Impairment of the metabolism of dipyrone in asymptomatic carriers of the hepatitis-B virus does not occur in rapid acetylators.

OBJECTIVE: We previously found that, compared with healthy subjects. asymptomatic hepatitis-B virus (HBV) carriers displaying slow acetylator phenotype demonstrate a significant prolongation of the elimination half-life of 4-methylaminoantipyrine (MAA) and a decrease in the clearance of formation of 4-aminoantipyrine (AA) and 4-formylaminoantipyrine (FAA). However, the formation of 4-acetylaminoantipyrine (AAA) was unchanged. The present study was designed to examine the effect of the asymptomatic HBV carrier state on the metabolism of dipyrone. as a model drug, in rapid acetylators. METHODS: The plasma and urine concentrations of the metabolites of dipyrone were measured in eight asymptomatic HBV carriers and eight healthy subjects who had normal liver function tests, all displaying the rapid acetylation phenotype and genotype, after the administration of a 1.0-g oral dose of dipyrone. RESULTS: The following pharmacokinetic parameters were evaluated: peak plasma concentration, time to peak plasma concentration, elimination rate constant, area under the plasma concentration-time curve (0-->infinity), amount excreted (0-->infinity), renal and non-renal clearances for MAA and the clearances of formation for AA, FAA and AAA. No significant differences were found between the two subject groups. CONCLUSION: The effect of hepatic viral carrier state on drug metabolism may vary according to metabolic pathways and genetic polymorphism.

Abrupt increase of tacrolimus blood levels during an episode of Shigella infection in a child after liver transplantation.

The authors report the case of an 8-year-old girl who underwent a liver transplant at the age of 18 months because of biliary atresia. She was treated with cyclosporin for more than 5 years. Increased hirsutism prompted a change to tacrolimus therapy. During 11 months the mean tacrolimus level was 8.2 ng/mL. The patient was hospitalized because of an episode of Shigella infection and a threefold increase in tacrolimus level was measured. Despite a reduction of tacrolimus dose, the trough tacrolimus levels were in the range of 16.5 to 22.0 ng/mL during the subsequent 2 weeks. On resolution of the diarrhea, tacrolimus levels returned to those observed before the Shigella infection. It is suggested that the marked increase in tacrolimus levels observed in this patient is a direct result of the damage produced to the gastrointestinal mucosa by the Shigella infection.

Pharmacokinetics of methotrexate in cerebrospinal fluid and serum after osmotic blood-brain barrier disruption in patients with brain lymphoma.

OBJECTIVE: To evaluate the pharmacokinetics of methotrexate in ventricular cerebrospinal fluid and serum after osmotic blood-brain barrier disruption and intra-arterial administration compared with intravenous or simple intra-arterial infusion in patients with primary central nervous system lymphoma. METHODS: Serum and ventricular cerebrospinal fluid were sampled after methotrexate administration in 12 patients. Blood-brain barrier disruption was induced on 2 sequential days by mannitol (25%) infusion delivered to the vertebral or internal carotid artery territories followed by intra-arterial methotrexate (dose, 1.4 g/m2; 47 treatments). Sixteen treatments were given without barrier disruption by intravenous (3.5 g/m2; nine treatments) or intra-arterial (2.8 g/m2; seven treatments) infusion. RESULTS: Ventricular cerebrospinal fluid-methotrexate peak levels after blood-brain barrier disruption of the vertebral and the internal carotid arteries territories were 19.3 +/- 2.9 and 8.5 +/- 0.7 micromol/L (P < .001), and the area under the curve from time 0 to infinity was 178.0 +/- 21.3 and 110.0 +/- 12.4 [micromol/L x h, respectively (P < .01). No significant differences were observed in serum levels. After intra-arterial infusion was performed without disruption, the serum peak level was higher than that achieved by intravenous treatment (518.2 +/- 67.7 versus 180.6 +/- 31.8 micromol/L; P < .001). No differences were observed in cerebrospinal fluid concentrations, which dropped below 1 micromol/L at 6 hours. The cerebrospinal fluid/serum ratio [AUC(%)] of methotrexate after blood-brain barrier disruption was three to four times greater than that by systemic administration. CONCLUSION: Enhanced methotrexate delivery to the central nervous system can be attained by intra-arterial administration combined with osmotic disruption of the blood-brain barrier compared with simple intra-arterial or intravenous administration.

The effect of short-term dipyrone administration on cyclosporin pharmacokinetics.

