Hepatic drug metabolism is increased in poorly controlled insulin-dependent diabetes mellitus
Steven
Goldstein,
Anna
Simpson and Paul Saenger
Department of Pediatrics, Division of Pédiatrie Endocrinology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, USA
to increased glycosylation of hemoglobin, abnormalities of other heme proteins such as cytochrome P-450 might also occur in patients with insulin-dependent diabetes mellitus. Antipyrine is a useful marker drug for cytochrome P-450 dependent hepatic drug metabolism. Antipyrine kinetics and urinary excretion of antipyrine metabolites were measured in 14 patients with insulin-dependent diabetes mellitus in poor metabolic control. Improvement in diabetic control in 9 patients, as measured by more normal HbA1 values, led to normalization of plasma antipyrine half-time (t\m=1/2\) and metabolism: the mean antipyrine t\m=1/2\ slowed from 4.7\m=+-\0.2(sem) initially to 7.8\m=+-\0.3h in these 9 patients and was thus nearly identical to that of normal subjects 8.6\m=+-\1.0.Antipyrine plasma clearance improved in the 9 diabetic patients whose diabetic control improved. The
Abstract. In addition
apparent volume of distribution was normal on both occasions in the diabetic patients. These findings provide a new argument for tight metabolic control in patients with insulin-dependent diabetes mellitus.
Hepatic drug metabolism is altered in response to induction of diabetes mellitus with alloxan or streptozotocin in animals (1-6). Hepatic microsomal cy¬ tochrome P-450 and the arylhydrocarbon hydroxylase activity is increased in female rate (4). From these studies it remained, however, unclear whether insulin deficiency and the resultant hyperglycemia or whether insulin resistance caused the increase in hepatic microsomal cytochrome P-450. Knodell et al. (7) concluded from their stud¬ ies in mice with genetic or chemically induced di¬ abetes mellitus that hypoinsulinemia, as well as hy-
perglycemia, may separately and significantly stim¬ ulate hepatic drug metabolism. Fat accumulation and parenchymal inflamma¬ tory changes, common hepatic alterations in adult diabetic patients, may lower hepatic cytochrome P-
450 levels (8-10). Therefore, young children and adolescents with recent onset diabetes mellitus to be more appropriate study subjects for investigation of changes in hepatic drug metab¬ olism in insulin-dependent diabetes mellitus (IDDM) than patients with longstanding non-insu¬ lin-dependent diabetes mellitus (NIDDM). The purpose of our study was to evaluate hepatic cyto¬ chrome P-450 dependent drug metabolism in such IDDM patients. Antipyrine was used as a model drug. Antipyrine is particularly well suited for such studies because it is rapidly absorbed, not signifi¬ cantly bound to plasma proteins, distributed evenly throughout body water, metabolized predomi¬ nantly by hepatic hydroxylation, and its metab¬ olism is relatively constant in a given person (11,12). The patients were studied when their di¬ abetic control was poor and again when it had im¬ proved, as judged by HbAj values.
appear an
Patients and Methods The study was approved by the Internal Review Board at Montefiore Medical Center and informed consent was given by the patients and their parents. Assent was ob¬ tained from minors. Six males and 8 females with IDDM
Association guidelines (14). Their weight changed by
Steven
Goldstein,
Anna
Simpson and Paul Saenger
Department of Pediatrics, Division of Pédiatrie Endocrinology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, USA
to increased glycosylation of hemoglobin, abnormalities of other heme proteins such as cytochrome P-450 might also occur in patients with insulin-dependent diabetes mellitus. Antipyrine is a useful marker drug for cytochrome P-450 dependent hepatic drug metabolism. Antipyrine kinetics and urinary excretion of antipyrine metabolites were measured in 14 patients with insulin-dependent diabetes mellitus in poor metabolic control. Improvement in diabetic control in 9 patients, as measured by more normal HbA1 values, led to normalization of plasma antipyrine half-time (t\m=1/2\) and metabolism: the mean antipyrine t\m=1/2\ slowed from 4.7\m=+-\0.2(sem) initially to 7.8\m=+-\0.3h in these 9 patients and was thus nearly identical to that of normal subjects 8.6\m=+-\1.0.Antipyrine plasma clearance improved in the 9 diabetic patients whose diabetic control improved. The
Abstract. In addition
apparent volume of distribution was normal on both occasions in the diabetic patients. These findings provide a new argument for tight metabolic control in patients with insulin-dependent diabetes mellitus.
Hepatic drug metabolism is altered in response to induction of diabetes mellitus with alloxan or streptozotocin in animals (1-6). Hepatic microsomal cy¬ tochrome P-450 and the arylhydrocarbon hydroxylase activity is increased in female rate (4). From these studies it remained, however, unclear whether insulin deficiency and the resultant hyperglycemia or whether insulin resistance caused the increase in hepatic microsomal cytochrome P-450. Knodell et al. (7) concluded from their stud¬ ies in mice with genetic or chemically induced di¬ abetes mellitus that hypoinsulinemia, as well as hy-
perglycemia, may separately and significantly stim¬ ulate hepatic drug metabolism. Fat accumulation and parenchymal inflamma¬ tory changes, common hepatic alterations in adult diabetic patients, may lower hepatic cytochrome P-
450 levels (8-10). Therefore, young children and adolescents with recent onset diabetes mellitus to be more appropriate study subjects for investigation of changes in hepatic drug metab¬ olism in insulin-dependent diabetes mellitus (IDDM) than patients with longstanding non-insu¬ lin-dependent diabetes mellitus (NIDDM). The purpose of our study was to evaluate hepatic cyto¬ chrome P-450 dependent drug metabolism in such IDDM patients. Antipyrine was used as a model drug. Antipyrine is particularly well suited for such studies because it is rapidly absorbed, not signifi¬ cantly bound to plasma proteins, distributed evenly throughout body water, metabolized predomi¬ nantly by hepatic hydroxylation, and its metab¬ olism is relatively constant in a given person (11,12). The patients were studied when their di¬ abetic control was poor and again when it had im¬ proved, as judged by HbAj values.
appear an
Patients and Methods The study was approved by the Internal Review Board at Montefiore Medical Center and informed consent was given by the patients and their parents. Assent was ob¬ tained from minors. Six males and 8 females with IDDM
Association guidelines (14). Their weight changed by
