Reduction of Oral Bioavailability of Lignocaine by Induction of First Pass Metabolism in Epileptic Patients

Br. J. clin. Pharmac. (1979), 8, 21-31

REDUCTION OF ORAL BIOAVAILABILITY OF LIGNOCAINE BY INDUCTION OF FIRST PASS METABOLISM IN EPILEPTIC PATIENTS

E. PERUCCA & A. RICHENS Department of Clinical Pharmacology, St Bartholomew's Hospital, London EClA 7BE, and the National Hospitals-Chalfont Centre for Epilepsy, Chalfont St Peter, Bucks

1 The pharmacokinetics of lignocaine following single oral and intravenous doses have )een investigated in six normal volunteers and in six patients receiving chronic antiepile tic drug therapy. 2 After intravenous administration, serum lignocaine levels declined biexponentially in all subjects. The serum clearance (mean + s.d.) was slightly higher in the patients (0.85 + 0.09 v 0.77 + 0.07 1/min) but the difference was not statistically significant. 3 Lignocaine bioavailability after oral administration was more than two-fold lower in the patients than in the normal subjects (0.15 +0.06 v 0.37 +0.09, P < 0.001). 4 It is suggested that the reduced bioavailability of lignocaine in the patients is a consequence of stimulation of hepatic first-pass metabolism by antiepileptic drugs.

Introduction The perfusion limited pharmacokinetic model with enzyme-inducing agents. Lignocaine is almost (Gibaldi, Boyes & Feldman, 1971; Rowland, 1972; ideal as a model drug because (i) it is subject to high Rowland, Benet & Graham, 1973; Wilkinson, 1975; hepatic clearance in man, as indicated by a high liver Wilkinson & Shand, 1975) has recently been extraction ratio (Stenson, Constantino & Harrison, successfully applied to describe the disposition 1971) and evidence of extensive first-pass metabolism kinetics of high clearance drugs such as nortriptyline on oral administration (Boyes, Scott, Jebson, (Alvin, BorgA, Lind, Palmer & Siwers, 1977), Godman & Julian, 1971; Bending, Bennett, Rowland alprenolol (Alvan, Piafsky, Lund & von Bahr, 1977) & Steiner, 1976); (ii) it is metabolized by an and paracetamol (Perucca & Richens, 1978) in man. enzymatic system in the liver which involves the According to this model, the systemic clearance of mixed function oxidase (Hollunger, 1960; K^enaghan drugs subject to high hepatic extraction is mainly & Boyes, 1972; von Bahr, Fellenius 8' Ft .d, 1972; determined by the rate of liver blood flow (LBF) and Strong, Parker & Atkinson, 1973) and which is only marginally influenced by changes in the activity induced by phenobarbitone treatment the dog (Di of the hepatic drug metabolizing enzymes. On the Fazio & Brown, 1972); (iii) it has been previously other hand, when these drugs are administered orally, selected to test the perfusion limited model in animal the fraction of the dose which escapes first-pass studies (Branch, Shand, Wilkinson & Nies, 1973; metabolism in the liver and reaches the systemic Benowitz, Forsyth, Melmon & Rowland, 1974a; circulation is not limited by LBF and is totally Benowitz, Forsyth, Melmon & Rowland, 1974b; dependent on the intrinsic metabolic activity of the Rane, Wilkinson & Shand, 1977) and (iv) it is organ (Perrier & Gibaldi, 1974) or intrinsic clearance relatively safe at the plasma concentrations achieved as defined by Wilkinson & Shand (1975). It follows in our subjects. This study adds further information that induction of the hepatic microsomal enzymes to the question of lignocaine bioavailability on oral will have negligible effects on the disposition of these administration. drugs after intravenous administration but will result in marked reduction ofbioavailability (Meikle, Jubiz, Matsukura, West & Tyler, 1969; Alvan et al., 1977) Methods and steady state plasma levels (Alvan, Lund, Mellstr6m & von Bahr, 1977) on oral administration. Experimental design In the present study the perfusion limited model has been applied to describe the pharmacokinetics of Six healthy subjects and six epileptic patients, resident the local anaesthetic and antidysrhythmic drug, at the National Hospitals-Chalfont Centre for lignocaine, in normal subjects and in patients treated Epilepsy, gave their informed consent to participate 0306-5251/79/070021-11 $01.00 0 5 0 $ Macmillan Journals Ltd 1979 22 E. PERUCCA & A. RICHENS

