(1/113) Incidence of analgesic nephropathy in Berlin since 1983.
BACKGROUND: Phenacetin was removed from the German market in 1986 and was replaced mainly in analgesic compounds by acetaminophen. Our objective was to examine the effect of this measure on the incidence of analgesic nephropathy in light of the changes in other end-stage renal diseases. METHODS: We therefore compared the proportion of renal diseases in all patients starting dialysis treatment during three 18-month periods: 4/1982-9/1983 (n=57); 1/1991-6/1992 (n=81); and 10/1995-3/1997 (n=76). RESULTS: On the one hand, the proportion of end-stage analgesic nephropathy decreased significantly from 30% in 1981-1982 to 21% in 1991-1992 and 12% in 1995-1997 (P=0.01). On the other hand, type II diabetes increased significantly from 7% to 22% (P=0.01) and 29%, (P=0.001). Using the chi2 distribution test to analyze the frequencies of seven diseases at three different time intervals, however, showed that the changes in renal-disease proportions between 1982-1983, 1991-1992 and 1995-1997 were not significantly independent. There was a significant median age increase from 52 years (CI0.95 44-58) in 1982-1983 to 63 (CI0.95 55-67) in 1991-1992 and 63 (CI0.95 60-66) in 1995-1997 (P=0.003) for all patients starting dialysis but not for those with analgesic nephropathy [59 (55-71) vs 64 (53-67) and 61 (50-72); n.s.]. CONCLUSION: The decrease of end-stage analgesic nephropathy since 1983 may be partially due to the removal of phenacetin from the German market in 1986. However, considering the general increase in numbers of dialysis patients, their higher age and the increased incidence of type II diabetes, the decrease in analgesic nephropathy is not a statistically significant independent variable. Altered admittance policies for dialysis treatment have yielded a new pattern of renal-disease proportion which interferes with changes in the incidence of analgesic nephropathy. (+info)
(2/113) Involvement of CYP2E1 as A low-affinity enzyme in phenacetin O-deethylation in human liver microsomes.
Phenacetin O-deethylation (POD) exhibits biphasic kinetics in human liver microsomes. Although cytochrome P-450 (CYP) 1A2 is responsible for the high-affinity component of POD, the enzyme(s) that catalyzes the low-affinity reaction is still unknown. We examined the roles of human CYPs in POD by using human liver microsomes and recombinant CYPs from baculovirus-infected insect cells. Of the recombinant CYPs studied, CYP1A2 showed the highest POD activity. CYP1A1, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 also showed POD activity at 500 microM phenacetin. K(M) values of recombinant CYP1A2 and CYP2E1 (28 +/- 2 microM and 785 +/- 125 microM, respectively) were similar to those of the high- and low-affinity components of POD in pooled human liver microsomes (15 +/- 5 and 894 +/- 189 microM, respectively). Fluvoxamine (10 microM) and anti-CYP1A2 antibodies potently inhibited POD activity at 500 microM phenacetin in pooled human liver microsomes to 22.8 and 34.2% of controls, respectively. CYP2E1 inhibitors diethyldithiocarbamate and aniline also reduced POD activity. The combination of fluvoxamine (10 microM) and aniline (1 mM) further inhibited the residual POD activity not inhibited by fluvoxamine alone. Microsomal POD activity in 12 human livers in the absence of fluvoxamine was correlated with immunoquantified CYP1A2 levels (r = 0.961, p <.001) and, in the presence of 10 microM fluvoxamine, was correlated with immunoquantified CYP2E1 levels (r = 0.589, p <.01) or chlorzoxazone 6-hydroxylase activity (r = 0.823, p <.001). These results suggest that CYP2E1 is responsible for the low-affinity component of POD in human liver microsomes. (+info)
(3/113) Role of CYP1A2 in the toxicity of long-term phenacetin feeding in mice.
