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1.
BMC Med ; 5: 13, 2007 May 30.
Article in English | MEDLINE | ID: mdl-17537264

ABSTRACT

BACKGROUND: Hepatic failure has been associated with reported therapeutic use of acetaminophen by alcoholic patients. The highest risk period for alcoholic patients is immediately after discontinuation of alcohol intake. This period exhibits the largest increase in CYP2E1 induction and lowest glutathione levels. Our hypothesis was that common liver tests would be unaffected by administration of the maximum recommended daily dosage of acetaminophen for 3 consecutive days to newly-abstinent alcoholic subjects. METHODS: Adult alcoholic subjects entering two alcohol detoxification centers were enrolled in a prospective double-blind, randomized, placebo-controlled trial. Subjects were randomized to acetaminophen, 4 g/day, or placebo for 3 consecutive days. The study had 95% probability of detecting a 15 IU/L difference in serum ALT. RESULTS: A total of 443 subjects were enrolled: 308 (258 completed) received acetaminophen and 135 subjects (114 completed) received placebo. Study groups did not differ in demographics, alcohol consumption, nutritional status or baseline laboratory assessments. The peak mean ALT activity was 57 +/- 45 IU/L and 55 +/- 48 IU/L in the acetaminophen and placebo groups, respectively. Subgroup analyses for subjects presenting with an elevated ALT, subjects fulfilling a diagnosis of alcoholic hepatitis and subjects attaining a peak ALT greater than 200 IU/L showed no statistical difference between the acetaminophen and control groups. The one participant developing an increased international normalized ratio was in the placebo group. CONCLUSION: Alcoholic patients treated with the maximum recommended daily dose of acetaminophen for 3 consecutive days did not develop increases in serum transaminase or other measures of liver injury. Treatment of pain or fever for 3 days with acetaminophen appears safe in newly-abstinent alcoholic patients, such as those presenting for acute medical care.


Subject(s)
Acetaminophen/adverse effects , Alcoholism/complications , Analgesics, Non-Narcotic/adverse effects , Liver Diseases, Alcoholic/etiology , Acetaminophen/administration & dosage , Acetaminophen/therapeutic use , Adolescent , Adult , Alanine Transaminase/blood , Analgesics, Non-Narcotic/administration & dosage , Analgesics, Non-Narcotic/therapeutic use , Aspartate Aminotransferases/blood , Bilirubin/blood , Female , Fever/complications , Fever/drug therapy , Glutathione/blood , Humans , International Normalized Ratio , Liver Diseases, Alcoholic/blood , Male , Middle Aged , Pain/complications , Pain/drug therapy , Risk Assessment , Temperance
2.
Clin Pharmacol Ther ; 81(6): 840-8, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17377528

ABSTRACT

The objective of this study was to determine the disposition and tolerability of 1, 1.5, and 2 g acetaminophen every 6 h for 3 days. Group I healthy adults received acetaminophen (4 then 6 g/day) or placebo; Group II received acetaminophen (4 then 8 g/day) or placebo. Acetaminophen and metabolites were measured in plasma and urine. Hepatic aminotransferases were measured daily. At steady state, acetaminophen concentrations were surprisingly lower than predicted from single-dose data, although sulfate formation clearance (fCL) was lower as expected, indicating cofactor depletion with possible sulfotransferase saturation. In contrast, glucuronide fCL was unexpectedly higher, strongly suggesting glucuronosyltransferase induction. This is the first evidence that acetaminophen induces its own glucuronidation. No dose-dependent differences were detected in fCL of thiol metabolites formed via cytochrome P4502E1. Hepatic aminotransferases stayed within reference ranges, and the incidence and frequency of adverse events were similar for acetaminophen and placebo. Although dose-dependence of acetaminophen disposition was reported previously, this study shows a novel finding of time-dependent disposition during repeated dosing. Unexpected increases in glucuronide fCL more than offset decreases in sulfate fCL, thus increasing acetaminophen clearance overall. Thiol metabolite fCL remained constant up to 8 g/day. These findings have important implications in short-term (3 day) tolerability of supratherapeutic acetaminophen doses in healthy adults.