in the study. Age, body weight and sex distribution experiment but a small cup ofweak tea was permitted were similar in the two groups (Table 1). None of the after 2 h. healthy subjects was taking any drug with the Blood samples (4 ml) were collected at 15, 30, 45, exception of AT who was occasionally taking 60, 90, 120, 150, 180, 210 and 240 min after dosing. lorazepam (4 mg) at night. One patient was treated Additional samples were collected 3 and 8 min when with phenytoin alone (450 mg daily). The remaining the drug was injected intravenously. The serum was five patients were receiving long-term treatment with kept frozen at - 20'C until analysed for lignocaine a combination of at least two of the following drugs: concentration within 1 week. phenobarbitone, primidone, phenytoin and carba- The implications of the study were explained to mazepine (Table 1). All these agents are potent each of the patients and volunteers, and the protocol inducers of the hepatic microsomal enzymes was approved by a local Ethics Committee. (Richens, 1976). Prior to admission to the trial an electrocardiogram (ECG) was carried out in each of the subjects. No abnormalities were found. Each subject received in random order, and separated by Analytical methods an interval of approximately one week, a single oral dose of 750 mg lignocaine monohydrate and a single The serum concentration of lignocaine was deter- intravenous dose of 100 mg lignocaine hydrochloride mined in duplicate by enzyme-immunoassay (EMIT, (Xylocard, 2%, Astra). The oral dose (equivalent to Syva) using a Syva-pipetter-diluter model 1500 and a 608 mg lignocaine base) was administered in aqueous Gilford 300-N spectrophotometer connected to a solution (25 mg/ml) and was considered optimal for Syva timer-printer model 2400. Serum standards were the purposes of the study after preliminary experi- made up containing from 0.4 to 8.5 pmol/l of ments in which the serum concentration of lignocaine lignocaine. An approximately six-fold increase in the was measured following different oral doses. The sensitivity of the method was obtained by omitting intravenous dose (equivalent to 86 mg base) was one ofthe two initial sample dilutions described in the given into an antecubital vein over 2.5 min. On both standard procedure (Syva Corporation, 1977). Apart occasions the drug was administered at approxi- from this modification, samples were analysed mately 08.00 h after an overnight fast. The subjects according to the manufacturer's instructions. The were kept supine during the injection and remained in difference between the absorbance reading of each of a sitting position for most of the duration of the the standards and the average absorbance reading of experiment. Food was not allowed during the the zero calibrator (AA-AA0) was plotted on the