BACKGROUND: A large number of drugs have been shown to affect the metabolism of cyclosporin A (CSA) and, since cyclosporin is characterized by a narrow therapeutic range, the consequences of such drug interactions may often be of clinical importance. OBJECTIVE: To evaluate the effect of short-term administration of dipyrone on steady state CSA pharmacokinetics. METHODS: Six kidney- and two heart-transplanted patients on chronic CSA therapy participated in this study, which consisted of two 4-day study periods separated by 3-week washout periods. The patients received, in addition to their usual drugs, dipyrone 500 mg or placebo t.i.d., as identical-looking tablets, and the order of administration was randomized. CSA concentrations were measured in whole blood by means of radio-immunoassay (CYCLO-Trac SP) daily during the study periods and periodically over 24 h on the fourth study day. RESULTS: CSA concentrations over time were reduced after dipyrone (ANOVA, P < 0.01), but statistical significance was noted only at 2, 4, 5 and 10 h after drug intake (P < 0.05). Peak CSA concentration was not altered by dipyrone, but the time required to reach maximal concentration was longer with dipyrone treatment than with the placebo (3.8 +/- 2.6 h vs 2.1 +/- 0.6 h, P < 0.05). No consistent changes were noted for CSA trough level, elimination half-life and area under the concentration-time curve from 0 h to 12 h. Separate analysis of the kidney transplanted patients yielded similar results. CONCLUSIONS: Short-term administration of dipyrone is associated with a mild decrease in CSA blood concentration, which is most prominent in the first few hours after drug intake. In practice, no dose adjustment of CSA seems to be indicated during a short course of dipyrone treatment.

Influence of external biliary drainage on cyclosporin A (Neoral) absorption in a pediatric liver transplant recipient.

We report on a patient who underwent a liver transplant 8 yr ago at the age of 2. The post-operative course and further follow-up were uneventful, maintaining immunosuppression with cyclosporin A (CsA) (Sandimmune) and prednisone; 1.5 yr ago, the patient was converted to Neoral. The mean +/- SD trough CsA level was 127 +/- 37.2 ng/mL, when the patient was maintained on a daily dose of 180 mg. Following an increase in gamma-GTP levels, a biliary-enteric anastomotic stricture was found. Dilatation was performed and a tube placed for external biliary drainage. Three days later the trough CsA level was at the limit of detection; consequently, the Neoral dose was increased to 480 mg/d. CsA concentration measured 5 days later reached 164 ng/mL. After restoring internal biliary drainage the dose was decreased to 180 mg/d and the CsA level was 142 ng/mL. Later on the CsA dose was further reduced to 160 mg/d (a third of the dose during external biliary drainage) and trough levels were maintained at 90-120 ng/mL. We suggest that CsA dose adjustment and continuous drug monitoring are necessary when bile flow is compromised, in order to prevent rejection of the transplanted liver.

Systemic absorption of lidocaine after topical application for the treatment of oral mucositis in bone marrow transplantation patients.

This paper evaluates lidocaine absorption via oral mucosa following its topical application for symptomatic treatment of bone marrow transplantation (BMT)-induced oral mucositis. Five patients with high-grade oral mucositis after allogeneic BMT were entered consecutively into the study. Five healthy individuals served as controls. All 10 participants rinsed their mouth with 5 ml of a 2% lidocaine solution for 1 min, after which they expectorated the liquid. Blood samples were drawn at 1, 5, 10, 20, 30 and 60 min after rinsing and centrifuged. Plasma lidocaine levels were measured by fluorescence polarization immunoassay. In the BMT patients, plasma lidocaine levels were lower than the therapeutic range of this drug (0.2 microg/ml vs 1.5-5.5 microg/ml), while in the controls no detectable lidocaine levels were noted. The data from this preliminary study indicate that lidocaine prescribed as an anesthetic mouthwash in BMT patients with oral mucositis results in minor systemic absorption of the drug.

Cerebrospinal fluid and plasma concentrations of dipyrone metabolites after a single oral dose of dipyrone.

