Pharmacokinetics Of Lidocaine Research Articles

Transient Oblong Anisocoria and Orbital Surgery

We present a rare case of transient oblong (segmental) anisocoria occurring at the time of limited orbital surgery. Observation of this previously undescribed phenomenon prompted us to review the relevant anatomy and physiology of the iris and the pharmacokinetics of lidocaine as it pertains to surgery in the region of the eyelids and the orbit.

296 Pharmacokinetics, Clinical Efficacy and Safety of Lidocaine in Asphyxiated Newborns Treated with Therapeutic Hypothermia

Background and AimsTherapeutic moderate hypothermia for neuroprotection in asphyxiated newborns can influence pharmacokinetics and pharmacodynamics. Lidocaine is administered if seizures persist despite initial therapy. Because cardiotoxicity is a potential risk...

The Local Pharmacokinetics of 3H-Ropivacaine and 14C-Lidocaine After Maxillary Infiltration Anesthesia in Rats

The effects of infiltration anesthesia with ropivacaine on the dental pulp are considered to be weak. This may be partly associated with its permeation into the oral tissue. With the objective of investigating the local pharmacokinetics of ropivacaine and lidocaine following infiltration anesthesia, we injected (3)H-ropivacaine or (14)C-lidocaine to the palatal mucosa in rats, measured distributions of radioactivity in the maxilla, and compared the local pharmacokinetics of these agents. The animals were sacrificed at various times and the maxillas were removed. The palatal mucosa and maxillary nerve were resected, and the bone was divided into 6 portions. We measured radioactivity in each tissue and calculated the level of each local anesthetic (n = 8). Lidocaine diffused to the surrounding tissue immediately after the injection, whereas ropivacaine tended to remain in the palatal mucosa for a longer period. Lidocaine showed a higher affinity for the maxillary bone than ropivacaine. There was a correlation between the distribution level of local anesthetics in the maxillary bone and that in the maxillary nerve. The lower-level effects of infiltration anesthesia with ropivacaine on the dental pulp may be because ropivacaine has a high affinity for soft tissue, and its transfer to bone is slight.

Pharmacokinetics of lidocaine and its active metabolite monoethylglycinexylidide after a single intravenous administration in chickens (Gallus domesticus) anesthetized with isoflurane

Pharmacokinetics of lidocaine and its active metabolite monoethylglycinexylidide after a single intravenous administration in chickens (<i>Gallus domesticus</i>) anesthetized with isoflurane

Pharmacokinetic Compatibility Study of Lidocaine with EXPAREL in Yucatan Miniature Pigs

We explored the potential for EXPAREL to interact with lidocaine. Sixty (60) male Yucatan Swine were randomized into 20 groups (N = 3/group). EXPAREL (2 or 4 mg/kg) and/or lidocaine HCl solution 1% or 2% (with epinephrine 1 : 200,000) were injected subcutaneously along a 5 cm virtual incision line. The effects on the pharmacokinetics of bupivacaine and lidocaine were examined when 5, 10, 20, and 40 minutes had passed between administration of lidocaine and EXPAREL. Systemic exposure to lidocaine was increased (AUC0−24 hr by 48%; C max by 1,640%) when lidocaine (4 mg/kg) was followed 5 minutes later by EXPAREL (4 mg/kg) compared to lidocaine administered alone. Plasma bupivacaine was increased (AUC0−24 hr by 50–95%; C max by 67–1,000%) when lidocaine (4 mg/kg) was followed 5 or 10 minutes later by EXPAREL (4 mg/kg) compared to EXPAREL alone. While EXPAREL should not be admixed with lidocaine, this study shows that local administration of EXPAREL after at least 20 minutes following local administration of lidocaine did not increase the release of either drug.