Table 1 Details of subjects included in the study

Healthy subjects Sex Age Drug treatment (years) (mg/day) AT F 36 Lorazepam 4 GM M 21 MD F 25 GS F 28 TT M 19 KE F 21 Mean 25 s.d. 6 Epileptic patients JK M 37 DPH 450 AW F 27 DPH 200 Pb 90 PC M 27 DPH 100 C 800 Diazepam 20 EW F 27 DPH 300 Pb 240 DT M 31 DPH 300 Pmd 750 SV 800" SH F 22 DPH 400 Pmd 500 Mean 28 s.d. 5 DPH = phenytoin, C = carbamazopine, Pb = phenobarbitone, Pmd = primidone, SV = sodium valproate, **+pericyazine 15. FIRST PASS METABOLISM OF LIGNOCAINE 23 appropriate graph paper supplied with the reagent The oral availability (F) was calculated as kit, allowing for the shift in concentration due to the AUCoMI/AUCiv corrected for the difference in dose. omission of the dilution step. Samples containing The systemic serum clearance (Cl,) and the volume of more than 8.5 pmol/l were diluted prior to distribution (Vdfi) were calculated from intravenous estimation. data according to the formulae (Gibaldi, Nagashima Within assay variability was found to be 3.2% and & Levy, 1969; Rowland, 1972): 7.9% (coefficient of variation) for serum samples containing 1.1 and 8.5 pmol/l respectively (n =10). Cl4 = Dose/AUC,v and Vd/) = Dose/(AUCjvv). Day-to-day variability estimated for a sample The serum clearance was converted to blood containing 2.4 gmol/l was found to be 6.5% (n = 10). clearance (Cl) by using a conversion factor A No interference with the assay was found with (= concentration of lignocaine in whole blood: carbamazepine (40 pmol/1), phenobarbitone in (340 jsmol/l), phenytoin (120 pmol/l) and primidone concentration of lignocaine serum) (Rowland, (92 jmol/l). Interference by monoethylglycine- 1972): xylidide (MEGX) and glycinexylidide (GX) A = PCV/K + (I -PCV) (2) was not tested. However, the cross-reactivity of the Where PCV is the packed cell volume and K the antiserum with the metabolites is reported to be partition coefficient for lignocaine between serum negligible (Syva Corporation, 1977), concentrations and red cells. A K value of 1.6 was used (Tucker & above 150 jmol/l for MEGX and above 560 pimol/l Mather, 1975). for GX being necessary to produce a 30% The hepatic blood clearance (Clh) was calculated measurement error in a sample containing as: 13.0 j±mol/l of lignocaine (Chang & Bastiani, 1977). Clh = C'-Clt After oral administration oflignocaine in man, serum (3) MEGX levels are comparable to those of the parent Where Clr is the renal clearance of unchanged drug (Adjepon-Yamoah & Prescott, 1973; Bending et lignocaine which equals fu x Cl, where fu is the al., 1976); lower MEGX concentrations are found fraction of the intravenous dose excreted unchanged after intravenous lignocaine (Bending et al., 1976). in the urine. An average value for fu of 0.01 (for Serum levels of GX after oral and parenteral normal conditions of urinary pH) was assigned from administration are reported to be lower than those of the literature (Lalka, Manion, Berlin, Baer, Dodd & MEGX (Adjepon-Yamoah & Prescott, 1973). Meyer, 1976). Equation 3 assumes that lignocaine metabolism is exclusively hepatic. Pharmacokinetic analysis The hepatic blood flow (LBF) was calculated The decline of the serum concentration of lignocaine according to the relationship (Wilkinson & Shand, after intravenous administration can be adequately 1975): described by a two compartment open model (Boyes LBF = Clh/E (4) et al., 1971; Rowland, Thompson, Guichard & Melmon, 1971). According to this model, at time t Where E is the hepatic excretion ratio. The latter was after a single intravenous dose, the serum concen- estimated by the relationship E = 1-F, which tration is given by the equation: assumes complete absorption and first order kinetics. Ct Equation 4 was also used to predict the oral t = A.e-"t+B.e-t availability from intravenous data, assuming a liver where a and ,B are the rate constants of the initial blood flow of 1.5 I/min (Wilkinson & Shand, 1975). rapid and terminal slower phase respectively and A The intrinsic clearance (Clint) was estimated accord- and B the contribution of the corresponding ing to Wilkinson & Shand (1975) as: exponentials at t = 0. The 1 slope was obtained by = A (5) linear regression from the terminal part of the serum Clin, DoseO,,/AUC.., concentration curve and extrapolated back to zero This term, which equals LBF E/I - E (or in terms of time. The a slope was calculated by linear regression Michaelis-Menten kinetics the ratio V,.,.,/Km) as- from the values obtained after subtracting the ,B slope sumes that absorption is complete and that to the serum concentration ofthe early samples. Half- elimination is exclusively by hepatic metabolism. lives (Tia and T /) were obtained by the relation- shipsT:a = 0.693/a and Tip = 0.693/f. Areas under the serum concentration curves (AUC) were es- Results timated by the trapezoidal rule and extrapolated to infinity by the relationship Ct,/f) where Ct. is the Adverse effects concentration at the last sampling time. The added area (mean ± s.d.) comprised 11.6 + 6.7 of the total No serious adverse effects were encountered. Eight area. subjects (five normal volunteers and three epileptic 24 E. PERUCCA & A. RICH ENS

