Fundam Clin Pharmacol(l992) 6,197-203 0 Elsevier, Paris
197
Pharmacokinetics of glafenine and glafenic acid in patients with cirrhosis, compared to healthy volunteers N Vermerie*, D Kusielewicz, M Tod**,P Nicolas, G Perret, F Fauvelle, 0 Petitjean Ddpartement de Phnmco-Toxirologie Cliniquc, Hapitnl Avicenne, 125 route de Stalingrd, 93000 Bobigny, France
(Received 9 January 1992; accepted 17 April 1992)
Summary - Pharmacolrinetic parameters were evaluated in 12 patients with alcoholic cirrhosis and 12 healthy volunteers after a single 400 mg oral dose of glafenine. Glafenine (G) and its major active metabolite glafenic acid (GA) were measured at regular intervals using a specific high performance liquid clironiatognphic method. Glafenine absorption was significantly delayed in cirrhotic ,( = 2.8 f 1.3 hvs 1.5 f 0.4 ti, p < 0.01) and was dramatically reduced in 3 patients. The large hepatic ‘first pass’ patients (CP) ,T effect observed in healthy volunteers was markedly reduced in CP (ratio C, GNC,,, G = 3.6 f 2.9 vs 18.9 f 9.8, p < 0.001; ratio areas under the curves AUC GAlAUC G = 2.3 f 2.3 vs 18.2 f 11.2, p < 0.001). The eliniination half-life of G was prolonged in the CP (13.0 f 13.1 h vs 1.5 f 0.5 ti, p c 0.01). In CP, GA elimination half-life was increased (12.0 f 13.4 h vs 4.3 f 1.3 h, NS) but tlie diffe= 2.2 f rence did not reach statistical significance because of large variability. The significant rise of G plasma concentrations (C, 2.1 mg/L vs 0.7 f 0.2 nig/L, p < 0.05) and its longer half-life would lead to an accumulation if tlie usual dosage regimen was prescribed for CP and could result in nephmtoxicity. On the other hand, lower dosage would be ineffective because only GA is active and nephmtoxic. Hence, G should be given with great caution to CP. glafenine / glafenic acid / pharniacokinetics / cirrhosis
Introduction
Glafenine*** was a widely used analgesic. Its pharmacological activity has been demonstrated in clinical trials with placebo or with reference analgesic drugs (Peterfalvi et 01, 1966). Although the tolerance of this drug is generally good, the possibility of an immunoallergic reaction must be borne in mind, and the risk of acute renal insufficiency after massive absorption is real (the number of
cases reported in the literature is probably underestimated). It is commonly assumed that glafenic acid, the major metabolite of glafenine breakdown, is involved in renal toxicity but very little data is available concerning this problem and glafenine itself (Gaultier et al; 1972, Montagnac et 01, 1982; Daudon el 01.1983). This reflects the poor knowledge of glafenine pharmacokinetics in man due to the difficulty concerning its analysis. To date, most pharmaco-
* Present address: CHG Gilles de Corbeil, Pliarmacie, 59 hd IIenri Dunant, 91 106 Corbeil-Essonne, France ** Correspondence and reprints *** During the editorial process, the registration agreenient of drugs containing glafeiune (Glifanan, Adalgur) was temporarily pended (on January 14th 1992) under tlie charge of anaphylactic reactions.