Pharmacokinetics of lidocaine after intravenous administration to cows

Journal of Veterinary Pharmacology and TherapeuticsVolume 35, Issue 3 p. 305-308 SHORT COMMUNICATION Pharmacokinetics of lidocaine after intravenous administration to cows S. COX, S. COX Department of Comparative Medicine, College of Veterinary Medicine, University of Tennessee, River Drive, Knoxville, TN, USASearch for more papers by this authorJ. WILSON, J. WILSON Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, River Drive, Knoxville, TN, USA Present address: Matthew J. Ryan Hospital for Small Animals, 3900 Spruce Street, Philadelphia, PA 19104, USA.Search for more papers by this authorT. DOHERTY, T. DOHERTY Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, River Drive, Knoxville, TN, USASearch for more papers by this author S. COX, S. COX Department of Comparative Medicine, College of Veterinary Medicine, University of Tennessee, River Drive, Knoxville, TN, USASearch for more papers by this authorJ. WILSON, J. WILSON Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, River Drive, Knoxville, TN, USA Present address: Matthew J. Ryan Hospital for Small Animals, 3900 Spruce Street, Philadelphia, PA 19104, USA.Search for more papers by this authorT. DOHERTY, T. DOHERTY Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, River Drive, Knoxville, TN, USASearch for more papers by this author First published: 11 August 2011 https://doi.org/10.1111/j.1365-2885.2011.01328.xCitations: 8 Sherry Cox, Departments of Comparative Medicine, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA. E-mail: [email protected] Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume35, Issue3June 2012Pages 305-308 RelatedInformation

Lidocaine (Lignocaine) Dosing Regimen Based upon a Population Pharmacokinetic Model for Preterm and Term Neonates with Seizures

The application of lidocaine (lignocaine) as an anticonvulsant in neonates originated more than 40 years ago in Scandinavia. Lidocaine has been shown to be an effective anticonvulsant for the treatment of neonatal seizures that persist in spite of first-line anticonvulsant therapy. However, lidocaine toxicity, mainly in the form of cardiac arrhythmias, can be life threatening. Therapeutic drug monitoring can be useful to prevent toxicity. In a previous study, a dosing regimen was developed for term neonates, but it was not evaluated for preterm neonates. Extrapolation of the previously developed dosing regimen to premature neonates without accounting for differences in pharmacokinetics because of immaturity of phase I metabolism and body fat/water ratio may result in serious toxicity or therapy failure. The objective of this study was to develop an optimized dosing regimen for lidocaine in preterm as well as term neonates, using population pharmacokinetic modelling and simulation. The requirements for this dosing regimen were simplicity of implementation, equal initial doses for all weight categories and avoidance of plasma concentrations >9 mg/L. After lidocaine administration, blood samples were collected from an arterial line from a total of 46 preterm and term neonates with convulsion, within 10 days after birth. Lidocaine concentrations were measured in plasma using a fluorescence polarization immunoassay. Population pharmacokinetic modelling started with assessment of two important aspects of paediatric pharmacokinetics: relation to body size and the effects of maturation. In the studied neonatal population (term and preterm neonates with gestational ages up to 10 days), gestational age and bodyweight were closely related. Therefore, the effects of allometry and maturation on lidocaine pharmacokinetics could not be described independently and were described by a combined power estimate of bodyweight on clearance and volume of distribution. Based on this pharmacokinetic model, a dosing strategy for lidocaine for neonatal seizure control was developed, which allows rapid and safe administration of lidocaine in this population. When prospective validation confirms our model, routinely performed therapeutic drug monitoring should no longer be necessary and would only be advised in cases of (suspected) clinical symptoms of over- or underdosing. A lidocaine dosing regimen for seizure control in preterm and term neonates has been developed using population pharmacokinetic modelling and simulation. Allometry and maturation exponents were combined into one exponent for each pharmacokinetic parameter and could not be described independently. Based on this model, this regimen allows rapid and safe administration of lidocaine in this population.