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1 2 3 4 1 2 3 4 Time (h) Figure 1 Mean serum lignocaine concentration (±s.d.) after intravenous administration of lignocaine hydrochloride (100 mg) in six healthy subjects (@) and in six epileptic patients (0). (1 pmol/l -0.23 pg/mI.) patients) complained of drowsiness, dizziness and/or Within groups, terminal half-lives and systemic disorientation and tinnitus during the injection. serum clearances showed low interindividual These symptoms disappeared completely 4 to 8 min variability. after the injection. It was the observer's subjective Comparison of data in Tables 3 and 4 indicates impression that adverse effects were less prominent in that the estimated kinetic parameters were similar in the patients. Numbness of the tongue was common the two groups of subjects. for 3-5 min following oral intake of the lignocaine There was a trend for the systemic serum clearance solution. Five subjects (four normal volunteers and to be higher in the epileptic patients but the difference one epileptic patient) complained of moderate was not statistically significant (P 0.1). dizziness for a short period (usually between 30 and 90 min) after the oral dose. Invariably, a serum Lignocaine kinetics after oral administration and lignocaine concentration of 8.7 jmol/l or more was comparison with intravenous data found at the time these symptoms were reported, and the only patient to complain of dizziness (AW) was Serum lignocaine concentration values after oral also the only patient in whom a serum lignocaine doses in normal subjects and epileptic patients are concentration exceeded this value after oral intake shown in Table 5. Mean values (± s.d.) are illustrated (Table 7). Many subjects reported a feeling of in Figure 2. At all sampling times lignocaine tiredness for up to 12 h after drug administration. concentrations were considerably lower in the This symptom occurred as frequently after oral epileptic patients resulting in an almost threefold administration as after intravenous, and was noted by difference in the areas under the curve between the the volunteers and by the patients. No alteration was two groups. Peak serum concentrations were reached noted in the frequency or pattern of epileptic seizures after approximately 45 win in both groups; half-lives in the patients. were similar to those calculated after intravenous administration and did not differ significantly in the Lignocaine kinetics after intravenous administration two groups (Tables 6 and 7). Tables 6 and 7 illustrate kinetic parameters calculated by comparing oral and The serum concentration values of lignocaine at intravenous data. The mean oral availability was 37% various sampling times after intravenous adminis- in the normal subjects and 15% in the epileptic tration in healthy subjects and epileptic patients are patients (P < 0.001). There was a good agreement shown in Table 2. Mean values + s.d. are illustrated in between mean predicted and observed bioavailability Figure 1 while calculated kinetic parameters are in the normal subjects, but individual values were shown in Tables 3 and 4. In all subjects, serum weakly correlated to those predicted (r = 0.48, lignocaine concentrations declined biexponentially P> 0.05). On the other hand, observed bio- following the injection. In subjects GS and EW, availability values in the epileptic patients were found however, slight irregularities in the early part of the to be lower than but significantly correlated to those concentration curve prevented an accurate estimation calculated from intravenous data (r = 0.97, of the a phase. P < 0.01). Estimated values for intrinsic clearance FIRST PASS METABOLISM OF LIGNOCAINE 25

14 were approximately three times higher in the epileptic patients. Estimated values for hepatic blood flow ranged from 1.1 to 1.7 I/min and were lower in the patients than in the normal subjects.

101 Discussion 0 E The two compartment open pharmacokinetic model proved to be adequate to describe the decline of the Z. 81 C serum concentration of intravenously administered c0 lignocaine in both normal volunteers and epileptic ._v0 patients. Distribution was rapid and almost complete after 45-60 min in most of the subjects. A value of E approximately 70 min for the terminal half-life in a, normal subjects is considerably lower than commonly C, reported (Rowland et al., 1971; Rowland, 1974; Sasyniuk & Ogilvie, 1975), probably as a consequence of the relatively young age of the subjects studied (Nation, Triggs & Selig, 1977). Although knowledge of kinetic parameters such as half-life and systemic clearance is invaluable for a rational use of the drug, data derived from healthy volunteers should be 1 2 3 4 extrapolated to patients cautiously. Factors such as Time (h) age (Nation et al., 1977), duration of administration Figure 2 Mean serum lignocaine concentration (Le Lorier, Latour, Grenon, Caille, Loiseau, Solignac (+s.d.) after oral administration of lignocaine & Du Mont, 1975; Le Loner, Moisan, Gagne & hydrochloride (750 mg) in six normaI subjects (0) Caille, 1977) and disease (Thompson, Melmon, and in six epileptic patients (0). fP < 0.05 at all Richardson, Cohn, Steinbrunn, Cudihee & Rowland, sampling times except 0.25 and 0.5 h. 1973; Halkin, Meffin, Melmon & Rowland, 1975; (1 pmol/l -0.23 pg/mI.) Nation et al., 1977) appear to play an important role