Subject(s)
Acetaminophen/pharmacokinetics , Analgesics, Non-Narcotic/pharmacokinetics , Acetaminophen/administration & dosage , Acetaminophen/adverse effects , Adolescent , Adult , Alanine Transaminase/blood , Analgesics, Non-Narcotic/administration & dosage , Analgesics, Non-Narcotic/adverse effects , Area Under Curve , Aspartate Aminotransferases/blood , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Liver Function Tests , Male , Middle Aged , Time Factors
3.
Bone Marrow Transplant ; 30(3): 167-73, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12189535

ABSTRACT

We retrospectively analyzed the relationship between busulfan average steady-state plasma concentration (C(SS)) and graft rejection in 53 children receiving busulfan/cyclophosphamide (BU/CY) preparative regimens prior to hematopoietic stem cell transplantation (HSCT). Patients received a total oral busulfan dose of 11 to 28 mg/kg followed by a total cyclophosphamide dose of 120 to 335 mg/kg in preparation for allogeneic grafts (HLA-matched or HLA partially matched sibling, parent or unrelated donor). Graft rejection occurred in eight (15%) patients. Busulfan C(SS) (P = 0.0024) was the only statistically significant predictor of rejection on univariate logistic regression analysis, with the risk of rejection decreasing with an increase in busulfan C(SS). Severe (grade 3 or 4) regimen-related toxicity (RRT) occurred in four patients. Ten patients (19%) had a busulfan C(SS) higher than 900 ng/ml, one of whom had severe RRT. Higher and variable doses of cyclophosphamide may explain the lack of a relationship between busulfan C(SS) and RRT in children. It may be possible to improve the outcome of HSCT in pediatric patients receiving the BU/CY regimen through optimization of busulfan C(SS) and better definition of the contribution of activated cyclophosphamide metabolites to toxicity.


Subject(s)
Busulfan/blood , Graft Rejection/diagnosis , Hematopoietic Stem Cell Transplantation/adverse effects , Adolescent , Analysis of Variance , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/toxicity , Busulfan/administration & dosage , Busulfan/pharmacokinetics , Child , Child, Preschool , Cyclophosphamide/administration & dosage , Drug Monitoring , Female , Hematologic Diseases/therapy , Histocompatibility , Humans , Infant , Male , Probability , Prognosis , Retrospective Studies , Transplantation, Homologous/adverse effects , Treatment Outcome
4.
Eur Phys J E Soft Matter ; 9(5): 443-6, 2002 Dec.
Article in English | MEDLINE | ID: mdl-15011091

ABSTRACT

We present a model for the structure of binary mixtures of smectic compounds in freely suspended films of 2-7 layers. The compounds are the hexyl (6AB) and dodecyl (10AB) homologues of p, p'-dialkylazoxybenzene that differ by about 40% in molecular length. X-ray reflectivity indicates that no demixing occurs between 6AB and 10AB molecules, while also there is no indication found of increased roughness at the film surfaces. However, the surface layers are somewhat expanded compared to the interior layers. This can be explained by backfolding of the dodecyl end chains of 10AB molecules at the surface via two gauche kinks, which ensures dense packing. This model is supported by surface tension measurements that indicate an increased amount of alkyl groups at the surfaces.