Population Pharmacokinetics of Lidocaine Administered During and After Cardiac Surgery

The objective of this study was to determine the pharmacokinetics of lidocaine in a 48-hour infusion in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). A retrospective substudy of a clinical trial assessing the efficacy of intravenous lidocaine for postoperative cognitive decline. A university hospital. Ninety-nine patients undergoing cardiac surgery with CPB. After the induction of anesthesia, lidocaine was administered as a bolus of 1 mg/kg and followed by a continuous infusion at 4 mg/min for the 1st hour, 2 mg/min for the 2nd hour, and 1 mg/min for the next 46 hours. Blood samples were taken at baseline, the end of CPB, and 24 and 48 hours after CPB for the measurement of the plasma concentration of lidocaine. Lidocaine levels increased significantly over time despite a constant rate of infusion (p < 0.05). The pharmacokinetics of lidocaine was best described by a 2-compartment model, and body weight was found to be a significant factor for the volume of the central compartment and clearance. The final pharmacokinetic parameters were V(1)(L) = 0.0619*weight, V(2)(L) = 187, CL(1) (L/min) = 0.00419*weight, and CL(2) (L/min) = 8.92. A 2-compartment pharmacokinetic model best describes the plasma concentrations of a 48-hour lidocaine infusion in patients undergoing cardiac surgery with CPB. The inclusion of body weight as a covariate on clearance and central compartment improves the model. Lidocaine infusions should be dosed by body weight and decreased after 24 hours to avoid potential toxicity in long-term infusions.

Pharmacokinetics of Lidocaine, Bupivacaine, and Levobupivacaine in Plasma and Brain in Awake Rats

We have compared the pharmacokinetics and brain distribution of lidocaine, racemic bupivacaine (bupivacaine), and levobupivacaine in awake, spontaneously breathing rats. Lidocaine (0.5 mg x kg x min), bupivacaine (0.1 mg x kg x min), or levobupivacaine (0.1 mg x kg x min) was continuously administered to rats for 2 h (n = 12, each anesthetic). Blood samples and cerebral dialysate were collected during infusion and for 2 h after termination of infusion. Concentrations of anesthetics in the cerebral extracellular fluid were measured by microdialysis using the retrodialysis calibration method. Tissue-to-plasma partition coefficients calculated from the total (protein-bound and unbound) and unbound concentrations in plasma and brain as well as pharmacokinetic parameters in plasma and cerebral extracellular fluid were compared among the three anesthetics. There were no differences in plasma total or unbound concentrations between bupivacaine and levobupivacaine. Concentrations of bupivacaine in the cerebral extracellular fluid were significantly higher than levobupivacaine (P < 0.001). Despite no differences in the ratio of total brain concentration to total plasma concentration among the three anesthetics, the ratio of cerebral extracellular fluid concentration to plasma unbound fraction of bupivacaine was significantly higher than lidocaine and levobupivacaine (0.58 +/- 0.09, 0.47 +/- 0.18, and 0.40 +/- 0.09, respectively; P = 0.03 and 0.003, respectively). Although the ratio of total brain concentration to total plasma concentrations of lidocaine, bupivacaine, and levobupivacaine was similar, concentration ratio of bupivacaine in the cerebral extracellular fluid to plasma unbound fraction was significantly higher than lidocaine and levobupivacaine.

