The study was done in 17 children and young adults with ALL in remission (10 males and 7 females) aged 7–24 years (mean age 14 ± 4 years). 12 healthy subjects (7 males and 5 females) aged 7–24 years (mean age 14 ± 4 years) constituted the control group. Mean remission time was 61
± 30 months. Eleven patients with ALL also had chronic viral hepatitis type B and/or C. Three groups were formed:
1) group I – ALL without hepatitis (6 patients), 2) group II – ALL with hepatitis (11 patients), 3) group III – healthy controls (12 subjects). Patients were treated at the First De-partment of Pediatrics, Pomeranian Medical University, Szczecin, Poland.
The following laboratory tests were done: alanine ami-notransferase (ALT), aspartate amiami-notransferase (AST), gamma-glutamyl transpeptidase (GGTP), alkaline phos-phatase, total bilirubin, prothrombin time, acid α1 -glyco-protein, HBs antigen, and anti-HCV antibodies. Lidocaine pharmacokinetics were determined following intravenous injection of 1 mg/kg lidocaine during 3 minutes and meas-urement of lidocaine and MEGX concentrations in serum at 15, 30, 60, 120, 240, and 360 min. from administration of lidocaine. Lidocaine and MEGX concentrations were measured with high-performance liquid chromatography [13]. Pharmacokinetic parameters of lidocaine and MEGX included: area under the plasma concentration vs time curve (AUC), relative (VSS/BW) and absolute (VSS) volume of distribution, elimination rate constant (λz), half-life time for the elimination phase (t1/2), relative (CL/BW) and absolute (CL) total drug clearance. Parameters were calculated ac-cording to the open one-compartment model for intravenous administration.
Data were expressed as mean values ± SD. Statistical analysis was done using Student’s t-test and the level of significance was taken as p = 0.05. The study protocol was approved by the Ethics Committee of the Pomeranian Medi-cal University. Written informed consent was obtained from the parents and from patients older than 16 years.
Results
Mean values for biochemical parameters are shown in Table 1. Activities of ALT, AST, and GGTP were signifi-cantly elevated in children with ALL and hepatitis (group II) compared to the control group (p < 0.05) and group I (p < 0.05). Alkaline phosphatase, bilirubin, acid glycoprotein and prothrombin index did not differ significantly between the groups (table 1).
Mean lidocaine concentrations are presented in table 2 and figure 1. There were no statistically significant dif-ferences between the groups during the six hours of the test. The highest lidocaine concentrations were observed in children with ALL and hepatitis (group II) 15 and 30 min. after drug administration. Mean MEGX
concentra-ASSESSMENT OF LIVER FUNCTION IN CHILDREN WITH ACUTE LYMPHObLASTIC LEUKEMIA IN REMISSION 63
tions did not differ significantly during the test except for significantly (p < 0.05) higher values 30 minutes after drug administration in children with ALL and hepatitis (tab. 3 and fig. 2) as compared to the control group.
Pharmacokinetic parameters of lidocaine and MEGX are shown in tables 4 and 5. In patients with ALL and hepatitis (group II), decreased elimination of lidocaine was observed.
This was reflected by reduction in the drug elimination rate constant (λz) and prolongation of lidocaine half-life time (t1/2) – table 4. MEGX elimination rate constant was increased in patients with ALL. Consequently, MEGX half-life time was reduced and absolute clearance (CL) was increased
T a b l e 1. Mean values of standard liver function tests ± SD (n = 29) T a b e l a 1. Średnie wartości testów wątrobowych ± SD (n = 29) Parameter (unit)
Parametr (jednostka) Group / Grupa
I (n = 6) II (n = 11) III (n = 12)
ALAT (U/L) 30.43 ± 7.63 42.07 ± 12.46a, b 25.29 ± 6.69
ASPAT (U/L) 22.75 ± 15.57 62.97 ± 30.97a, b 21.48 ± 6.50
GGTP (U/L) 12.40 ± 3.87 27.26 ± 21.11a, b 14.02 ± 3.54
AP (U/L) 265.35 ± 72.20 168.61 ± 118.90 212.78 ± 103.40
Bilirubin / Bilirubina (mg%) 0.47 ± 0.11 0.69 ± 0.47 0.54 ± 0.19
Prothrombin index / Indeks protrombinowy 1.08 ± 0.05 1.03 ± 0.07 1.03 ± 0.07
AAG (mg%) 72.90 ± 14.72 65.07 ± 21.76 71.10 ± 17.83
ALAT – alanine aminotransferase / aminotransferaza alaninowa, ASPAT – aspartate aminotransferase / aminotransferaza asparaginiano-wa, GGTP – gamma-glutamyl transpeptidase / gamma-glutamylotranspeptydaza, AP – alkaline phosphatase / fosfataza alkaliczna, AAG – acid α1-glycoprotein / kwaśna α1-glikoproteina
