573
Atherosclerosis, 26 (1977) 573-582 Scientific @ Elsevier/North-Holland
Publishers,
Ltd.
PHARMACOKINETICS OF CLOFIBRATE HYPERCHOLESTEROLEMIA
RAFAEL
PICHARDO
Department of Montreal, of Montreal,
(By invitation,
*, LUCIE BOULET
of Lipid Metabolism Section of Vascular School of Medicine,
received
January,
IN FAMILIAL
and JEAN DAVIGNON
and Atherosclerosis Research, Medicine, HGtel-Dieu Hospital Montreal, Que. (Canada)
Clinical Research Institute of Montreal, and University
1977)
Summary Some patients with familial hypercholesterolemia (FHC, type II) are highly responsive to the cholesterol-lowering effect of clofibrate, while others are not only resistant to this effect but may even show an increase in plasma beta-lipoproteins. In an attempt to find an explanation for these striking differences, we have studied the pharmacokinetics of clofibrate in FHC patients at both extremes of responsiveness. The results disclosed several major differences between the two groups. Plasma clofibric acid (CPIB) measured during the chronic administration of the drug was significantly higher in the responders than in the non-responders, whether all patients in each group or only those with tendon xanthomas were considered. Plasma CPIB concentrations were negatively correlated with body weight in the responders but not in CPIB-resistant patients. They were also inversely proportional to decreases in plasma beta-lipoprotein cholesterol after chronic clofibrate administration in the responsive group, but directly proportional to increases in the non-responders. Increasing the dose of clofibrate from 2 to 3 g/day in CPIB-resistant patients always resulted in an increase in plasma CPIB levels, but this was followed in some patients by a decrease and in others by an increase in plasma beta-lipoprotein cholesterol concentrations, so that the overall effect was not statistically significant. The half-life of plasma CPIB was measured over 48 h after a single l-g dose of clofibrate in patients who had not received this drug for at This paper is dedicated to Professor, F.G. Schettler on the occasion of his sixtieth birthday. Part of this work was presented at the IVth International Symposium on Atherosclerosis, Tokyo, August 1976, and at the Club de Recherches Cliniques du Quebec, Orford. PQ, October 1976. It was supported by grants from the Quebec Heart Foundation, the Macdonald-Stewart Foundation, and the Medical Research Council of Canada (MA-2432). Reprint requests and correspondence should be addressed to Dr. J. Davignon, Clinical Research Institute. 110 Pine Avenue West, Montreal, Quebec HZW lR7, Canada. * Present address: Centro Cardiovascular Josefa Perdomo esq. J. Joaquin Perez, Santa-Domingo, Republica Dominicana.
least 3 weeks. Half-life was significantly longer in the responsive patients. In addition, the bioavailability and the rate of absorption of clofibrate tended to be higher in this group than in the resistant patients. We suspect that both groups differ not only in the metabolic handling of clofibrate but also in some aspect of their beta-lipoprotein cholesterol metabolism. Key words:
Beta-lipoprotein - Clofibrate Familial hypercholesterolemia
-
Clofibric
acid pharmacokinetics
-
Introduction In the treatment of primary hyperlipoproteinemias, the response of plasma cholesterol to a lipid-lowering drug is far from being uniformly predictable. This is especially striking for clofibrate in the management of familial hypercholesterolemia (FHC, Type II) [l]. Although a 20% reduction of plasma triglycerides may be expected in most instances, a wide range of responses may be observed for plasma cholesterol from patient to patient. At one extreme, the responsive FHC patient may show a 30% decrease in plasma cholesterol concentration, while at the other extreme a 10% increase may be elicited by clofibrate administration. Type IIa patients, with values of plasma cholesterol and triglycerides widely apart, are more likely to be among the “responders”, while Type IIb patients, with elevated plasma triglycerides, are more often resistant to the cholesterol-lowering effect of this drug [ 11. In an attempt to find an explanation for these differences, we have studied several aspects of the pharmacokinetics of clofibrate in familial hypercholesterolemia. We have selected patients at the two extremes of response for comparison. The results show that the metabolic handling of clofibrate differs widely between the two groups. In the responders, the circulating form of clofibrate - clofibric acid (CPIB) - has a longer half-life and is maintained at higher plasma concentrations on sustained oral administration. Materials and Methods Patients