Airway topicalisation using atomisation of lidocaine

We read the recent article of Woodruff et al. [1] with interest. A major advantage of the atomisation with lidocaine used in this study is the rapidity with which the airway can be anaesthetised, but this is achieved at the expense of administration of a large dose over a short time (about 5 min). We have concerns over the safety of this topicalisation method in general clinical practice, particularly when the drug is rapidly administered to non-obese patients. The British Thoracic Society has recommended a maximum lidocaine dosage of 8.2 mg.kg−1 for airway topical anaesthesia during bronchoscopy [2], but these drugs are administered in fractional doses at different sites in the airway over a prolonged time period. Compared with a large dose used in a shorter time, fractional doses sprayed over a longer period result in a lower plasma drug level [3]. Moreover, we do not agree that a large dose of lidocaine is safe in routine clinical practice for two reasons. First, lidocaine pharmacokinetics are complex, being affected by many factors, so the plasma lidocaine concentration achieved in a particular patient is often unpredictable. Even with recommended doses, patients may still sometimes achieve an unexpectedly high plasma concentration [4]. After large doses of lidocaine (7.1–14.8 mg.kg−1) administered by a spray-as-you-go technique, 36–92% of subjects report symptoms attributable to lidocaine toxicity [5, 6]. In addition, a healthy volunteer has died from lidocaine toxicity after fibreoptic bronchoscopy [7]. Second, lidocaine toxicity can occur even when the plasma lidocaine levels are in a ‘safe’ range [3, 8]. The authors suggest that airway topicalisation using nebulisation requires a long preparation time and may interfere with rapid turnover of patients. However, this technique can be safely performed in the holding area. We would also like to call the authors’ attention to the two papers in which low doses of nebulised lidocaine (100 or 160 mg) achieved adequate airway anaesthesia in most patients [9, 10]. We appreciate the reference to our recent article [3], but believe that Woodruff et al. have misrepresented our time (> 20 min) for airway topicalisation. As the main aim of our study was to compare the safety and efficacy of 2% and 4% lidocaine to produce airway topical anaesthesia with a spray-as-you-go technique, the repeated lidocaine sprays in the airway were performed at a 3–5 min interval to provide adequate penetration of local anaesthetic into the mucosa for maximal effect, and the whole airway topicalisation protocol required 19.2–28.2 min. The authors think that this prolonged time for airway topicalisation may sometimes be unacceptable. However, we feel that, as with other local anaesthetic methods, ‘tincture of time’ is a useful supplement to the application of airway topical anaesthesia. Inadequate airway topical anaesthesia due to the slow onset of the maximal effect can often result in larger doses' being given or repeated drug delivery in a short time, leading to overdose.

Pharmacokinetics of lidocaine in serum and milk of mature Holstein cows

The purpose of this study was to evaluate the pharmacokinetics of lidocaine in mature Holstein cows following an inverted L and caudal epidural nerve block. Plasma and milk concentrations were determined using high-performance liquid chromatography assay. Pharmacokinetic parameters were estimated using a noncompartmental method. Following administration via inverted L nerve block, serum T(max) was 0.521 +/- 0.226 h and serum C(max) was 572 +/- 207 ng/mL. Serum AUC was 1348 +/- 335 ng.h/mL. Apparent serum t((1/2)beta) was 4.19 +/- 1.69 h and MRT was 5.13 +/- 2.33 h with clearance uncorrected for the extent of absorption of 2.75 +/- 0.68 L/kg/h. The last measurable time of lidocaine detection in serum was 8.5 +/- 1.4 h with a mean concentration of 51 +/- 30 ng/mL. Milk T(max) was detected at 1.75 +/- 0.46 h with C(max) of 300 +/- 139 ng/mL. Milk AUC till the last time was 1869 +/- 450 ng.h/mL with the mean AUC milk to AUC serum ratio of 1.439 +/- 0.374. The last measurable time of lidocaine detection in milk was 32.5 +/- 16.2 h with a mean concentration of 46 +/- 30 ng/mL. There was no detectable lidocaine concentration in any samples following caudal epidural administration.

Pharmacokinetics of Anorectal Nifedipine and Lidocaine (Lignocaine) Ointment following Haemorrhoidectomy