OBJECTIVE: Dipyrone is a veteran analgesic and antipyretic drug. After oral administration it is rapidly converted by hydrolysis to 4-methylaminoantipyrine (MAA), which is further metabolized to 4-formylaminoantipyrine (FAA), 4-aminoantipyrine (AA) and 4-acetylaminoantipyrine (AAA). It is still debated whether the site of dipyrone action is in the central nervous system or in the periphery. The purpose of this study was to assess whether dipyrone metabolites cross the blood-brain barrier (BBB) when administered systemically. METHODS: Twenty-eight patients undergoing diagnostic lumbar puncture (LP) were randomly assigned to receive two 0.5-g dipyrone tablets either 30 min, 1, 1.5, 2, 4, 6, 8 h or 12 h before the lumbar tap. A 5-ml blood sample was drawn concomitantly. RESULTS: All four metabolites were found in the cerebrospinal fluid (CSF). Their appearance in the CSF lagged but followed that found in the plasma. Mean CSF/plasma ratios were 0.40 (for samples taken between 0.5-2 h) and 0.83 (for samples taken between 4-12 h) for MAA, 0.62 for AA, 0.55 for FAA and 0.40 for AAA (for all samples). Significant correlation was found between plasma and CSF concentrations for MAA, AA, FAA and AAA. CONCLUSION: The concentration-time course of dipyrone metabolite CSF concentrations are in agreement with that of their plasma concentrations and the analgesic effect of dipyrone.

Cerebrospinal fluid prostaglandins after systemic dipyrone intake.

OBJECTIVE: The object of this study was to evaluate the time course of thromboxane B2 and prostaglandin E2 concentrations in cerebrospinal fluid after oral administration of dipyrone (INN, metamizole). METHODS: A single 1.0 gm oral dose of dipyrone was given to consenting patients undergoing elective diagnostic lumbar puncture 0.5, 1, 1.5, 2, 4, 6, 8, or 12 hours before the tap. RESULTS: For thromboxane B2 a time decrease in cerebrospinal fluid concentration was apparent. In contrast, for prostaglandin E2 cerebrospinal fluid levels no consistent trend was observed. CONCLUSIONS: A time-related decrease in cerebrospinal fluid thromboxane B2 level was noted in patients receiving dipyrone. Thirty minutes after dipyrone intake cerebrospinal fluid thromboxane B2 levels already tended to be lower than those seen in patients with neurologic diseases who were not receiving dipyrone. These results are consistent with the hypothesis that dipyrone acts in the central nervous system by inhibition of particular prostanoids.

Digoxin intoxication in a patient with end-stage renal disease: efficacy of digoxin-specific Fab antibody fragments and peritoneal dialysis.

Digoxin intoxication is a serious medical problem, and impairment of renal function is a common risk factor for toxicity. Digoxin specific antibody fragments (Fab) is the most effective treatment available for severe digitalis intoxication. The use of Fab therapy in a patient with renal disease is considered as effective as in patients with normal renal function, although the increased risk of rebound digoxin toxicity mandates a longer period of observation. In patients with kidney failure, neither digoxin nor Fab can be removed efficiently from the systemic circulation by hemodialysis or continuous arteriovenous hemofiltration. Knowledge about the clearance of both compounds by peritoneal dialysis is limited. The authors describe a patient with end stage renal disease who was treated with Fab and peritoneal dialysis for life threatening digoxin intoxication. Like other forms of dialysis, peritoneal dialysis, even when performed in an intensive schedule, is not associated with an enhanced clearance of digoxin.

Impairment of the metabolism of dipyrone in asymptomatic carriers of the hepatitis B virus.

BACKGROUND: The pharmacokinetics of a number of drugs has been shown to be impaired in patients with acute or chronic viral liver disease. OBJECTIVE: To examine the effect of the asymptomatic hepatitis B virus carrier state on the metabolism of dipyrone (INN, metamizole) as a model drug. METHODS: The pharmacokinetics of the metabolites of dipyrone-4-methylaminoantipyrine, 4-aminoantipyrine, 4-formylaminoantipyrine, and 4-acetylaminoantipyrine-after a 1.0 gm oral dose of dipyrone were evaluated in nine asymptomatic carriers of hepatitis B virus with normal liver function tests and nine healthy subjects. All subjects displayed the slow acetylator phenotype. RESULTS: The nonrenal (metabolic) clearance of 4-methylaminoantipyrine was significantly reduced (mean +/- SEM) (123.3 +/- 15.8 versus 182.9 +/- 15.1 ml.min-1, respectively; p < 0.02) in the carriers of hepatitis B virus compared with the healthy subjects, and the elimination half-life of this metabolite was significantly longer (3.69 +/- 0.35 versus 2.64 +/- 0.28 hours, respectively; p < 0.03). The formation clearances of 4-aminoantipyrine and 4-formylaminoantipyrine were significantly smaller in the carriers of hepatitis B virus compared with healthy subjects (33.8 +/- 6.2 versus 55.2 +/- 6.4 ml.min-1; p < 0.03, and 16.7 +/- 2.2 versus 34.2 +/- 4.2 ml.min-1; p < 0.002; respectively). However, the elimination half-life of 4-formylaminoantipyrine was found to be slightly shorter in the carriers of hepatitis B virus. No significant differences were noted between the groups in the pharmacokinetics of 4-acetylaminoantipyrine. CONCLUSION: The metabolism of dipyrone is impaired in asymptomatic carriers of hepatitis B virus. Clinically latent infection with hepatitis B virus seems to exert a differential effect on metabolism of the drug. Oxidative pathways to produce 4-aminoantipyrine and 4-formylaminoantipyrine were significantly affected, whereas acetylation remained intact. This study provided an additional example of the effect of a virus on the disposition of a drug.