5.
Bone Marrow Transplant ; 28(11): 1013-8, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11781609

ABSTRACT

Published data suggest that the average concentration of busulfan at steady state (Bu Css) is critical for successful engraftment in children receiving busulfan as a conditioning agent for bone marrow transplantation (BMT). We previously found in children that a Bu Css <600 ng/ml correlated with autologous recovery/mixed chimerism; there was no correlation between Bu Css and regimen-related toxicity (RRT). In a cohort continuous with the previous trial, we prospectively evaluated targeted busulfan concentrations in 32 pediatric patients (age 0.6-18.5 years) with AML (n = 6), CML (n = 6) and non-malignant disorders (n = 20) receiving HLA-closely matched donor grafts. In this trial, individual busulfan pharmacokinetics were performed prior to admission. Busulfan doses were then adjusted to achieve a Bu Css target range of 600-900 ng/ml +/- 10% depending on donor source and disease. A repeat study was done following dose 1 of the conditioning regimen. Thirty of thirty-two (94%) patients achieved target concentrations. Total busulfan doses ranged from 10.9 to 29 mg/kg. Thirty of thirty-two patients (94%) have durably engrafted. Grade 3/4 RRT occurred in seven patients (21%). Targeting Bu Css ranges of 600-900 ng/ml significantly improved our rate of successful engraftment from 74% to 94% (P = 0.043). These results indicate that targeted busulfan dosing optimizes allogeneic engraftment in children.


Subject(s)
Bone Marrow Transplantation/methods , Busulfan/administration & dosage , Transplantation Conditioning/methods , Administration, Oral , Adolescent , Adult , Bone Marrow Transplantation/statistics & numerical data , Busulfan/adverse effects , Busulfan/pharmacokinetics , Busulfan/therapeutic use , Child , Child, Preschool , Cohort Studies , Drug Administration Schedule , Graft Rejection/diagnosis , Humans , Infant , Prospective Studies , Transplantation Conditioning/statistics & numerical data
6.
Clin Pharmacokinet ; 39(2): 155-65, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10976660

ABSTRACT

High dosage busulfan (1 mg/kg orally every 6 hours x 16 doses) is frequently used in preparative regimens for haemopoietic stem cell transplantation (HSCT). Busulfan is well absorbed after oral administration, exhibits low protein binding and is metabolised through conjugation with glutathione to form a thiophenium ion. At a given dose, there is considerable variability in the systemic exposure of busulfan, typically expressed as area under the plasma concentration-time curve (AUC) or average concentration at steady state (Css). Relative to that in adolescents and adults, patients less than 4 years of age have an increased apparent oral clearance (CL/F) of busulfan and a higher conjugation rate of busulfan with glutathione in the enterocyte. Several investigators have identified relationships between busulfan Css and outcome in patients undergoing HSCT. Busulfan concentration-response relationships are regimen-, age- and disease-dependent. The busulfan/cyclophosphamide (BU/CY) regimen is the only regimen for which substantial concentration-outcome data exist. Generally, the risk of hepatic veno-occlusive disease is increased with busulfan Css > 900 microg/L. The impact of busulfan Css on veno-occlusive disease may be influenced by the age of the patient and the dose of cyclophosphamide. Lower rates of relapse in chronic myelogenous leukaemia occur in patients with a busulfan Css > 917 microg/L without an increased risk of toxicity. Busulfan Css is also related to the engraftment rate in children, and escalating busulfan doses to achieve a target Css > 600 microg/L improves graft retention. Therapeutic drug monitoring of busulfan should be performed to maximise the likelihood of engraftment and minimise the risk of toxicity and relapse in HSCT patients receiving the BU/CY preparative regimen.


Subject(s)
Busulfan/pharmacokinetics , Drug Monitoring/methods , Graft Rejection/metabolism , Hematopoietic Stem Cell Transplantation , Immunosuppressive Agents/pharmacokinetics , Adult , Age Factors , Animals , Busulfan/therapeutic use , Child , Child, Preschool , Graft Rejection/drug therapy , Humans , Immunosuppressive Agents/therapeutic use
7.
Clin Pharmacol Ther ; 67(6): 591-9, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10872641