This study aimed to assess whether topical anorectal application of an ointment containing nifedipine (0.3% w/w) and lidocaine (lignocaine) [1.5% w/w] to patients undergoing Milligan-Morgan haemorrhoidectomy achieves pharmacologically relevant serum concentrations of the active ingredients and has any haemodynamic effects or adverse effects. A single dose of 3 g of study ointment was circumferentially applied inside the anus to 24 patients (17 males and 7 females) aged 23-71 years (mean +/- SD: 42.9 +/- 4.9 years) during postoperative dressing after Milligan-Morgan haemorrhoidectomy from March 2007 to January 2008. Blood samples for the determination of nifedipine and lidocaine serum concentrations were drawn before surgery and at 20, 40, 60, 90, 120, 240, 360, 480 and 720 minutes after application. Serum concentrations of nifedipine and lidocaine were determined by a high-performance liquid chromatography method in order to calculate pharmacokinetic parameters. Patients' BP, heart rate and ECG readings were monitored during the study. Chromatographic signals of nifedipine were sporadically observed in only five patients (20.8%), consistent with therapeutically negligible concentrations and insufficient to permit calculation of any pharmacokinetic parameters. The serum concentrations of nifedipine in these five patients ranged from 5.9 to 18.8 ng/mL. Lidocaine concentrations were detectable in all patients. The means +/- SD and medians of pharmacokinetic parameters for lidocaine were as follows: maximum serum concentration (C(max)) 245.1 +/- 370.8 ng/mL, 73.6 ng/mL; time to reach C(max) (t(max)) 69.2 +/- 78.3 minutes, 40 minutes; area under the serum concentration-time curve from 0 to 6 hours (AUC(6)) 756.5 +/- 1254.1 ng.h/mL, 238.2 ng.h/mL. Only three patients had maximum serum concentrations above 1000 ng/mL (1037.8, 1044.75 and 1364.1 ng/mL). These outlier concentrations were four to five times lower than the threshold of CNS lidocaine toxicity (5000-6000 ng/mL). No serious local or systemic adverse events were observed throughout the study, and no subjects developed arrhythmias or significant ECG changes. Neither BP nor mean heart rate varied significantly after application of a single dose. This study demonstrates that single-dose topical application of an ointment containing nifedipine (0.3% w/w) and lidocaine (1.5% w/w) to patients undergoing Milligan-Morgan haemorrhoidectomy is safe to use. Following application onto damaged anorectal mucosa, nifedipine and lidocaine are absorbed into the bloodstream in small quantities that do not have any major implications for the safety of the product. Further studies are required to evaluate nifedipine and lidocaine concentrations in serum using a multiple-dose regimen.

Pharmacokinetics of lidocaine and its metabolite in peridural anesthesia administered to pregnant women with gestational diabetes mellitus

Peridural blockade with lidocaine, bupivacaine, and fentanyl is an anesthetic procedure extensively used in obstetrics, justifying the pharmacokinetic study of these drugs during labor. To investigate the influence of the physiopathological changes of gestational diabetes mellitus (GDM) on the pharmacokinetics of lidocaine and its metabolite monoethylglycinexylidide (MEGX) in pregnant women subjected to peridural anesthesia. Ten normal pregnant women (group 1) and six pregnant women with GDM (group 2) were studied, all of them at term. The patients received 200 mg 2% lidocaine hydrochloride without a vasoconstrictor by the peridural locoregional route. Maternal blood samples were collected at predetermined times for the analysis of lidocaine and MEGX by chromatography and pharmacokinetic analysis. The median pharmacokinetic parameters of lidocaine for groups 1 and 2 (P </= 0.05), respectively, were as follows: for Cmax 879.11 and 1,145.58 ng/ml, AUC(0-infinity) 256.01 and 455.95 mug min(-1) ml(-1), Cl/f/kg 10.61 and 5.64 ml min(-1) kg(-1), and Vd/f/kg 3.26 and 2.19 L/kg. The median pharmacokinetic parameters of MEGX for groups 1 and 2 (P </= 0.05), respectively, were as follows: for Cmax 82.71 and 141.38 ng/ml, Tmax 44.71 and 193.14 min, t(1/2)alpha 7.64 and 59.77 min, alpha 0.097 and 0.012/min, and AUC(0-infinity) 29.91 and 108.23 mug min(-1) ml(-1). The present data permit us to conclude that the apparent clearance of lidocaine and MEGX was reduced in diabetic patients compared to normal women, suggesting that GDM inhibits the CYP1A2/CYP3A4 isoforms responsible for the metabolism of this drug and its metabolite.