Treatment of glioblastoma U-87 by systemic administration of an antisense protein kinase C-alpha phosphorothioate oligodeoxynucleotide.

Glioblastoma multiforme is the most common form of malignant brain cancer in adults and, unfortunately, is not amenable to treatment with current therapeutic modalities. Human glioblastoma U-87 has many of the distinguishing phenotypic features of primary glioblastoma, including an autocrine form of proliferation, high levels of protein kinase C alpha (PKC alpha), and infiltration via white matter tracts. We show that treatment of mice bearing U-87 xenografts with an antisense phosphorothioate oligodeoxynucleotide (S-oligodeoxynucleotide) against the 3'-untranslated region of PKC alpha mRNA results in suppression of tumor growth. Growth was inhibited in both subcutaneous and intracranial tumors, and in the latter instance, treatment with the antisense PKC alpha S-oligodeoxynucleotide resulted in a doubling in median survival time ( > 80 days), with 40% long term survivors. The antisense S-oligodeoxynucleotide did not produce systemic toxicity in mice with subcutaneous or intracranial tumors after daily intraperitoneal injection for 21 or 80 days, respectively, and a scrambled S-oligodeoxynucleotide with the same nucleotide composition as the antisense S-oligodeoxynucleotide did not produce an antitumor effect. The intratumoral levels of both antisense and scrambled S-oligodeoxynucleotide in subcutaneous tumors were 2 microM after 21 daily doses of 20 mg/kg S-oligodeoxynucleotide. The antisense S-oligodeoxynucleotide selectively reduced the levels of PKC alpha in subcutaneous tumors but not those of protein kinase C epsilon or protein kinase C zeta. This is the first demonstration that the growth of glioblastoma multiforme can be suppressed by an antisense PKC alpha S-oligodeoxynucleotide and suggests that this may represent an effective therapy for this type of malignancy.

Carbamazepine pharmacokinetics in obese and lean subjects.

OBJECTIVE: To compare carbamazepine pharmacokinetic parameters between obese and lean subjects following the administration of a single 200-mg tablet. DESIGN: Single-dose intervention, open study. SETTING: Teaching university hospital. SUBJECTS: Eighteen obese (group A) otherwise healthy subjects, referred to the metabolic outpatient clinic, and 13 healthy lean (group B) volunteers. Inclusion criterion for the obese subjects was a body mass index (BMI = weight/height2) of more than 30 kg/m2. In the obese group, mean +/- SD total body weight (TBW), BMI, and percent of ideal body weight (IBW) were 111.4 +/- 19.9 kg, 38.8 +/- 6.0 kg/m2, and 182.7% +/- 30.7%, respectively. These values were significantly greater than the respective values of 63.2 +/- 8.3 kg, 22.4 +/- 1.6 kg/m2, and 105.8% +/- 5.8% obtained in the lean group (p < 0.001). INTERVENTION: Single-dose oral administration of carbamazepine 200-mg tablet (Teril, Taro, Israel). OUTCOMES: Carbamazepine elimination half-life (t1/2), apparent volume of distribution (Varea/F), and its oral clearance (Clpo/F) were derived from the drug concentration-time curves. RESULTS: Carbamazepine Varea/F and t1/2 were significantly greater in group A than in group B (98.4 +/- 26.9 vs. 60.7 +/- 8.5 L, respectively, p < 0.001; and 59.4 +/- 14.7 vs. 31.0 +/- 5.0 h, respectively, p < 0.001), but its Clpo/F was reduced only slightly in obese as compared with lean subjects (19.8 +/- 5.2 vs. 23.0 +/- 4.6 mL/min, respectively, p = 0.07). Correction for IBW yielded similar results for Varea/F and t1/2, but Clpo/F per kg of IBW was significantly smaller in the obese than in the lean subjects (0.32 +/- 0.07 vs. 0.39 +/- 0.06 mL/min/kg of IBW, respectively, p < 0.02). Linear correlations were observed between Varea/F and TBW for both group A (r = 0.92, p < 0.001) and group B (r = 0.77, p < 0.002). CONCLUSIONS: In comparison with lean subjects, carbamazepine Varea/F is significantly greater in obese subjects and its t1/2 is markedly prolonged. The minor nonsignificant effect of obesity on carbamazepine Clpo/F suggests that in obese subjects the carbamazepine daily dose should be based on IBW, not on TBW.

