Eur J Clin Pharmacol (1991) 41:233-237 EurapeanJournalof ( ~ [ ] ~ ( ~ @ ~
003169709100220B
@ Springer-Verlag 1991
Effect of pentoxifylline on liver plasma flow in normal man A. Suren t, F. E. Bauer 1, B. Rosenkranz 2, and J. Bircher 1 Division of Clinical Pharmacology, University of Goettingen and 2 Institute for Clinical Pharmacology, Hoechst AG, Frankfurt, FRG Received: May 5, 1990/Accepted in revised form: January 5, 1991
Summary. In ten healthy, male subjects the acute effect of pentoxifylline (a m e t h y l x a n t h i n e derivative) on liver plasm a flow was investigated b y the extrarenal sorbitol clearance m e t h o d and on cardiac o u t p u t by i m p e d a n c e cardiography. O n the p l a c e b o day liver plasma flow decreased within 4 h f r o m 769 to 683 m l - m i n ~ (P < 0.05) and on the pentoxifylline day (300 mg i.v.) it increased f r o m 764 to 801 ml. rain- 1 (NS). A t the end of the experiment the difference b e t w e e n the groups was also significant (P < 0.05). T h e r e was no significar/t change in cardiac output, b l o o d pressure or heart rate and individual changes in those values were n o t correlated with liver plasma flow. T h e r e was no correlation either b e t w e e n the plasma concentrations of pentoxifylline or its metabolites and the changes in liver plasma flow. It is c o n c l u d e d that, relative to the s p o n t a n e o u s decrease in liver plasma flow at rest on the p l a c e b o day, pentoxifylline increased splanchnic perfusion i n d e p e n d e n t of any change in cardiac output.
patic extraction, which are eliminated mainly in p r o p o r tion to hepatic b l o o d or plasma flow [14]. This implies that, apart f r o m the effects of pentoxifylline on the liver itself, the drug might have clinical i m p o r t a n c e because of h a e m o d y n a m i c drug interactions.
Subj ects and methods
Subjects Ten male subjects (age 22-30 y; height 171-191 cm; body weight 59-98 kg) participated in the study. History, physical examination and laboratory screening showed all of them to be in good health, with no evidence of hepatic, renal or cardiac dysfunction, and none had a dietary history of fructose intolerance. Laboratory test results were within the normal range. Regular medication, abuse of alcoholic beverages, or participation in a trial with an investigationai drug during the 4 preceding weeks led to exclusion from the study.
Study protocol Key words: Pentoxifylline, hepatic plasma flow, sorbitol clearance, i m p e d a n c e cardiography, h a e m o d y n a m i c effects
Pentoxifylline (1-(5)oxohexyl-3,7,dimethylxanthine; Trental) has b e e n a d v o c a t e d for the t r e a t m e n t of peripheral vascular disease, because it m a y r e d u c e b l o o d viscosity and increase erythrocyte flexibility [1]. In addition, it m a y increase cardiac output, leading p r e s u m a b l y to a b a r o r e f l e x - m e d i a t e d r e d u c t i o n in systemic vascular resistance [2], whilst arterial b l o o d pressure remains unaffected. Ballet et al., 1987 [3] d e m o n s t r a t e d that pentoxifylline decreased portal resistance in the isolated cirrhotic rat liver. As such an effect might be beneficial to patients with cirrhosis clinical studies were initiated [4]. T h e effect of pentoxifylline on liver plasma flow in subjects w i t h o u t liver disease, however, was not known, and any such change could be of i m p o r t a n c e for drugs with a high he-
All volunteers were studied at the Department of Clinical Pharmacology, University of G0ttingen, after giving informed consent. The protocol was approved by the local Ethics Committee. The study followed a randomized, placebo-controlled double-blind cross-over design. The washout period between the two study days varied between 1 and 2 weeks. The subjects abstained from strenuous physical activity, alcohol and beverages containing caffeine for 24 h before each study day. At 08.00 h after an overnight fast an indwelling venous cannula was inserted into a vein in each forearm, one for infusion of the study drugs and sorbitol and the other for blood sampling. Four electrodes were placed around the neck and the abdomen for impedance cardiography. The first measurements were taken after a rest of about 20 min. The subjects remained recumbent for 6 h and did not receive anything by mouth during the study. Blood pressure, pulse and cardiac output were measured and blood was sampled for analysis of sorbitol and pentoxifylline (including metabolites) before the start of the sorbitol infusion and at 15 min intervals thereafter. Sorbitol (Sorbito140% B. Braun, Melsungen, FRG) was infused intravenously using a constant-rate perfusor 50mg.min -1 (Secura, B.Braun, Melsungen, FRG) from zero to 360 min. Infusion of pentoxifylline (2.5 mg. min 1for 2 h) or place-