ABSTRACT

BACKGROUND: Recent case reports suggest that consumption of ethanol may increase the risk of liver injury induced by acetaminophen (INN, paracetamol). However, this possibility is at odds with previous clinical studies that showed that acute ethanol ingestion could protect against hepatotoxicity by inhibiting CYP-mediated acetaminophen oxidation. We tested the hypothesis that ethanol ingestion can increase susceptibility to acetaminophen toxicity if acetaminophen ingestion occurs shortly after ethanol is cleared from the body. METHODS: Ten healthy volunteers each received a 6-hour intravenous infusion of ethanol (to achieve a blood concentration of 100 mg/dL ethanol) or 5% dextrose in water, administered in random order. Acetaminophen (500 mg) was ingested 8 hours after the end of the infusion. Blood and urine were collected for assessment of formation of N-acetyl-p-benzoquinone imine (NAPQI), the hepatotoxic metabolite of acetaminophen. RESULTS: Mean NAPQI formation was enhanced by 22% (range, 2% to 38%; P < .03) when the acetaminophen dose was given after an ethanol infusion, compared with after 5% dextrose in water infusion. This mean increase was similar in magnitude to that predicted by a mathematical model describing the induction of CYP2E1, the main enzyme catalyzing NAPQI formation, by a mechanism of enzyme stabilization. CONCLUSIONS: Consumption of up to one 750-mL bottle of wine, six 12-ounce cans of beer, or 9 ounces of 80-proof liquor over the course of a single evening modestly increases the fraction of an acetaminophen dose converted to its toxic metabolite, NAPQI, when acetaminophen is ingested soon after ethanol has been cleared from the body. This change in acetaminophen metabolism may present an incremental increase in the risk of acetaminophen hepatotoxicity.


Subject(s)
Acetaminophen/adverse effects , Benzoquinones/metabolism , Cytochrome P-450 CYP2E1/metabolism , Ethanol/adverse effects , Imines/metabolism , Liver/drug effects , Acetaminophen/administration & dosage , Acetaminophen/pharmacokinetics , Adult , Benzoquinones/blood , Benzoquinones/urine , Cross-Over Studies , Ethanol/administration & dosage , Ethanol/pharmacokinetics , Female , Humans , Imines/blood , Imines/urine , Infusions, Intravenous , Male , Middle Aged , Models, Theoretical , Reference Values , Time Factors
8.
Bone Marrow Transplant ; 25(9): 925-30, 2000 May.
Article in English | MEDLINE | ID: mdl-10800058

ABSTRACT

Autologous recovery is a major problem with busulfan as a marrow ablative agent in conditioning children for allogeneic BMT. Data suggest the average concentration of busulfan at steady state (Bu Css) is critical for successful engraftment. We prospectively evaluated busulfan pharmacokinetics in 31 children (age 0.6-18 years) with AML (n = 9), and non-malignant diseases (n = 22) receiving HLA-closely matched (sibling, parent, unrelated) donor grafts. Blood samples were obtained following dose 1 and 13 of a standard 16 dose, 4-day regimen. The busulfan dose varied from 14 to 20 mg/kg. Patients received cyclophosphamide 200-240 mg/kg; 22/31 received 80-90 mg/kg of ATG. Eight patients failed to engraft (26%). ATG did not appear to influence engraftment (P = 0.38). Bu Css levels <600 ng/ml correlated with autologous recovery/mixed chimerism (P = 0.018). There were no graft failures in patients with a Bu Css >600 ng/ml. A correlation between Bu Css levels and regimen-related toxicity (RRT) was not identified for grade 2 or higher toxicities, only 1/31 had a Bu Css >900 ng/ml. Our data support the use of pharmacokinetic monitoring of busulfan.


Subject(s)
Bone Marrow Transplantation , Busulfan/blood , Genetic Diseases, Inborn/therapy , Immunosuppressive Agents/blood , Leukemia/therapy , Adolescent , Busulfan/administration & dosage , Busulfan/pharmacokinetics , Child , Child, Preschool , Female , Genetic Diseases, Inborn/blood , Graft Survival , Histocompatibility Testing , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/pharmacokinetics , Infant , Leukemia/blood , Male , Prospective Studies , Transplantation, Homologous
9.
Clin Pharmacol Ther ; 67(3): 275-82, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10741631