Dipyrone metabolism in liver disease.

BACKGROUND AND OBJECTIVES: Dipyrone is an analgesic, antipyretic, and anti-inflammatory drug. After oral administration it is hydrolyzed to 4-methylaminoantipyrine and further metabolized to 4-aminoantipyrine, 4-formylaminoantipyrine, and 4-acetylaminoantipyrine. This study investigated the disposition of dipyrone metabolites in 12 hospitalized patients with cirrhosis (age, 25 to 65 years) and 27 healthy subjects of two age groups (young, 21 to 40 years; elderly, 73 to 90 years). METHODS: Subjects received 1 gm dipyrone orally, and blood samples were drawn and urine collected over 72 hours. Plasma and urine concentrations of the four metabolites were determined by HPLC. RESULTS: 4-Methylaminoantipyrine terminal elimination half-life (t1/2 beta) in patients with cirrhosis was prolonged compared with young and elderly subjects (mean +/- SEM, 10.6 +/- 0.6 versus 3.1 +/- 0.2 and 4.9 +/- 0.6 hours, p < 0.001), and the nonrenal clearance was reduced compared with the young subjects (1.069 +/- 0.243 versus 2.165 +/- 0.154 ml/min/kg, p < 0.005). 4-Formylaminoantipyrine was undetectable in two patients and in the remaining 10 patients, t1/2 was longer than in the young subjects (26.4 +/- 4.3 versus 10.8 +/- 0.7 hour, p < 0.01), whereas the elderly had intermediate values (18.1 +/- 2.8 hours). Clearance for production of 4-formylaminoantipyrine was reduced in the patients with cirrhosis than in the young and elderly subjects (0.109 +/- 0.024 versus 0.363 +/- 0.031 and 0.340 +/- 0.053 ml/min/kg, p < 0.001). The acetylation phenotype was determined to evaluate the pharmacokinetic parameters of 4-aminoantipyrine and 4-acetylaminoantipyrine. Prolongation of the 4-aminoantipyrine t1/2 and decrease in its clearance for production was found for the patients with cirrhosis, both slow and rapid acetylators, compared with the young and elderly subjects (p < 0.01). 4-Acetylaminoantipyrine t1/2 was also prolonged for patients with cirrhosis, slow and rapid acetylators, compared with the young subjects (p < 0.005). In the slow acetylators, clearance for production of 4-acetylaminoantipyrine did not differ between the patients with cirrhosis and the young subjects (p < 0.5); however, a difference was found for the rapid acetylators (p < 0.001). CONCLUSION: Our results show that the disposition of 4-methylaminoantipyrine, 4-aminoantipyrine, 4-formylaminoantipyrine, and 4-acetylaminoantipyrine is reduced by chronic liver disease after a single oral dose of dipyrone.

Caffeine pharmacokinetics in obesity and following significant weight reduction.