Procaine Spinal Neurotoxicity

THE rare but devastating complication of cauda equina syndrome (CES) after spinal anesthesia has been reported with several local anesthetics, most frequently lidocaine. 1 A separate complication of spinal anesthesia, transient neurologic syndrome (TNS), consisting of potentially severe but transient lumbosacral pain, has also been reported and is also most frequent with lidocaine. 2 The mechanism of CES from local anesthesia is most likely necrotic or apoptotic neuronal death, depending on the intensity of the local anesthetic exposure. 3 The mechanism of TNS is unknown but seems to be distinct from that of CES. 4,5 Lidocaine's pharmacokinetics are ideal for spinal anesthesia for short-duration, ambulatory surgery. The increased frequency of CES and TNS with lidocaine has encouraged the study of other local anesthetics to substitute for lidocaine, without complete success. 6-8 Procaine has been reported to be less likely to produce TNS than lidocaine, with a kinetic profile also suitable for short-duration surgery. 9,10 However, there has been no modem study of procaine and CES. We now report a case of permanent CES after procaine spinal anesthesia.

Pharmacokinetics of lidocaine following the application of 5% lidocaine patches to cats

Lidocaine patches have been used to provide local analgesia in dogs and cats. We conducted this study to assess the systemic and local absorption of lidocaine from topical patches in cats. Eight 2-year-old cats received either intravenous lidocaine at 2 mg/kg or one 700 mg lidocaine patch placed on the lateral thorax for 72 h, in a cross-over randomized repeated measures design. Plasma was collected at specific times and the skin was biopsied at the time of patch removal for the quantitative analysis of lidocaine and its major metabolite, monoethylglycinexylidide (MEGX), by gas chromatography with mass spectrometry. Percent absorption time plots for systemic lidocaine appearance were constructed using the Loo-Riegelman method. Approximately, constant rate absorption was observed from 12-72 h after patch application at a mean +/- SD rate of 109 +/- 49 microg/kg/h, resulting in steady-state lidocaine plasma concentrations of 0.083 +/- 0.032 microg/mL and MEGX concentrations of 0.012 +/- 0.009 microg/mL. Overall bioavailability of transdermal lidocaine was 6.3 +/- 2.7%, and only 56 +/- 29% of the total lidocaine dose delivered by the patch reached systemic circulation. Skin lidocaine concentrations were much higher than plasma concentrations, at 211 +/- 113 microg/g in the thoracic skin beneath the patch and 2.2 +/- 0.6 microg/g in the contralateral thoracic skin without the patch. As both lidocaine and MEGX were recovered from contralateral skin, it is likely that lidocaine accumulated in the skin from low systemic concentrations of circulating lidocaine over the 72-h period of patch application. Plasma lidocaine concentrations remained well below systemically toxic concentrations, and no obvious clinical side effects were observed in any of the cats. The low systemic absorption rate coupled with high local lidocaine concentrations on the skin support the safe use of lidocaine patches in cats.

Intoxication néonatale à la lidocaïne après analgésie par bloc des nerfs honteux : à propos de trois observations

Pudendal nerve block may be indicated during instrumental delivery in situations where peridural anesthesia is unavailable. We report three cases of neonatal lidocaine intoxication following maternal pudendal block during delivery. Clinical features were hypotonia, pupillary mydriasis fixed to light, apnea, cyanosis and seizures. Two neonates required mechanical ventilation. Lidocaine was found in the serum of two babies. In all three cases, recovery was complete. The pharmacokinetics of lidocaine in a highly vascularized perineum during labor increase the risk of neonatal intoxication. A possible intoxication by local anesthetics should be considered in neonates presenting an acute distress in the delivery room.