a statistically significant (p < 0.05) compared to control group / znamienny statystycznie (p < 0.05) w porównaniu do grupy kontrolnej
b statistically significant (p < 0.05) compared to group I / znamienny statystycznie (p < 0.05) w porównaniu do grupy I
T a b l e 2. Mean serum concentrations of lidocaine (mg/l) ± SD (n = 29) T a b e l a 2. Średnie stężenie lidokainy w surowicy (mg/l) ± SD (n = 29)
TimeCzas (min)
Concentrations / Stężenia Group I
Grupa I Group II
Grupa II Group III Grupa III 15 1.08 ± 0.37 1.12 ± 0.36 0.97 ± 0.42 30 0.69 ± 0.22 0.77 ± 0.21 0.62 ± 0.26 60 0.39 ± 0.09 0.41 ± 0.13 0.44 ± 0.19 120 0.16 ± 0.07 0.22 ± 0.08 0.22 ± 0.10 240 0.07 ± 0.06 0.08 ± 0.06 0.07 ± 0.02 360 0.04 ± 0.02 0.03 ± 0.03 0.03 ± 0.03 T a b l e 3. Mean concentrations of MEGX (ng/ml) ± SD (n = 29)
T a b e l a 3. Średnie stężenie MEGX (ng/ml) ± SD (n = 29) TimeCzas
(min)
Concentrations / Stężenia Group I
Grupa I Group II
Grupa II Group III Grupa III 15 67.78 ± 34.29 95.60 ± 49.69 81.54 ± 28.96 30 96.02 ± 45.71 97.43 ± 27.68* 78.01 ± 24.50 60 84.80 ± 25.90 83.49 ± 30.28 76.51 ± 28.25 120 75.12 ± 38.03 82.54 ± 22.17 67.39 ± 32.71 240 50.19 ± 25.19 54.35 ± 24.68 52.22 ± 18.63 360 35.09 ± 14.18 41.79 ± 22.18 32.37 ± 15.98
* statistically significant (p < 0.05) compared to control group / sta-tystycznie znamienny (p < 0,05) w stosunku do grupy kontrolnej
I – patients with acute lymphoblastic leukemia / pacjenci z ostrą białaczką limfoblastyczną, II – patients with acute lymphoblastic leukemia and chronic hepatitis / pacjenci z ostrą białaczką limfoblastyczną i przewlekłym
zapaleniem wątroby, III – control group / grupa kontrolna Fig. 1. Mean concentrations of lidocaine in groups
Ryc. 1. Średnie stężenia lidokainy w grupach
I – patients with acute lymphoblastic leukemia / pacjenci z ostrą białaczką limfoblastyczną, II – patients with acute lymphoblastic leukemia and chronic hepatitis / pacjenci z ostrą białaczką limfoblastyczną i przewlekłym
zapaleniem wątroby, III – control group / grupa kontrolna Fig. 2. Mean concentrations of MEGX in groups
Ryc. 2. Średnie stężenia MEGX w grupach
in ALL patients compared to the control group. However, these differences were not significant.
64 MAłGORZATA MOKRZYCKA, ANDRZEJ PAWLIK, MARIA KAłDOŃSKA, BARBARA MILLO T a b l e 4. Mean values of pharmacokinetic parameters of lidocaine
± SD (n = 29)
T a b e l a 4. Średnie wartości parametrów farmakokinetycznych lidokainy ± SD (n = 29) AUC – area under the drug plasma concentration time curve / pole powierzchni pod krzywą zmian stężenia leku w czasie, Vss – volu-me of distribution (absolute) / objętość dystrybucji (bezwzględna), Vss/BW – volume of distribution per body weight (relative) / objętość dystrybucji na kg masy ciała (względna), CL – total drug clearance / klirens całkowity leku, CL/BW – total drug clearance per body weight (relative) / całkowity klirens leku na kg masy ciała (względny), λz – elimination rate constant / stała szybkości dla fazy eliminacji, t1/2 – half-life time for the elimination phase / czas półtrwania dla fazy eliminacji
T a b l e 5. Mean values of pharmacokinetic parameters of MEGX ± SD (n = 29)
T a b e l a 5. Średnie wartości parametrów farmakokinetycznych MEGX ± SD (n = 29)
(ng/mL×h) 574.85 ± 252.47 650.85 ± 231.47 675.41 ± 281.37 t1/2 (h) 3.69 ± 0.86 4.13 ± 1.06 4.68 ± 1.63 λz (h-1) 0.19 ± 0.05 0.18 ± 0.05 0.17 ± 0.06 Cmax
(ng/mL) 96.02 ± 45.71 97.43 ± 27.68 81.54 ± 28.96
tmax (min) 30 30 15
AUC – area under the drug plasma concentration time curve / pole powierzchni pod krzywą zmian stężenia leku w czasie, t1/2 – half-life time for the elimination phase / czas półtrwania dla fazy eliminacji, λz – elimination rate constant / stała szybkości dla fazy eliminacji, Cmax – highest MEGX concentration / stężenie maksymalne MEGX, / stężenie maksymalne MEGX, tmax – time of highest MEGX concen-tration / czas wystąpienia stężenia maksymalnego MEGX
Discussion
Following intravenous administration of lidocaine in healthy subjects, MEGX rapidly appears in the blood and its serum level reaches a steady state within 15 minutes [14, 15, 16]. In contrast, MEGX concentration in patients with liver cirrhosis increases slowly reaching its peak value 3 to
4 hours after lidocaine injection [6, 17]. In the present study, the highest concentration (Cmax) of MEGX was observed after 15 min. from lidocaine administration in the control group and after 30 min. in children with ALL and hepatitis.