Table 2 Serum lignocaine concentration values after intravenous administration of lignocaine hydrochloride (100 mg) in six healthy subjects and in six epileptic patier Serum lignocaine concentration (pmol/l) Time after administration (min) 3 8 15 30 45 60 90 120 150 180 210 240 Healthy subjects AT 5.0 4.1 3.7 3.2 3.2 2.5 1.8 1.4 1.2 0.77 0.68 0.55 GM 11.9 7.7 4.7 3.8 2.4 1.9 1.4 1.0 0.7 0.68 0.51 0.38 MD 6.1 5.9 4.3 3.3 3.0 2.4 1.7 1.2 1.1 0.64 0.38 0.34 GS 8.9 5.6 5.0 3.9 3.7 2.9 2.1 1.2 0.6 0.47 0.34 0.21 TT 8.1 5.1 3.0 2.5 2.0 1.6 1.3 1.0 0.8 0.55 0.55 0.43 KE 13.7 9.2 5.3 3.4 2.9 2.2 1.6 1.3 0.8 0.73 0.51 0.43 Mean 8.9 6.3 4.3 3.4 2.9 2.3 1.6 1.1 0.9 0.64 0.50 0.39 s.d. 3.3 1.8 0.8 0.5 0.6 0.5 0.3 0.1 0.2 0.13 0.12 0.11 Epileptic patients JK 7.3 4.9 3.8 2.9 2.1 1.7 1.4 1.1 0.8 0.55 0.43 0.38 AW 11.9 6.8 4.7 3.3 3.1 2.6 1.5 1.4 1.1 0.73 0.60 0.34 PC 4.0 3.2 2.6 2.3 1.7 1.6 1.2 1.0 1.0 0.77 0.60 0.51 EW 8.3 5.1 4.1 3.4 3.2 2.4 1.4 1.1 0.7 0.43 0.30 0.17 DT 8.5 5.5 4.6 3.2 2.4 1.9 1.5 0.9 0.7 0.43 0.34 0.26 SH 10.2 7.4 4.7 3.6 2.6 2.4 1.7 1.2 0.8 0.51 0.38 0.26 Mean 8.4 5.5 4.1 3.1 2.5 2.1 1.4 1.1 0.8 0.57 0.44 0.32 s.d. 2.6 1.4 0.8 .5 0.6 0.4 0.2 0.2 0.2 0.15 0.13 0.12 Lignocaine 1 pmol/l -0.23 pg/mI. 26 E. PERUCCA & A. RICHENS

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Table 5 Serum lignocaine concentration values after oral administration of lignocaine hydrochloride monohydrate (750 mg) in six healthy subjects and in six epileptic patients

Serum lignocaine concentration (pmol/l) Time after administration (min) 15 30 45 60 90 120 150 180 210 240 Healthy subjects AT 2.5 10.2 11.0 9.2 7.3 4.8 4.6 4.1 2.8 2.3 GM 10.1 15.5 11.7 8.9 6.9 4.5 3.8 2.7 2.2 1.6 MD 1.6 8.3 9.6 6.8 6.8 4.4 3.3 2.9 2.1 1.6 GS 7.0 8.5 7.3 6.6 3.7 2.7 2.0 1.5 0.9 0.6 TT 1.2 2.1 5.8 4.4 3.6 2.8 2.0 1.7 1.4 1.2 KE 1.2 3.4 6.4 7.8 8.5 6.7 4.8 3.8 2.9 2.1 Mean 3.9 8.0 8.6 7.3 6.2 4.3 5.4 2.7 2.0 1.6 s.d. 3.7 4.8 2.6 1.7 2.0 1.5 1.2 1.0 0.8 0.6 Epileptic patients JK 0.7 2.3 2.5 2.4 1.3 0.8 0.6 0.5 0.3 0.3 AW 2.6 7.3 9.6 7.7 5.1 3.2 2.1 1.5 1.2 0.6 PC 0.3 0.5 0.8 1.7 1.8 1.3 1.1 1.0 0.8 0.6 EW 1.4 3.0 2.7 2.6 1.7 1.4 1.0 0.9 0.4 0.3 DT 1.5 1.7 1.5 1.5 1.4 1.3 0.9 0.7 0.6 0.4 SH 3.2 5.8 5.5 4.8 3.8 2.4 1.9 1.4 1.0 0.7 Mean 1.6 3.4 3.8 3.5 2.5 1.7 1.2 1.0 0.7 0.5 s.d. 1.1 2.6 3.3 2.4 1.6 0.9 0.8 0.4 0.3 0.2 Lignocaine 1 pmol/l -0.23 pg/mI. 28 E. PERUCCA & A. RICH ENS