sus-
198
N Verrnerie et nl
kinetic data on glafenine were obtained from glafenic acid measurements (Rondelet et al, 1966; 1985). This led us to develop a specific and sensitive high performance liquid chromatography (HPLC) method (Ennachachibi et al, 1988). Using this reliable assay, we evaluated the real pharmacokinetic parameters of glafenine itself and glafenic acid, in 12 healthy volunteers. The Occurrence of a high hepatic first pass effect prompted us to study the consequences of liver disease on glafenine and glafenic acid pharmacokinetics in 12 patients with alcoholic cirrhosis. Materials and methods Pa tien ts Healthy subjects Twelve volunteers, 4 women and 8 men, 21-38 years-old (mean 33.4). weighing 50-80 kg (mean 68.5) entered the study after giving informed consent. No medication other than glafenine was allowed throughout the period of the pharmacokinetic study. During the inclusion step,
each volunteer underwent a thorough medical examination including history, physical examination and mutine hematological and biochemical analysis to ensure normal hepatic and renal functions. This protocol had been approved by the Local Scientific Committee for Human Subject Investigations. Patients with liver disease Twelve Cirrhotic patients, 7 males and 5 females, took part in the study; their age range was 42-63 years (mean 53.3) and weight 50-85 kg (mean 64.7). Physical examination, liver function tests and Pugh's score classification (Pugh et al, 1973) were carried out upon entry into the study. Alcoholic cirrhosis was established either by liver biopsy or by clinical, biological and gastroesophageal fiber-optic endoscopy. Portal hypertension was demonstrated by the presence of esophageal varices. At the time of investigation, none of the cirrhotic patients had encephalopathy, renal failure or recent history of gastrointestinal hemorrhages. Alcohol consumption had heen stopped at least 2 weeks before the study. No drug able to modify glafenine pharmacokinetics was administered during the last 2 weeks preceding the experimcnt. All patients were non smokers. Other relevant data concerning cirrhotic patients are given in table I.
Table 1. Characteristics of the 12 patients with liver disease. Age
Sex
1 2 3 4 5 6 7 8 9 10 11 12
Mean sd
M
5
F
F M M F
M M M F F
M
Weight Crent cleara (kg) {tialhiain)
6 60 59 55 59 42 55 45 61 63 57 52
64 47
53.3 6.3
64.7 13.3
85
55 56 60 82 69 50 67 56 85
Piiglt score
Ascites
(L)
SCOT (IJ/L)
SGPT Protliroiirl~iri Albumin yCTb Bilirubin PALC (lI/L) test(%) (g/L) (U/L) (nlM/L) (UL)
200 35 75 65
85
10
197
Pharmacokinetics of glafenine and glafenic acid in patients with cirrhosis, compared to healthy volunteers N Vermerie*, D Kusielewicz, M Tod**,P Nicolas, G Perret, F Fauvelle, 0 Petitjean Ddpartement de Phnmco-Toxirologie Cliniquc, Hapitnl Avicenne, 125 route de Stalingrd, 93000 Bobigny, France
(Received 9 January 1992; accepted 17 April 1992)
Summary - Pharmacolrinetic parameters were evaluated in 12 patients with alcoholic cirrhosis and 12 healthy volunteers after a single 400 mg oral dose of glafenine. Glafenine (G) and its major active metabolite glafenic acid (GA) were measured at regular intervals using a specific high performance liquid clironiatognphic method. Glafenine absorption was significantly delayed in cirrhotic ,( = 2.8 f 1.3 hvs 1.5 f 0.4 ti, p < 0.01) and was dramatically reduced in 3 patients. The large hepatic ‘first pass’ patients (CP) ,T effect observed in healthy volunteers was markedly reduced in CP (ratio C, GNC,,, G = 3.6 f 2.9 vs 18.9 f 9.8, p < 0.001; ratio areas under the curves AUC GAlAUC G = 2.3 f 2.3 vs 18.2 f 11.2, p < 0.001). The eliniination half-life of G was prolonged in the CP (13.0 f 13.1 h vs 1.5 f 0.5 ti, p c 0.01). In CP, GA elimination half-life was increased (12.0 f 13.4 h vs 4.3 f 1.3 h, NS) but tlie diffe= 2.2 f rence did not reach statistical significance because of large variability. The significant rise of G plasma concentrations (C, 2.1 mg/L vs 0.7 f 0.2 nig/L, p < 0.05) and its longer half-life would lead to an accumulation if tlie usual dosage regimen was prescribed for CP and could result in nephmtoxicity. On the other hand, lower dosage would be ineffective because only GA is active and nephmtoxic. Hence, G should be given with great caution to CP. glafenine / glafenic acid / pharniacokinetics / cirrhosis