Mean MEGX concentrations after 30 min. in patients with ALL and hepatitis were significantly higher compared to the control group (p < 0.05). This observation seems to be surprising because children with hepatitis have the highest risk of liver damage but may be explained by large functional reserve of the liver and its marked regeneration potency in this group of children, as well as by the low sensitivity of the lidocaine test. High concentrations of MEGX may be also caused by extrahepatic production of MEGX because up to 20% of MEGX originates from other organs, such as pancreas, kidneys, and intestine [18].
A strong correlation between MEGX concentration and liver histology makes it possible to differentiate healthy subjects from cirrhotic patients [5, 16, 19, 20, 21]. In the study of Meyer-Wyss et al., MEGX values ranged from 5 to 100 ng/mL in non-cirrhotic patients with chronic hepatitis [22]. They concluded that lidocaine metabolite formation based on microsomal drug metabolism quantitates a very specific enzymatic reaction which may not be representative for the functional reserve of the entire organ [22]. Many factors influencing the transformation of lidocaine into MEGX, such as hepatic blood flow, gene polymorphism, activity of cytochrome P-450 isoenzymes, age, gender, and drug administration diminish the diagnostic value of the lidocaine test and make it difficult to assess liver function.
There is a consensus, however, that the value of this test is much higher in advanced stages of cirrhosis. Patients with MEGX values < 10 ng/mL have a particularly poor one-year survival rate [3, 8, 15, 19].
It appears from the present results that lidocaine is not useful as a model drug to assess metabolic liver function in children with ALL in remission. In patients with ALL and chronic hepatitis, the lidocaine test seems to be less sensitive than standart liver function tests.
Conclusions
This study has demonstrated that lidocaine pharmacoki-netics are not significantly changed by long-term chemother-apy and chronic viral hepatitis. However, patients with ALL and hepatitis may have an impared process of lidocaine me-tabolism as reflected by decreased elimination rate constant, prolonged lidocaine half-life time and reduced clearance.
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Komentarz
Lidokaina eliminowana jest z organizmu głównie na drodze metabolizmu wątrobowego, a szybkość jej biotrans-formacji zależy od szybkości przepływu wątrobowego krwi oraz od aktywności enzymów mikrosomalnych cytochro-mu P450 z rodziny 3A (CYP3A4). Test lidokainowy został wprowadzony po raz pierwszy w 1987 r. przez Oellericha i wsp. Polega on na jednorazowym, dożylnym podaniu tego leku (1 mg/kg m.c.) i oznaczeniu stężenia monoetyloglicy-noksylidydu (ang. MEGX), głównego metabolitu lidokainy, w 1 próbie krwi, pobranej po 15 min po podaniu lidokainy.
Na aktywność CYP3A4, a więc i ilość powstającego MEGX, ma wpływ wiele czynników, m.in. równocześnie stosowane leki (indukcja enzymatyczna), płeć, czynniki genetyczne, dlatego też test ten nie jest powszechnie stosowany do oceny funkcji czynnościowej wątroby. Znalazł on głównie zastosowanie w transplantologii oraz do monitorowania przewlekłych zapaleń i marskości wątroby.
Autorzy potwierdzili wcześniejsze obserwacje, że test lidokainowy (oznaczanie stężenia MEGX) nie zawsze jest dobrym wskaźnikiem oceniającym stan czynnościo-wy wątroby. W przeprowadzonych badaniach czynnościo-wykazano większą przydatność standardowych prób wątrobowych (istotny wzrost stężenia ALAT, ASPAT i GGTP u dzie-ci z OBL i wirusowym zapaleniem wątroby). Niewielkie zmiany w wartościach parametrów farmakokinetycznych lidokainy, świadczące o zmniejszonej szybkości eliminacji (matabolizm i wydalanie) obserwowano u dzieci z OBL i wirusowym zapaleniem wątroby. Na brak istotnych różnic mogły mieć wpływ mała liczebność analizowanych grup i duże różnice osobnicze w wartościach oznaczonych stężeń lidokainy i MEGX.
Praca pt. „Liver function assessment in children with acute lymphoblastic leukemia in remission” jest wartościo-wym opracowaniem dotyczącym oceny funkcji metabolicz-nej wątroby i farmakokinetyki lidokainy u dzieci z OBL w okresie remisji.
prof. dr hab. n. med. Barbara Gawrońska-Szklarz
ANNALES ACADEMIAE MEDICAE STETINENSIS
R O C Z N I K I P O M O R S K I E J A K A D E M I I M E D Y C Z N E J W S Z C Z E C I N I E ANNALS OF THE POMERANIAN MEDICAL UNIVERSITY
2006, 52, 3, 67–70
EWA GAJEWSKA, MAGDAlENA SObIESKA, WłODZIMIERZ SAMbORSKI