OBJECTIVES: To compare caffeine pharmacokinetics (200 mg single oral dose) between obese and lean subjects and in obese subjects prior to and following weight reduction. In the obese group antipyrine (1000 mg single oral dose) pharmacokinetics were also evaluated one week before caffeine administration. SETTING: Teaching university hospital. DESIGN: Single dose, open study. SUBJECTS: Twenty obese subjects (Group A) (BMI exceeding 30 kg/m2), referred from the outpatient metabolic clinic and 14 lean (Group B) subjects participated in the study. Weight (mean +/- s.d.) and BMI were significantly greater in the obese than the lean subjects (110.4 +/- 19.2 vs 66.9 +/- 13.3 kg respectively, and 38.5 +/- 5.8 vs 22.6 +/- 1.7 kg/m2 respectively, P < 0.001). INTERVENTIONS: Single dose oral administration of caffeine (200 mg) and antipyrine (1000 mg) in Group A and only caffeine in Group B. Twice single dose oral administrations of caffeine (200 mg) in six subjects (Group C), prior to and following weight loss. MAIN OUTCOME MEASURES: Caffeine and antipyrine pharmacokinetics were derived from the plasma concentrations-time curves. RESULTS: Caffeine elimination half-life (T1/2) and clearance (CLo) were similar in obese and lean subjects (6.54 +/- 2.85 vs 6.08 +/- 2.23 h respectively and 100.7 +/- 49.5 vs 82.6 +/- 34.0 ml/min respectively, P > 0.05). Caffeine Varea was greater in group A than in Group B (48.3 +/- 11.4 vs 40.1 +/- 13.0 L respectively, P = 0.06) but when corrected for body weight significantly reduced values were obtained in the obese group (0.44 +/- 0.06 vs 0.59 +/- 0.10 L/kg respectively, P < 0.001). In group A subjects caffeine and antipyrine Varea were similar (48.3 +/- 11.4 vs 49.9 +/- 9.3 L respectively, P > 0.3). Caffeine T1/2 and CLo were not significantly altered by the 30.2 +/- 12.3 kg weight loss obtained in Group C subjects, but caffeine Varea was significantly reduced (55.6 +/- 9.3 L before, 47.8 +/- 9.5 L after, P < 0.04) and Varea corrected for body weight was significantly increased (0.46 +/- 0.03 L/kg before, 0.52 +/- 0.05 L/kg after, P < 0.05). CONCLUSIONS: Caffeine pharmacokinetics are only minimally altered by obesity. The use of caffeine containing drugs in obese subjects does not necessitate significant dosage modification.

Clinical pharmacokinetics of dipyrone and its metabolites.

The pharmacokinetics of dipyrone are characterised by rapid hydrolysis to the active moiety 4-methyl-amino-antipyrine (MAA), which has 85% bioavailability after oral administration in tablet form, and takes a short time to achieve maximal systemic concentrations (tmax of 1.2 to 2.0 hours). Absolute bioavailability after intramuscular and rectal administration is 87 and 54%, respectively. MAA is further metabolised with a mean elimination half-life (t1/2) of 2.6 to 3.5 hours to 4-formyl-amino-antipyrine (FAA), which is an end-metabolite, and to 4-amino-antipyrine (AA), which is then acetylated to 4-acetyl-amino-antipyrine (AAA) by the polymorphic N-acetyl-transferase (t1/2 of AA is 3.8 hours in rapid acetylators and 5.5 hours in slow acetylators). Urinary excretion of these 4 metabolites accounts for about 60% of the administered dose of dipyrone. Protein binding of the 4 main metabolites is less than 60%. The volume of distribution of MAA is about 1.15 L/kg of lean body mass. All 4 metabolites are excreted into breast milk. A single-dose study (0.75, 1.5 and 3g) and a multiple-dose study (1g 3 times a day for 7 days) revealed nonlinear pharmacokinetics consistent with a shift of MAA metabolism from FAA to AA. Apparent MAA clearance decreased by 22% during multiple administration. MAA clearance was reduced by 33% in the elderly. In patients with cirrhosis of the liver, the apparent clearance of all metabolites is generally reduced. In patients with renal disease, apparent clearance of MAA remains unchanged, whereas elimination of the renally excreted metabolites AAA and FAA is markedly impaired. No clinically important drug interactions have thus far been recognised. Dipyrone does not affect the pharmacodynamic response to alcohol (ethanol), glibenclamide (glyburide), oral anti-coagulants or furosemide (frusemide). The low toxicity of dipyrone and its efficacy support its use in clinical practice, despite some complex aspects of its disposition.

Multiple drug interactions with cyclosporine in a heart transplant patient.