We reviewed records of 125 patients studied at our lipid clinic in order to obtain a number of subjects which met the following criteria: familial hypercholesterolemia, absence of secondary causes for hyperlipidemia, “responsiveness” or “resistance” to the cholesterol-lowering effect of clofibrate as defined below, dependability, and willingness to participate in the study. Thirty-three ambulatory patients aged 14-61 years were included. There were 19 women and 14 men, all French-Canadian Caucasians. The diagnosis of familial hypercholesterolemia was based on clinical features and family history as well as on abnormalities of plasma lipids and lipoproteins [1,2]. All secondary causes of hyperlipidemia were excluded by a thorough clinical evaluation, supplemented by appropriate laboratory tests. None of the subjects had alcoholism, hypothyroidism or abnormal glucose tolerance. fl-Lipoprotein cholesterol (“PLP-cholesterol”) plasma concentration was higher than 190 mg/dl in all
575 TABLE
1
CLINICAL AND LABORATORY DATA, PLASMA LIPID CHANGES AND PLASMA CPIB LEVELS IN TYPE II PATIENTS RESPONSIVE OR RESISTANT TO THE CHOLESTEROL-LOWERING EFFECT OF CLOFIBRATE CPIB-responsive Number of patients Number of women Number with tendon xanthomas Family history of premature CHD Number of Types IIa
18 12 10 8 14
Age (X + SD) Age range Weight (kg, X f. SD Height (cm.? ? SD) Ponderal index ’ @? SD) Range of ponderal index Fasting blood
Basal plasma PLP-cholesterol PLP-cholesterol on CPIB b Percent change (A?%) Basal plasma triglycerides Triglycerides on CIPB b Percent change (A%%) Basal plasma TG/TC
b
b
15 7 8 9 7 41.9 + 10.5 (27-59)
N.S.
59.9 + 8.9 160.6 + 11.5 12.5 + 0.77 (11.2-14.0)
67.3 f 13.0 167.1 + 7.5 12.4 + 0.47 (11.5-13.3)
Atherosclerosis, 26 (1977) 573-582 Scientific @ Elsevier/North-Holland
Publishers,
Ltd.
PHARMACOKINETICS OF CLOFIBRATE HYPERCHOLESTEROLEMIA
RAFAEL
PICHARDO
Department of Montreal, of Montreal,
(By invitation,
*, LUCIE BOULET
of Lipid Metabolism Section of Vascular School of Medicine,
received
January,
IN FAMILIAL
and JEAN DAVIGNON
and Atherosclerosis Research, Medicine, HGtel-Dieu Hospital Montreal, Que. (Canada)
Clinical Research Institute of Montreal, and University
1977)
Summary Some patients with familial hypercholesterolemia (FHC, type II) are highly responsive to the cholesterol-lowering effect of clofibrate, while others are not only resistant to this effect but may even show an increase in plasma beta-lipoproteins. In an attempt to find an explanation for these striking differences, we have studied the pharmacokinetics of clofibrate in FHC patients at both extremes of responsiveness. The results disclosed several major differences between the two groups. Plasma clofibric acid (CPIB) measured during the chronic administration of the drug was significantly higher in the responders than in the non-responders, whether all patients in each group or only those with tendon xanthomas were considered. Plasma CPIB concentrations were negatively correlated with body weight in the responders but not in CPIB-resistant patients. They were also inversely proportional to decreases in plasma beta-lipoprotein cholesterol after chronic clofibrate administration in the responsive group, but directly proportional to increases in the non-responders. Increasing the dose of clofibrate from 2 to 3 g/day in CPIB-resistant patients always resulted in an increase in plasma CPIB levels, but this was followed in some patients by a decrease and in others by an increase in plasma beta-lipoprotein cholesterol concentrations, so that the overall effect was not statistically significant. The half-life of plasma CPIB was measured over 48 h after a single l-g dose of clofibrate in patients who had not received this drug for at This paper is dedicated to Professor, F.G. Schettler on the occasion of his sixtieth birthday. Part of this work was presented at the IVth International Symposium on Atherosclerosis, Tokyo, August 1976, and at the Club de Recherches Cliniques du Quebec, Orford. PQ, October 1976. It was supported by grants from the Quebec Heart Foundation, the Macdonald-Stewart Foundation, and the Medical Research Council of Canada (MA-2432). Reprint requests and correspondence should be addressed to Dr. J. Davignon, Clinical Research Institute. 110 Pine Avenue West, Montreal, Quebec HZW lR7, Canada. * Present address: Centro Cardiovascular Josefa Perdomo esq. J. Joaquin Perez, Santa-Domingo, Republica Dominicana.