ABSTRACT

BACKGROUND: CYP2E1, 1A2, and 3A4 have all been implicated in the formation of N-acetyl-p-benzoquinone imine (NAPQI), the reactive intermediate of acetaminophen (INN, paracetamol), in studies in human liver microsomes and complementary deoxyribonucleic acid-expressed enzymes. However, recent pharmacokinetic evidence in humans has shown that the involvement of CYP1A2 is negligible in vivo. The purpose of this study was to evaluate the respective roles of CYP2E1 and 3A4 in vivo. METHODS: The involvement of CYP2E1 was assessed through pretreatment of adult human volunteers with disulfiram to inhibit the enzyme and the role of CYP3A4 through its induction in a second cohort of adults with rifampin (INN, rifampicin). Each of the respective studies was an open-label, balanced-randomized crossover design. Blood samples were obtained serially for 12 hours and urine was collected for 24 hours after acetaminophen administration. Acetaminophen was assayed in plasma, and acetaminophen and metabolites were assayed in urine. RESULTS: The recovery of the thiol metabolites formed by conjugation of NAPQI with glutathione was decreased by 69%, and the formation clearance of NAPQI was decreased by 74% (both P < .01) by pretreatment with disulfiram. Rifampin pretreatment had no effect on the formation of NAPQI or the recovery of thiol metabolites formed by conjugation of NAPQI with glutathione. CONCLUSIONS: CYP2E1 accounts for the formation of NAPQI in intact humans; the contribution of other isozymes of cytochrome P450 appears to be negligible. Under some conditions, disulfiram may be useful in diminishing the formation of NAPQI after acetaminophen overdose.


Subject(s)
Acetaminophen/pharmacokinetics , Analgesics, Non-Narcotic/pharmacokinetics , Benzoquinones/metabolism , Cytochrome P-450 CYP2E1/metabolism , Cytochrome P-450 Enzyme System/metabolism , Imines/metabolism , Mixed Function Oxygenases/metabolism , Acetaminophen/blood , Acetaminophen/urine , Adult , Analgesics, Non-Narcotic/blood , Analgesics, Non-Narcotic/urine , Cross-Over Studies , Cytochrome P-450 CYP3A , Female , Humans , Male , Reference Values
10.
Bone Marrow Transplant ; 25(2): 201-3, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10673681

ABSTRACT

The impact of hemodialysis on the clearance of busulfan was determined in a patient with chronic renal failure undergoing autologous peripheral stem cell transplantation for non-Hodgkin's lymphoma. The extraction ratio for busulfan across the dialyzer was 0.530 +/- 0.026 at a blood flow of 400 ml/min, which corresponds to a hemodialysis clearance of 2.23 +/- 0.11 ml/min/kg body weight. Apparent oral clearance of busulfan without hemodialysis was 3.38 +/- 0.56 ml/min/kg. Thus, a 4 h hemodialysis session enhanced the apparent oral clearance of busulfan by 65%. We conclude that hemodialysis effectively removes busulfan from circulating blood, but a standard hemodialysis period (ie, 4 h) does not significantly alter busulfan exposure. Bone Marrow Transplantation(2000) 25, 201-203.


Subject(s)
Busulfan/pharmacokinetics , Kidney Failure, Chronic/metabolism , Lymphoma, Non-Hodgkin/metabolism , Renal Dialysis , Transplantation Conditioning , Administration, Oral , Biological Availability , Blood Transfusion, Autologous , Busulfan/administration & dosage , Busulfan/therapeutic use , Hematopoietic Stem Cell Transplantation , Humans , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/physiopathology , Kidney Failure, Chronic/therapy , Lymphoma, Non-Hodgkin/complications , Lymphoma, Non-Hodgkin/therapy , Male , Metabolic Clearance Rate , Middle Aged , Time Factors , Transplantation Conditioning/methods
11.
Blood ; 95(4): 1188-94, 2000 Feb 15.
Article in English | MEDLINE | ID: mdl-10666189