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Thorgeirsson, Davies & Breckenridge, 1971; Branch, (Lalka et al., 1976) at least two separate multiple-dose Shand, Wilkinson & Nies, 1974). Indeed, the studies failed to show any change in lignocaine observation that serum clearance in the patients was bioavailability after single oral doses ranging from only marginally greater than in the normal volunteers 100 to 500 mg (Boyes et al., 1971; Bending et al., is evidence against a markedly increased LBF in the 1976). former group. In the present study, therapeutic serum lignocaine A slight shortening of the serum half-life of concentrations (,> 6 gmol/l) were obtained in five out lignocaine has been previously described in epileptic of six normal subjects after a 750 mg oral dose. patients (Heinonen, Takki & Jahro, 1970) and However, the critical issue determining the clinical considered as evidence of induced metabolism. usefulness oforal lignocaine is the possible toxicity of Although this conclusion is probably correct, it must metabolites which accumulate in comparatively high be appreciated that the half-life and clearance of concentrations when the drug is administered by this lignocaine are more dependent on the rate of LBF route. There have been an increasing number of than on the metabolizing capacity of the organ reports suggesting that these metabolites, particularly (Stenson et al., 1971). Provided the absorption if MEGX, may be partly responsible for signs ofcentral complete and the kinetics are first-order, the latter is nervous system toxicity (Beckett, Boyes & Appleton, best estimated by measuring the oral availability (oral 1966; Boyes et al., 1971; Blumer, Strong & Atkinson, clearance) which is equivalent to intrinsic clearance as 1973; Strong et al., 1973; Nation et al., 1977). In our defined by Wilkinson & Shand (1975) and as study, however, adverse effects were less prominent calculated by us. The oral availability was con- after relatively large oral doses than after a single siderably lower in our patients and this (together with intravenous injection and appeared to be related to the strong correlation between experimental values the concentration of the parent drug. We feel that and those calculated from intravenous data) provides further investigations are required to evaluate the evidence of induction of first-pass metabolism. potential toxicity of lignocaine metabolites. However, the fact that the reduction in bioavailability Karlsson, Collste & Rawlins (1974) have reported a was greater than predicted by the perfusion limited pharmacodynamic interaction between phenytoin model suggests that other factors may be operating, and lignocaine, leading to potentiation of toxic effects some of which are not necessarily related to enzyme when these agents are used in combination. Although induction. These include reduced absorption, in- this observation was not confirmed in our study, the creased metabolism within the gastrointestinal wall, experimental conditions were markedly different, and decreased binding of the drug to red cells in the particularly in respect of the lignocaine concentration epileptic patients. Each of these possibilities would achieved. Since both drugs can be used in result in an underestimation of LBF in the former combination for the treatment of cardiac dys- group. Alternatively, it might be argued that the oral rhythmias and status epilepticus (Bernhard, Bohm & availability was artificially elevated in the non- Hojeberg, 1955) a possible interaction may have induced subjects by the occurrence of saturation important clinical implications. kinetics during the absorption process. The agreement between predicted and observed bioavailability in the normal subjects does not support such an We thank Dr John Laidlaw for allowing us to study patients hypothesis and, although dose-dependent kinetics under his care, and the McAlpine Foundation and Chalfont have been reported during intravenous infusions Research Fund for financial support.

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Note added in proof: Reference Complete gastro-intestinal absorption of lignocaine HUET, M., LE LORIER, J., POMIER, G. & MARLEAU, D. hydrochloride has been recently demonstrated in five (1979). Bioavailability of lignocaine in normal volun- patients with hepatic cirrhosis and porto-caval shunt teers and cirrhotic patients. Clin. Pharmac. Ther., 25, (Huet, Le Lorier, Pomier & Marleau, 1979). 230.