234
A. Suren et al.: Pentoxifylline and liver plasma flow
Table 1. Effect of pentoxifylline and placebo on heart rate, blood pressure, cardiac output, total sorbitol clearance, renal sorbitol clearance and extrarenal sorbitol clearance in healthy volunteers (n = 10). Mean with (SEM) and (90%-confidence limits). For analysis only the last 3 measurements in each period were taken
Sampling period:
0 to 120 min
120 to 240 rain
240 to 360 min
Substance
Pentoxifylline
Placebo
Pentoxifylline
Placebo
Pentoxifylline
Placebo
Heart rate (min-i)
63 (2) (60-66)
63 (3) (59-67)
66 (2) (63~59)
63 (3) (59-67)
65 (2) (62-68)
62 (3) (58~56)
Blood pressure (mmHg) systolic
112 (2) (110-115)
111 (3) (107-115)
115 (2) (112-118)
112 (3) (108-116)
115 (2) (112-118)
113 (4) (108-119)
diastolic
74 (3) (70-78)
75 (2) (72-78)
76 (2) (73-80)
77 (2) (74-80)
77 (2) (74-80)
76 (3) (72-80)
Cardiac output (1. rain -1)
7.3 (0.5) (6.6-8.0)
7.6 (0.6) (6.8-8.4)
7.8 (0.6) (7.0-8.6)
7.4 (0.5) (6.4-8.1)
7.8 (0.8) (6.3-8.9)
6.9 (0.5) (6.4-7.6)
Total sorbitol clearance (ml.min 1)
885 (38) (832-938)
875 (47) (810-940)
914 (39) (860-968)
817 (39) (763-871)
915 (48) (849-984)
815 (44) (754-876)
Renal sorbitol clearance (ml. min 1)
117 (5) (110-124)
106 (7) (96-116)
126 (5) (119-133)
106 (6) (98-116)
114 (7) (104-124)
132 (11) (117-147)
Extrarenal sorbitol clearance (ml-min 1)
764 (35) (716-812)
769 (42) (711-827)
789 (37) (738-840)
711 (35) (663-759)
801 (477 (736-866)
683 (36) b (633-733)
Sorbitol plasma concentrations (rag. d1-1)
5.8 (0.3) (5.4-6.2)
5.9 (0.3) (5.5-6.3)
5.6 (0.2) (5.3-5.9)
6.3 (0.3) (5.9-6.7)
5.6 (0.3) (5.2-6.0)
6.5 (0.3) (6.1-6.9)
a significantly different from placebo (P
003169709100220B
@ Springer-Verlag 1991
Effect of pentoxifylline on liver plasma flow in normal man A. Suren t, F. E. Bauer 1, B. Rosenkranz 2, and J. Bircher 1 Division of Clinical Pharmacology, University of Goettingen and 2 Institute for Clinical Pharmacology, Hoechst AG, Frankfurt, FRG Received: May 5, 1990/Accepted in revised form: January 5, 1991
Summary. In ten healthy, male subjects the acute effect of pentoxifylline (a m e t h y l x a n t h i n e derivative) on liver plasm a flow was investigated b y the extrarenal sorbitol clearance m e t h o d and on cardiac o u t p u t by i m p e d a n c e cardiography. O n the p l a c e b o day liver plasma flow decreased within 4 h f r o m 769 to 683 m l - m i n ~ (P < 0.05) and on the pentoxifylline day (300 mg i.v.) it increased f r o m 764 to 801 ml. rain- 1 (NS). A t the end of the experiment the difference b e t w e e n the groups was also significant (P < 0.05). T h e r e was no significar/t change in cardiac output, b l o o d pressure or heart rate and individual changes in those values were n o t correlated with liver plasma flow. T h e r e was no correlation either b e t w e e n the plasma concentrations of pentoxifylline or its metabolites and the changes in liver plasma flow. It is c o n c l u d e d that, relative to the s p o n t a n e o u s decrease in liver plasma flow at rest on the p l a c e b o day, pentoxifylline increased splanchnic perfusion i n d e p e n d e n t of any change in cardiac output.
patic extraction, which are eliminated mainly in p r o p o r tion to hepatic b l o o d or plasma flow [14]. This implies that, apart f r o m the effects of pentoxifylline on the liver itself, the drug might have clinical i m p o r t a n c e because of h a e m o d y n a m i c drug interactions.
Subj ects and methods
Subjects Ten male subjects (age 22-30 y; height 171-191 cm; body weight 59-98 kg) participated in the study. History, physical examination and laboratory screening showed all of them to be in good health, with no evidence of hepatic, renal or cardiac dysfunction, and none had a dietary history of fructose intolerance. Laboratory test results were within the normal range. Regular medication, abuse of alcoholic beverages, or participation in a trial with an investigationai drug during the 4 preceding weeks led to exclusion from the study.