The mechanisms underlying phenacetin-induced toxicity and carcinogenicity are not clear. In particular, it is not known whether these effects are mediated by metabolic activation of the drug. CYP1A2 is known to metabolize phenacetin in vitro. To determine the role of this enzyme in vivo, the toxicity and carcinogenicity of phenacetin was examined in Cyp1a2-null mice (that lack CYP1A2). Six- to 8-week-old wild type (+/+) or null (-/-) mice were fed either a control diet, or one containing 1.25% phenacetin, ad libitum for up to 67 weeks. Representative groups of mice were examined for phenacetin-induced toxicity and carcinogenicity after 36, 48, 58, or 67 weeks of feeding. Consistent with the known role of CYP1A2 in phenacetin metabolism, plasma levels of phenacetin were higher and acetaminophen levels lower in the (-/-) mice fed phenacetin compared to phenacetin-fed (+/+) controls. Weight gain was significantly depressed in both groups of phenacetin-fed mice after 4 weeks of feeding, and continued to be lower for the remainder of the experiment, compared to controls. Hepatomegaly and splenomegaly were more severe in (-/-) mice but present in both genotypes fed phenacetin at all time points assessed. Histological analysis of liver, kidney, spleen, and urogenital tract also revealed a differential response in the (-/-) mice fed phenacetin compared to (+/+) mice fed the same diet. Further, mortality was the most severe in the (-/-) mice fed phenacetin than in all other groups. Despite significant toxicity in (-/-) mice fed phenacetin, only one renal carcinoma was found among them. Results from this work demonstrate that, in the absence of CYP1A2, phenacetin is more toxic than in controls. This provides evidence that metabolism of phenacetin by CYP1A2 alters toxicity in vivo, and suggests that alternate CYP1A2-independent metabolic pathways contribute to its toxicity. (+info)
(4/113) Regular use of analgesics is a risk factor for renal cell carcinoma.
Phenacetin-based analgesics have been linked to the development of renal pelvis cancer and renal cell carcinoma (RCC). The relationship between non-phenacetin types of analgesics and kidney cancer is less clear, although laboratory evidence suggests that these drugs possess carcinogenic potential. A population-based case-control study involving 1204 non-Asian RCC patients aged 25-74 and an equal number of sex-, age- and race-matched neighbourhood controls was conducted in Los Angeles, California, to investigate the relationship between sustained use of analgesics and risk of RCC according to major formulation categories. Detailed information on medical and medication histories, and other lifestyle factors was collected through in-person interviews. Regular use of analgesics was a significant risk factor for RCC in both men and women (odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.4-1.9 for both sexes combined). Risks were elevated across all four major classes of analgesics (aspirin, non-steroidal anti-inflammatory agents other than aspirin, acetaminophen and phenacetin). Within each class of analgesics, there was statistically significant increasing risk with increasing level of exposure. Although there was some minor variability by major class of formulation, in general individuals in the highest exposure categories exhibited approximately 2.5-fold increase in risk relative to non- or irregular users of analgesics. Subjects who took one regular-strength (i.e. 325 mg) aspirin a day or less for cardiovascular disease prevention were not at an increased risk of RCC (OR = 0.9, 95% CI = 0.6-1.4). (+info)
(5/113) Possible enhancement of the first-pass metabolism of phenacetin by ingestion of grape juice in Chinese subjects.
AIMS: This serendipitous study revealed an unexpected effect of Jufeng grape juice on the CYP1A2-mediated metabolism of phenacetin. Investigation of the inhibition of CYP1A2 by grapefruit juice was involved but a translation error led to the grape juice substitution. METHODS: Twelve healthy subjects took a single oral dose of phenacetin (900 mg) on two randomized occasions together with 200 ml water or grape juice. Plasma phenacetin and paracetamol concentrations were assessed by h.p.l.c. RESULTS: Ingestion of grape juice was associated with reduced plasma phenacetin concentrations, while paracetamol levels were unaffected. Paracetamol to phenacetin AUC ratios increased from 13.9+/-3.1 to 24.3+/-3.8 after ingestion of grape juice. CONCLUSIONS: These findings suggest enhanced first-pass metabolism of phenacetin, due to CYP1A2 activation by grape juice or to desaturation of CYP1A2 isoenzymes secondary to a slower rate of phenacetin absorption. (+info)
(6/113) In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6.