ABSTRACT

We carried out bone marrow transplantation (BMT) in 50 patients with myelodysplastic syndrome (MDS) who were 55.3 to 66.2 years of age (median, 58.8 years). According to the criteria of the French-American-British (FAB) classification, 13 patients had refractory anemia (RA), 19 had RA with excess blasts (RAEB), 16 had RAEB in transformation or acute myelogenous leukemia (RAEB-T/AML), and 2 had chronic myelomonocytic leukemia (CMML). According to the recently established International Prognostic Scoring System (IPSS), available for 45 patients, 2 patients were considered low risk; 14, intermediate 1 risk; 19, intermediate 2 risk; and 10, high risk. Conditioning regimens were cyclophosphamide (CY) (120 mg/kg of body weight) plus 12-Gy fractionated total-body irradiation (FTBI) (n = 15), CY plus FTBI with lung and liver shielding (n = 4), busulfan (7 mg/kg) plus FTBI (n = 4), or busulfan (16 mg/kg) plus CY (n = 27). The busulfan-plus-CY group included 16 patients in whom busulfan was targeted to plasma levels of 600 to 900 ng/mL. In these 16 patients, steady-state levels of busulfan actually achieved were 714 to 961 ng/mL (mean +/- SD, 845 +/- 64 ng/mL; median, 838 ng/mL). The donors were HLA-identical siblings for 34 patients, HLA-nonidentical family members for 4, identical twins for 4, and unrelated volunteers for 6. All 46 patients surviving > 21 days had engraftment, and 22 patients (44%) are surviving 9 to 80 months after BMT. Specifically, among 13 patients with RA, 1 had relapse (cumulative incidence [CI] at 3 years, 8%) and 8 are surviving, for a Kaplan-Meier (KM) estimate of survival at 3 years of 59% (disease-free survival [DSF], 53%). Among 19 patients with RAEB, 3 had relapse (CI at 3 years, 16%), and 8 are surviving disease free (KM estimate at 3 years, 46%). Among 18 patients with RAEB-T/AML or CMML, 6 had relapse (CI at 3 years, 28%), and the KM estimate of DSF at 3 years is 33%. Relapse-free survival had an inverse correlation with cytogenetic risk classification and with the risk score according to the IPSS. Survival in all FAB categories was highest among patients enrolled in a protocol in which busulfan plasma levels were targeted to 600 to 900 ng/mL. These data indicate that BMT can be carried out successfully in patients with MDS who are older than 55 years of age. (Blood. 2000;95:1188-1194)


Subject(s)
Bone Marrow Transplantation , Hematopoietic Stem Cell Transplantation , Myelodysplastic Syndromes/therapy , Transplantation, Homologous , Transplantation, Isogeneic , Aged , Anemia, Refractory, with Excess of Blasts/mortality , Anemia, Refractory, with Excess of Blasts/therapy , Cyclophosphamide/therapeutic use , Dose Fractionation, Radiation , Graft vs Host Disease/prevention & control , Humans , Immunosuppression Therapy/methods , Living Donors , Middle Aged , Myelodysplastic Syndromes/mortality , Recurrence , Retrospective Studies , Survival Analysis , Time Factors , Transplantation, Homologous/immunology , Transplantation, Isogeneic/immunology , Whole-Body Irradiation
12.
Drug Metab Dispos ; 27(12): 1466-9, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10570028

ABSTRACT

The relationship between age and busulfan apparent oral clearance (Cl/F) expressed relative to adjusted ideal body weight and body surface area (bsa) was evaluated in 135 children aged 0 to 16 years undergoing hematopoietic stem cell transplantation for various disorders. Busulfan plasma levels were measured by gas chromatography-mass spectrometry after the first daily dose of the 4-day dosing regimen. Cl/F expressed relative to adjusted ideal body weight (ml/min/kg) and bsa (ml/min/m(2)) was lower in 9- to 16-year-old (y.o.) compared with 0- to 4-y.o. children (49 and 30%; p<.001). We hypothesized that the greater busulfan Cl/F observed in young children was in part due to enhanced (first-pass intestinal) metabolism. Busulfan conjugation rate was compared in incubations with human small intestinal biopsy specimens from healthy young (1- to 3-y.o.) and older (9- to 17-y.o.) children. Villin content in biopsy specimens was determined by Western blot and busulfan conjugation rate was expressed relative to villin content to control for differences in epithelial cell content in pinch biopsies. Intestinal biopsy specimens from young children had a 77% higher busulfan conjugation rate (p =.037) compared with older children. We have previously shown that glutathione-S-transferase (GST) A1-1 is the major isoform involved in busulfan conjugation, and that this enzyme is expressed uniformly along the length of adult small intestine. Thus, the greater busulfan conjugation activity in intestinal biopsies of the young children was most likely due to enhanced GSTA1-1 expression. We conclude that age dependence in busulfan Cl/F appears to result at least in part from enhanced intestinal GSTA1-1 expression in young children.