Differential effect of chronic renal failure on the pharmacokinetics of lidocaine in patients receiving and not receiving hemodialysis

The effect of chronic renal failure (CRF) on the pharmacokinetics of lidocaine, a drug cleared almost exclusively by hepatic metabolism, has thus far only been evaluated in patients undergoing regular hemodialysis. This study had 2 objectives: (1) to investigate the effect of CRF on the pharmacokinetics of lidocaine in both patients undergoing hemodialysis and patients not undergoing hemodialysis and (2) to test the effects of plasma from the patients examined and of lidocaine metabolites possibly accumulated in vivo on lidocaine biotransformation in vitro. In a clinical investigation we studied the kinetics of lidocaine and its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), after intravenous injection of 1 mg/kg lidocaine in 15 healthy volunteers (creatinine clearance [CL(cr)] >80 mL/min x 1.73 m(-2)), 10 subjects with moderate renal insufficiency (CL(cr) between 30 and 60 mL/min x 1.73 m(-2)), 10 subjects with severe renal insufficiency (CL(cr) <30 mL/min x 1.73 m(-2)), and 10 functionally anephric patients undergoing long-term hemodialysis. In experiments in vitro we determined the effects of plasma and GX on the formation rate of the primary lidocaine metabolite, MEGX, by use of human liver microsomes. In patients not undergoing hemodialysis, lidocaine kinetic parameters were altered in proportion to the degree of renal function impairment, but only in patients with severe renal insufficiency were differences statistically significant: clearance was about half that of control subjects (mean +/- SD, 6.01 +/- 2.54 mL/min x kg versus 11.87 +/- 2.97 mL/min x kg; P < .001), and half-life was approximately doubled (4.55 +/- 1.71 hours versus 2.24 +/- 0.55 hours, P < .001). No such alterations were observed in patients undergoing regular hemodialysis, whose values were similar to those of the control group. The steady-state volume of distribution and MEGX levels were independent of renal function, whereas GX levels were more than double those of control subjects (P < .05) in all CRF groups. No inhibitory effect of plasma was observed, for any of the subjects examined, on lidocaine biotransformation in vitro. GX was found to be a competitive inhibitor, but its apparent inhibition constant value (52 +/- 6 micromol/L) was 2 orders of magnitude higher than its concentrations in vivo. Our in vivo findings have both clinical and methodologic implications: (1) Lidocaine dose adjustment may be required in patients with severe renal insufficiency who are not receiving hemodialysis. (2) Results of studies evaluating the effect of CRF on metabolic drug disposition are not of general validity, unless both patients undergoing hemodialysis and patients not undergoing hemodialysis have been examined. Our in vitro observations exclude that impairment of lidocaine disposition is the result of direct inhibition of metabolizing enzymes by accumulated metabolites or uremic toxins. Alternative mechanisms, suggested by the results of recent in vitro studies, are discussed.

The disposition of lidocaine during a 12‐hour intravenous infusion to postoperative horses

Lidocaine is administered as an intravenous infusion to horses for a variety of reasons, but no study has assessed plasma lidocaine concentrations during a 12-h infusion to horses. The purpose of this study was to evaluate the plasma concentrations and pharmacokinetics of lidocaine during a 12-h infusion to postoperative horses. A second purpose of the study was to evaluate the in vitro plasma protein binding of lidocaine in equine plasma. Lidocaine hydrochloride was administered as a loading dose, 1.3 mg/kg over 15 min, then by a constant rate IV infusion, 50 microg/kg/min to six postoperative horses. Lidocaine plasma concentrations were measured by a validated high-pressure liquid chromatography method. One horse experienced tremors and collapsed 5.5 h into the study. The range of plasma concentrations during the infusion was 1.21-3.13 microg/mL. Lidocaine plasma concentrations were significantly increased at 0.5, 4, 6, 8, 10 and 12 h compared with 1, 2 and 3 h. The in vitro protein binding of lidocaine in equine plasma at 2 microg/mL was 53.06+/-10.28% and decreased to 27.33+/-9.72% and 29.52+/-6.44% when in combination with ceftiofur or the combination of ceftiofur and flunixin, respectively. In conclusion, a lower lidocaine infusion rate may need to be administered to horses on long-term lidocaine infusions. The in vitro protein binding of lidocaine is moderate in equine plasma, but highly protein bound drugs may displace lidocaine increasing unbound concentrations and the risk of lidocaine toxicity.

