipril to the active metabolite ramiprilat, the variability in the rate of hydrolysis between males and females is similar. With a fixed dose (5 mg), females received a higher dose/kg than males and consequently showed a higher AUCt/kg of the active metabolite ramiprilat.

Similar motor block effects and disposition kinetics between lidocaine and (+/-)mepivacaine in patients undergoing axillary brachial plexus block during day case surgery.

The aim of this investigation was to compare the clinical effects and pharmacokinetics of lidocaine (one metabolite) and mepivacaine (two metabolites) in 2 groups of 15 patients undergoing axillary brachial plexus anaesthesia. The study had a randomised design. The 30 patients were divided into 2 groups. The patients received either lidocaine (600 mg = 2.561 mMol + 5 mg ml(-1) adrenaline) or mepivacaine (600 mg = 2.436 mMol + 5 microg ml(-1) adrenaline), injected via the axilla near the brachial plexus over a period of 30 s. Onset of surgical analgesia was defined as the period from the end of the local anaesthetic injection to the loss of pinprick sensation in the distribution of the ulnar, radial, and median nerve. Motor block was measured. Onset of motor block was similar for both drugs. Lidocaine is eliminated biexponentially with a t1/2alpha of 9.95 +/- 14.3 min and a t1/2beta of 2.86 +/- 1.55 h. Lidocaine is metabolised into MEGX (tmax 2.31 +/- 0.84 h; Cmax 0.32 +/- 0.13 mg l(-1); t1/2beta 2.36 +/- 2.35 h; total body clearance was 67.9 +/- 28.9 l h(-1)). Mepivacaine is eliminated rapidly and monoexponentially with a t1/2 of 4.78 +/- 2.38 h, a Cmax of 3.89 +/- 0.83 mg l(-1), and a tmax of 0.41 +/- 0.19 h. The total body clearance of mepivacaine is 50% of that of lidocaine, 26.9 +/- 10.6 l h(-1) vs. 67.9 +/- 28.9 l h-1, respectively (p < 0.0001). (+/-)mepivacaine is metabolised into (+/-)4-OHmepivacaine (Cmax 0.45 +/- 0.25 mg l(-1); t1/2beta 6.48 +/- 6.57 h) and (+/-)2,6-pipecoloxylidide (Cmax 0.56 +/- 0.30 mg l(-1); t1/2beta 1.48 +/- 0.74 h). For the axillary brachial plexus block, lidocaine and mepivacaine show similar pharmacodynamic and pharmacokinetic behaviour, despite the number of metabolites, and can therefore be used to the clinical preference for this regional anaesthetic technique.

Clinical pharmacology and the use of articaine for local and regional anaesthesia.

Quicker onset and shorter elimination time favours (+/-) articaine as a short-acting local anaesthetic for regional anaesthesia in day-case settings, e.g. arthroscopy (shoulder, knee), hand and foot surgery, and dentistry, because patients treated with articaine will be 'drug free' more quickly than those who receive other local anaesthetics. Articaine diffuses better through soft tissue and bone than other local anaesthetics. The concentration of articaine in the alveolus of a tooth in the upper jaw after extraction was about 100 times higher than that in systemic circulation. Articaine is metabolised via hydrolysis into articainic acid, 75% of which in turn is excreted as such and 25% in the glucuronidated form by the kidneys. The half-lives of elimination (t1/2alpha and t1/2beta) of articaine are 0.6 and 2.5 hours, whereas the apparent half-life of the metabolite articainic acid is 2.5 hours. Intrinsic half-lives of articainic acid are: t1/2alpha 12 minutes, and t1/2beta 64 minutes (1 hour). In dentistry, articaine is the drug of choice in the vast majority of literature. In other regional anaesthesia techniques (intravenous regional anaesthesia, epidural, spinal and plexus blocks) there are not enough data to prove that (+/-) articaine is safer and more effective than the short-acting local anaesthetics lidocaine, (+/-) prilocaine or (+/-) mepivacaine.

Pharmacokinetics of enterolignans in healthy men and women consuming a single dose of secoisolariciresinol diglucoside.

High concentrations of enterolignans in plasma are associated with a lower risk of acute coronary events. However, little is known about the absorption and excretion of enterolignans. The pharmacokinetic parameters and urinary excretion of enterodiol and enterolactone were evaluated after consumption of their purified plant precursor, secoisolariciresinol diglucoside (SDG). Twelve healthy volunteers ingested a single dose of purified SDG (1.31 micromol/kg body wt). Enterolignans appeared in plasma 8-10 h after ingestion of the purified SDG. Enterodiol reached its maximum plasma concentration 14.8 +/- 5.1 h (mean +/- SD) after ingestion of SDG, whereas enterolactone reached its maximum 19.7 +/- 6.2 h after ingestion. The mean elimination half-life of enterodiol (4.4 +/- 1.3 h) was shorter than that of enterolactone (12.6 +/- 5.6 h). The mean area under the curve of enterolactone (1762 +/- 1117 nmol/L . h) was twice as large as that of enterodiol (966 +/- 639 nmol/L . h). The mean residence time for enterodiol was 20.6 +/- 5.9 h and that for enterolactone was 35.8 +/- 10.6 h. Within 3 d, up to 40% of the ingested SDG was excreted as enterolignans via urine, with the majority (58%) as enterolactone. In conclusion, a substantial part of enterolignans becomes available in the blood circulation and is subsequently excreted. The measured mean residence times and elimination half-lives indicate that enterolignans accumulate in plasma when consumed 2-3 times a day and reach steady state. Therefore, plasma enterolignan concentrations are expected to be good biomarkers of dietary lignan exposure and can be used to evaluate the effects of lignans.

Identical pattern of highly variable absorption of clavulanic acid from four different oral formulations of co-amoxiclav in healthy subjects.

The aims of this investigation were to calculate the pharmacokinetic parameters of amoxicillin and clavulanic acid, and to identify parameters that may affect their observed differences in absorption. Data were obtained from plasma concentration-time curves from four different open, randomized, two-treatment, two-period, two-sequence, crossover Phase I bioequivalence studies, with the following co-amoxiclav formulations: tablets 250/125, 500/125 and 875/125 mg, or 10 mL of an oral suspension 250/62.5 mg per 5 mL. Data from 144 subjects and 288 drug administrations were available for evaluation. After a 125 mg clavulanic acid dose (administered as potassium clavulanate) for all four different formulations, the clavulanic acid AUC(t) data ranged from 1.5 to 8 mg.h/L, varying by a factor of 5. The absorption of clavulanic acid was not related to the absorption of amoxicillin, or demographic factors, and we were unable to identify the reasons for the large variability in the absorption of clavulanic acid. We conclude that the absorption of clavulanic acid, after oral administration, is highly variable and may vary over a five-fold range between patients.