Introduction
Glafenine*** was a widely used analgesic. Its pharmacological activity has been demonstrated in clinical trials with placebo or with reference analgesic drugs (Peterfalvi et 01, 1966). Although the tolerance of this drug is generally good, the possibility of an immunoallergic reaction must be borne in mind, and the risk of acute renal insufficiency after massive absorption is real (the number of
cases reported in the literature is probably underestimated). It is commonly assumed that glafenic acid, the major metabolite of glafenine breakdown, is involved in renal toxicity but very little data is available concerning this problem and glafenine itself (Gaultier et al; 1972, Montagnac et 01, 1982; Daudon el 01.1983). This reflects the poor knowledge of glafenine pharmacokinetics in man due to the difficulty concerning its analysis. To date, most pharmaco-
* Present address: CHG Gilles de Corbeil, Pliarmacie, 59 hd IIenri Dunant, 91 106 Corbeil-Essonne, France ** Correspondence and reprints *** During the editorial process, the registration agreenient of drugs containing glafeiune (Glifanan, Adalgur) was temporarily pended (on January 14th 1992) under tlie charge of anaphylactic reactions.
sus-
198
N Verrnerie et nl
kinetic data on glafenine were obtained from glafenic acid measurements (Rondelet et al, 1966; 1985). This led us to develop a specific and sensitive high performance liquid chromatography (HPLC) method (Ennachachibi et al, 1988). Using this reliable assay, we evaluated the real pharmacokinetic parameters of glafenine itself and glafenic acid, in 12 healthy volunteers. The Occurrence of a high hepatic first pass effect prompted us to study the consequences of liver disease on glafenine and glafenic acid pharmacokinetics in 12 patients with alcoholic cirrhosis. Materials and methods Pa tien ts Healthy subjects Twelve volunteers, 4 women and 8 men, 21-38 years-old (mean 33.4). weighing 50-80 kg (mean 68.5) entered the study after giving informed consent. No medication other than glafenine was allowed throughout the period of the pharmacokinetic study. During the inclusion step,
each volunteer underwent a thorough medical examination including history, physical examination and mutine hematological and biochemical analysis to ensure normal hepatic and renal functions. This protocol had been approved by the Local Scientific Committee for Human Subject Investigations. Patients with liver disease Twelve Cirrhotic patients, 7 males and 5 females, took part in the study; their age range was 42-63 years (mean 53.3) and weight 50-85 kg (mean 64.7). Physical examination, liver function tests and Pugh's score classification (Pugh et al, 1973) were carried out upon entry into the study. Alcoholic cirrhosis was established either by liver biopsy or by clinical, biological and gastroesophageal fiber-optic endoscopy. Portal hypertension was demonstrated by the presence of esophageal varices. At the time of investigation, none of the cirrhotic patients had encephalopathy, renal failure or recent history of gastrointestinal hemorrhages. Alcohol consumption had heen stopped at least 2 weeks before the study. No drug able to modify glafenine pharmacokinetics was administered during the last 2 weeks preceding the experimcnt. All patients were non smokers. Other relevant data concerning cirrhotic patients are given in table I.
Table 1. Characteristics of the 12 patients with liver disease. Age
Sex
1 2 3 4 5 6 7 8 9 10 11 12
Mean sd
M
5
F
F M M F
M M M F F
M
Weight Crent cleara (kg) {tialhiain)
6 60 59 55 59 42 55 45 61 63 57 52
64 47
53.3 6.3
64.7 13.3
85
55 56 60 82 69 50 67 56 85
Piiglt score
Ascites
(L)
SCOT (IJ/L)
SGPT Protliroiirl~iri Albumin yCTb Bilirubin PALC (lI/L) test(%) (g/L) (U/L) (nlM/L) (UL)
200 35 75 65
85
10