Lidocaine pharmacokinetics in postmenopausal women on hormone therapy

The study was designed to evaluate the effect of hormone therapy (HT) preparations containing 17beta-estradiol and micronized progesterone administered orally and transdermally on the pharmacokinetics of lidocaine, a probe drug that is metabolized by liver oxidative pathways involving cytochrome P-450 1A2 and 3A4 (CYP1A2 and CYP3A4). The study was carried out in 18 postmenopausal women divided into two groups administered HT for 6 months: group 1, 17beta-estradiol (orally) and micronized progesterone sublingually; and group 2, 17beta-estradiol (transdermally) and micronized progesterone sublingually. Pharmacokinetic study with intravenous lidocaine (1 mg/kg) and blood sampling during 360 minutes from injection was performed before the HT initiation and after 3 and 6 months of HT. Pharmacokinetic parameters of lidocaine demonstrated accelerated drug elimination in women on oral HT after 3 months. A significant reduction of area under the curve by 15.0% (P < 0.05), shortening of t(1/2) by 15.2% (P < 0.05), increase of lambda(z) by 10.0% (P < 0.05), and Cl/BW by 14.3% (P < 0.05) were observed. In contrast, transdermal administration of HT did not influence pharmacokinetic parameters of the drug. The effects of oral HT were not seen 6 months after the start of HT. HT can influence the pharmacokinetics of lidocaine, ie, its hepatic metabolism, through CYP3A4 and CYP1A2. The effect depends on the route of administration and therapy duration.

Effect of Fluvoxamine and Erythromycin on the Pharmacokinetics of Oral Lidocaine

Lidocaine is metabolized by cytochrome P450 3A4 (CYP3A4) and CYP1A2 enzymes, but inhibitors of CYP3A4 have had only a minor effect on its pharmacokinetics. We studied the effect of co-administration of fluvoxamine (CYP1A2 inhibitor) and erythromycin (CYP3A4 inhibitor) on the pharmacokinetics of lidocaine in a double-blind, randomized, three-way cross-over study. Eight healthy volunteers ingested daily either 100 mg fluvoxamine and placebo, 100 mg fluvoxamine and 1500 mg erythromycin, or their corresponding placebos (control) for five days. On day 6, 1 mg/kg lidocaine was administered orally. Plasma concentrations of lidocaine, monoethylglycinexylidide (MEGX) and 3-hydroxylidocaine (3-OH-lidocaine) were measured for 10 hr. During the fluvoxamine phase the area under the plasma concentration-time curve (AUC) and peak concentration (Cmax) of oral lidocaine were 305% (P<0.001) and 220% (P<0.05) of the control values. During the combination of fluvoxamine and erythromycin, lidocaine AUC was 360% (P<0.001) and Cmax 250% (P<0.05) of those during placebo. Fluvoxamine alone had no statistically significant effect on the half-life of lidocaine (t1/2), but during the combination phase t1/2 (3.8 hr) was significantly longer than during the placebo phase (2.4 hr; P<0.01). Fluvoxamine alone and in the combination with erythromycin decreased MEGX peak concentrations by approximately 50% (P<0.001) and 30% (P<0.01), respectively. We conclude that inhibition of CYP1A2 by fluvoxamine considerably reduces the presystemic metabolism of oral lidocaine and may increase the risk of lidocaine toxicity if lidocaine is ingested. The concomitant use of both fluvoxamine and a CYP3A4 inhibitor like erythromycin may further increase plasma lidocaine concentrations.