AIMS: To examine the potency of ticlopidine (TCL) as an inhibitor of cytochrome P450s (CYP450s) in vitro using human liver microsomes (HLMs) and recombinant human CYP450s. METHODS: Isoform-specific substrate probes of CYP1A2, 2C19, 2C9, 2D6, 2E1 and 3A4 were incubated in HLMs or recombinant CYPs with or without TCL. Preliminary data were generated to simulate an appropriate range of substrate and inhibitor concentrations to construct Dixon plots. In order to estimate accurately inhibition constants (Ki values) of TCL and determine the type of inhibition, data from experiments with three different HLMs for each isoform were fitted to relevant nonlinear regression enzyme inhibition models by WinNonlin. RESULTS: TCL was a potent, competitive inhibitor of CYP2C19 (Ki = 1.2 +/- 0.5 microM) and of CYP2D6 (Ki = 3.4 +/- 0.3 microM). These Ki values fell within the therapeutic steady-state plasma concentrations of TCL (1-3 microM). TCL was also a moderate inhibitor of CYP1A2 (Ki = 49 +/- 19 microM) and a weak inhibitor of CYP2C9 (Ki > 75 microM), but its effect on the activities of CYP2E1 (Ki = 584 +/- 48 microM) and CYP3A (> 1000 microM) was marginal. CONCLUSIONS: TCL appears to be a broad-spectrum inhibitor of the CYP isoforms, but clinically significant adverse drug interactions are most likely with drugs that are substrates of CYP2C19 or CYP2D6. (+info)
(7/113) Phenacetin deacetylase activity in human liver microsomes: distribution, kinetics, and chemical inhibition and stimulation.
Microsomal and cytosolic phenacetin deacetylase activities were examined in human liver and kidneys. Kinetic properties of the activities were also studied in human liver microsomes. Phenacetin deacetylase activity was predominantly localized in the liver microsomal fraction. The specific activities of phenacetin deacetylation in liver cytosol and in kidney microsomes and cytosol were all less than 5% of that in liver microsomes. In human liver microsomes, Eadie-Hofstee plots for phenacetin deacetylation were monophasic, indicating a single-enzyme catalytic reaction. The Michaelis-Menten parameters, K(m) and V(max), for the deacetylation were 4.7 mM and 5.54 nmol/min/mg of protein, respectively. The intrinsic clearance, calculated as V(max)/K(m), was 1.18 microl/min/mg of protein. Although the organophosphate bis(4-nitrophenyl)phosphoric acid markedly inhibited the reaction in human liver microsomes, the activity has a tolerance to the treatment of phenylmethylsulfonyl fluoride, a serine hydrolase inhibitor. Prazosin, a peripheral alpha(1)-adrenergic antagonist, noncompetitively inhibited the phenacetin deacetylation with a K(i) value of 19.0 microM. Flutamide, a nonsteroidal androgen receptor antagonist, stimulated the activity by up to 349%. This increase was accompanied by a decrease in the K(m) value and no change in the V(max) value, resulting in an increase in the intrinsic clearance by up to 700% of the control. These results suggest that the phenacetin deacetylase localized in human liver microsomes has not only a catalytic site but also a negative and/or positive modulation site or sites. (+info)
(8/113) Diseases causing end-stage renal failure in New South Wales.
The nature of the original renal disease was determined in 403 consecutive cases of end-stage renal failure, in 317 of which the clinical diagnosis was corroborated by histological examination of the kidney. Five diseases accounted for 20 or more cases--glomerulonephritis (31% of the total), analgesic nephropathy (29%), primary vesicoureteral reflux (8%), essential hypertension (6%), and polycystic kidneys (5%). In only four cases did renal failure result from chronic pyelonephritis without a demonstrable primary cause. Greater use of micturating cystography and cystoscopy and routine urine testing for salicylate are advocated for earlier diagnosis of the major causes of "pyelonephritis". The incidence of end-stage renal failure in people aged 15-55 in New South Wales was estimated to be at least 34 new cases per million of total population each year. (+info)