OBJECTIVE: To report multiple drug interactions with cyclosporine in a heart transplant recipient. CASE SUMMARY: A 53-year-old man underwent heart transplantation in December 1990. Immunosuppression therapy consisted of prednisone, azathioprine, and cyclosporine 300 mg/d. For 5 months, the trough specific cyclosporine (parent compound) concentration was stable (range 211-226 ng/mL). More recently, he developed a productive cough accompanied by high fever, chills, and weakness and was admitted to a hospital near his home. Antituberculosis therapy was advised including rifampin and isoniazid. After a week, erythromycin 3.6 g/d i.v. was added. After 10 days of the combined therapy he was transferred to our hospital, where the first cyclosporine blood concentrations measured were 77 and 238 ng/mL for specific and total cyclosporine (parent drug + metabolites). Because of the low cyclosporine blood concentration, the dose was increased to 400 mg/d. In light of negative sputum smears for acid-fast bacilli and culture, the rifampin/isoniazid therapy was withdrawn; the erythromycin was continued. At this time, the specific cyclosporine blood concentration rose to 934 ng/mL and the total cyclosporine concentration reached 1503 ng/mL. High cyclosporine blood concentrations were measured during the intravenous erythromycin treatment period, even though the cyclosporine dose had been decreased to 150 mg/d. A further increase in cyclosporine concentration was observed when erythromycin was given orally (4.0 g/d). The cyclosporine dose was then discontinued for 2 days and started again at 50 mg/d until the end of the erythromycin treatment period. The patient recovered, the cyclosporine dose was increased to 100 mg/d, and on regular monitoring the cyclosporine blood concentrations were within the therapeutic range (100-400 ng/mL for specific and 250-1000 ng/mL for total cyclosporine). DISCUSSION: Cyclosporine is metabolized almost completely in the liver by the cytochrome P-450IIIA enzyme system. Drugs such as rifampin and erythromycin, which are known to be inducers or substrates of cytochrome P-450IIIA, have the potential to alter cyclosporine blood concentrations. The present case shows a multiple drug interaction with cyclosporine. Coadministration of rifampin/isoniazid and cyclosporine for a week, and erythromycin for the last 4 days, resulted in low cyclosporine blood concentrations, probably because of microsomal induction by rifampin. When the rifampin/isoniazid treatment was discontinued, the cyclosporine blood concentrations rose, indicating the interacting effect of intravenous erythromycin. This effect was even more pronounced when therapy was changed from intravenous to oral administration. Erythromycin, a substrate that is metabolized with great affinity by the cytochrome P-450IIIA enzyme, prolonged the elimination of cyclosporine by competing for the same site of metabolism. CONCLUSIONS: Awareness of potential cyclosporine drug interactions in organ transplant patients of great clinical importance. Regular monitoring of cyclosporine blood concentrations and renal function are essential to detect such interactions, to allow adjustment of drug dosage, and to reduce toxicity and enhance therapeutic effect, in particular in patients coadministered the many drugs known to have pharmacokinetic interactions with cyclosporine.

Antipyrine disposition in obesity: evidence for negligible effect of obesity on hepatic oxidative metabolism.

Following an overnight fast and 2 days of abstention from caffeine, a single 1.0-g oral dose of antipyrine was administered to 20 obese but otherwise healthy subjects (group A) and 11 healthy volunteers (group B). Weight, Body Mass Index (BMI) and % of Ideal Body Weight (IBW) were significantly greater in the obese than in the lean group. (Mean 110.4 vs 62.7 kg; 38.5 vs 22.3 kg.m-2 and 181 vs 106% respectively). In a subgroup of 6 obese subjects (group C) antipyrine was given again 11.3 months later after a 29.8 kg mean weight loss. Antipyrine apparent volume of distribution (V) and elimination half-life (t1/2) were significantly greater in the obese than in the lean group (V 49.9 vs 34.3 l respectively; t1/2 15.5 vs 12.0 h respectively), but its clearance rate (CL0) values were similar. V corrected for total body weight was significantly reduced in group A than in group B (0.45 vs 0.55 l.kg-1 respectively). Stratified comparison of antipyrine pharmacokinetics between obese and lean subjects according to age, gender and smoking habits did not alter the overall results. In group C, weight reduction was associated with a significant decrease in antipyrine V (from 51.8 to 47.5 l) and t1/2 (from 15.1 to 12.7 h), and a non-significant increase in antipyrine CL0. We conclude that in severely obese subjects, antipyrine total V is mildly increased but V corrected for total body weight is significantly decreased. In addition, obesity is associated with a slight prolongation of antipyrine t1/2 whereas its CL0 is unaltered. These findings may indicate that obesity, even in its extreme form, has a negligible effect on the oxidative metabolic capacity of the liver.