Study protocol Key words: Pentoxifylline, hepatic plasma flow, sorbitol clearance, i m p e d a n c e cardiography, h a e m o d y n a m i c effects
Pentoxifylline (1-(5)oxohexyl-3,7,dimethylxanthine; Trental) has b e e n a d v o c a t e d for the t r e a t m e n t of peripheral vascular disease, because it m a y r e d u c e b l o o d viscosity and increase erythrocyte flexibility [1]. In addition, it m a y increase cardiac output, leading p r e s u m a b l y to a b a r o r e f l e x - m e d i a t e d r e d u c t i o n in systemic vascular resistance [2], whilst arterial b l o o d pressure remains unaffected. Ballet et al., 1987 [3] d e m o n s t r a t e d that pentoxifylline decreased portal resistance in the isolated cirrhotic rat liver. As such an effect might be beneficial to patients with cirrhosis clinical studies were initiated [4]. T h e effect of pentoxifylline on liver plasma flow in subjects w i t h o u t liver disease, however, was not known, and any such change could be of i m p o r t a n c e for drugs with a high he-
All volunteers were studied at the Department of Clinical Pharmacology, University of G0ttingen, after giving informed consent. The protocol was approved by the local Ethics Committee. The study followed a randomized, placebo-controlled double-blind cross-over design. The washout period between the two study days varied between 1 and 2 weeks. The subjects abstained from strenuous physical activity, alcohol and beverages containing caffeine for 24 h before each study day. At 08.00 h after an overnight fast an indwelling venous cannula was inserted into a vein in each forearm, one for infusion of the study drugs and sorbitol and the other for blood sampling. Four electrodes were placed around the neck and the abdomen for impedance cardiography. The first measurements were taken after a rest of about 20 min. The subjects remained recumbent for 6 h and did not receive anything by mouth during the study. Blood pressure, pulse and cardiac output were measured and blood was sampled for analysis of sorbitol and pentoxifylline (including metabolites) before the start of the sorbitol infusion and at 15 min intervals thereafter. Sorbitol (Sorbito140% B. Braun, Melsungen, FRG) was infused intravenously using a constant-rate perfusor 50mg.min -1 (Secura, B.Braun, Melsungen, FRG) from zero to 360 min. Infusion of pentoxifylline (2.5 mg. min 1for 2 h) or place-
234
A. Suren et al.: Pentoxifylline and liver plasma flow
Table 1. Effect of pentoxifylline and placebo on heart rate, blood pressure, cardiac output, total sorbitol clearance, renal sorbitol clearance and extrarenal sorbitol clearance in healthy volunteers (n = 10). Mean with (SEM) and (90%-confidence limits). For analysis only the last 3 measurements in each period were taken
Sampling period:
0 to 120 min
120 to 240 rain
240 to 360 min
Substance
Pentoxifylline
Placebo
Pentoxifylline
Placebo
Pentoxifylline
Placebo
Heart rate (min-i)
63 (2) (60-66)
63 (3) (59-67)
66 (2) (63~59)
63 (3) (59-67)
65 (2) (62-68)
62 (3) (58~56)
Blood pressure (mmHg) systolic
112 (2) (110-115)
111 (3) (107-115)
115 (2) (112-118)
112 (3) (108-116)
115 (2) (112-118)
113 (4) (108-119)
diastolic
74 (3) (70-78)
75 (2) (72-78)
76 (2) (73-80)
77 (2) (74-80)
77 (2) (74-80)
76 (3) (72-80)
Cardiac output (1. rain -1)
7.3 (0.5) (6.6-8.0)
7.6 (0.6) (6.8-8.4)
7.8 (0.6) (7.0-8.6)
7.4 (0.5) (6.4-8.1)
7.8 (0.8) (6.3-8.9)
6.9 (0.5) (6.4-7.6)
Total sorbitol clearance (ml.min 1)
885 (38) (832-938)
875 (47) (810-940)
914 (39) (860-968)
817 (39) (763-871)
915 (48) (849-984)
815 (44) (754-876)
Renal sorbitol clearance (ml. min 1)
117 (5) (110-124)
106 (7) (96-116)
126 (5) (119-133)
106 (6) (98-116)
114 (7) (104-124)
132 (11) (117-147)
Extrarenal sorbitol clearance (ml-min 1)
764 (35) (716-812)
769 (42) (711-827)
789 (37) (738-840)
711 (35) (663-759)
801 (477 (736-866)
683 (36) b (633-733)
Sorbitol plasma concentrations (rag. d1-1)
5.8 (0.3) (5.4-6.2)
5.9 (0.3) (5.5-6.3)
5.6 (0.2) (5.3-5.9)
6.3 (0.3) (5.9-6.7)
5.6 (0.3) (5.2-6.0)
6.5 (0.3) (6.1-6.9)
a significantly different from placebo (P