least 3 weeks. Half-life was significantly longer in the responsive patients. In addition, the bioavailability and the rate of absorption of clofibrate tended to be higher in this group than in the resistant patients. We suspect that both groups differ not only in the metabolic handling of clofibrate but also in some aspect of their beta-lipoprotein cholesterol metabolism. Key words:
Beta-lipoprotein - Clofibrate Familial hypercholesterolemia
-
Clofibric
acid pharmacokinetics
-
Introduction In the treatment of primary hyperlipoproteinemias, the response of plasma cholesterol to a lipid-lowering drug is far from being uniformly predictable. This is especially striking for clofibrate in the management of familial hypercholesterolemia (FHC, Type II) [l]. Although a 20% reduction of plasma triglycerides may be expected in most instances, a wide range of responses may be observed for plasma cholesterol from patient to patient. At one extreme, the responsive FHC patient may show a 30% decrease in plasma cholesterol concentration, while at the other extreme a 10% increase may be elicited by clofibrate administration. Type IIa patients, with values of plasma cholesterol and triglycerides widely apart, are more likely to be among the “responders”, while Type IIb patients, with elevated plasma triglycerides, are more often resistant to the cholesterol-lowering effect of this drug [ 11. In an attempt to find an explanation for these differences, we have studied several aspects of the pharmacokinetics of clofibrate in familial hypercholesterolemia. We have selected patients at the two extremes of response for comparison. The results show that the metabolic handling of clofibrate differs widely between the two groups. In the responders, the circulating form of clofibrate - clofibric acid (CPIB) - has a longer half-life and is maintained at higher plasma concentrations on sustained oral administration. Materials and Methods Patients
We reviewed records of 125 patients studied at our lipid clinic in order to obtain a number of subjects which met the following criteria: familial hypercholesterolemia, absence of secondary causes for hyperlipidemia, “responsiveness” or “resistance” to the cholesterol-lowering effect of clofibrate as defined below, dependability, and willingness to participate in the study. Thirty-three ambulatory patients aged 14-61 years were included. There were 19 women and 14 men, all French-Canadian Caucasians. The diagnosis of familial hypercholesterolemia was based on clinical features and family history as well as on abnormalities of plasma lipids and lipoproteins [1,2]. All secondary causes of hyperlipidemia were excluded by a thorough clinical evaluation, supplemented by appropriate laboratory tests. None of the subjects had alcoholism, hypothyroidism or abnormal glucose tolerance. fl-Lipoprotein cholesterol (“PLP-cholesterol”) plasma concentration was higher than 190 mg/dl in all
575 TABLE
1
CLINICAL AND LABORATORY DATA, PLASMA LIPID CHANGES AND PLASMA CPIB LEVELS IN TYPE II PATIENTS RESPONSIVE OR RESISTANT TO THE CHOLESTEROL-LOWERING EFFECT OF CLOFIBRATE CPIB-responsive Number of patients Number of women Number with tendon xanthomas Family history of premature CHD Number of Types IIa
18 12 10 8 14
Age (X + SD) Age range Weight (kg, X f. SD Height (cm.? ? SD) Ponderal index ’ @? SD) Range of ponderal index Fasting blood
Basal plasma PLP-cholesterol PLP-cholesterol on CPIB b Percent change (A?%) Basal plasma triglycerides Triglycerides on CIPB b Percent change (A%%) Basal plasma TG/TC
b
b
15 7 8 9 7 41.9 + 10.5 (27-59)
N.S.
59.9 + 8.9 160.6 + 11.5 12.5 + 0.77 (11.2-14.0)
67.3 f 13.0 167.1 + 7.5 12.4 + 0.47 (11.5-13.3)