Subject(s)
Enterocytes/enzymology , Glutathione Transferase/blood , Adolescent , Age Factors , Alkylating Agents/blood , Alkylating Agents/metabolism , Biopsy , Busulfan/blood , Busulfan/metabolism , Child , Child, Preschool , Enterocytes/metabolism , Female , Gas Chromatography-Mass Spectrometry , Humans , Intestinal Mucosa/metabolism , Intestines/cytology , Male , Up-Regulation
13.
J Chromatogr B Biomed Sci Appl ; 732(2): 287-98, 1999 Sep 24.
Article in English | MEDLINE | ID: mdl-10517350

ABSTRACT

An assay method for the quantification of cyclophosphamide (CY) and five metabolites from human plasma is presented. The procedure is adapted to the chemical properties of the compounds of interest: non-polar compounds are extracted into methylene chloride, concentrated and analyzed by GC-NPD after derivatization, and the remaining aqueous fraction is deproteinated with acetonitrile-methanol prior to separation via reversed-phase HPLC and detection using atmospheric pressure ionization (API)-MS. Standard curves are linear over the required range and reproducible over five months. Plasma concentration-time profiles of CY and metabolites from a patient receiving CY by intravenous infusion (60 mg/kg, once a day for two days) are presented.


Subject(s)
Antineoplastic Agents, Alkylating/blood , Chromatography, Gas/methods , Chromatography, Liquid/methods , Cyclophosphamide/blood , Mass Spectrometry/methods , Humans , Nitrogen/analysis , Phosphorus/analysis
14.
Blood ; 93(12): 4436-40, 1999 Jun 15.
Article in English | MEDLINE | ID: mdl-10361142

ABSTRACT

The apparent oral clearance (CL/F, mL/min) of busulfan was measured in 279 adolescent and adult patients. Significant (P <.05) determinants of CL/F by linear regression were: actual body weight (BW; r2 = 0.300), body surface area (BSA; r2 = 0.277), adjusted ideal body weight (AIBW; r2 = 0.265), and ideal body weight (IBW; r2 = 0.173); whereas body mass index (BMI), height, age, gender, and disease were less important predictors. CL/F (mL/min) for normal weight patients (BMI, 18 to 27 kg/m2) was 16.2% lower (P <.001) than for obese patients (BMI, 27 to 35 kg/m2). Thus, expressing CL/F relative to BW did not eliminate statistically significant differences between normal and obese patients. However, busulfan CL/F expressed relative to BSA (110 +/- 24 v 110 +/- 24 mL/min/m2, P = 1.0) or AIBW (3.04 +/- 0.65 v 3.19 +/- 0.67 mL/min/kg, P =.597) were similar in normal and obese patients. Non-Hodgkin's lymphoma patients (n = 10) had approximately 32% lower mean busulfan CL/F expressed relative to BW, BSA, or AIBW compared with patients with chronic myelogenous leukemia (n = 73). Routine dosing on the basis of BSA or AIBW in adults and adolescents does not require a specific accommodation for the obese. However, dosing based on BSA may be improved by considering CL/F differences in certain diseases. Adjusting dose for body size or disease does not diminish interpatient variability sufficiently to obviate plasma level monitoring in many indications.


Subject(s)
Busulfan/administration & dosage , Busulfan/pharmacokinetics , Obesity/metabolism , Administration, Oral , Adolescent , Adult , Body Mass Index , Body Surface Area , Body Weight , Drug Monitoring , Female , Humans , Kidney Function Tests , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Linear Models , Liver Function Tests , Lymphoma, Non-Hodgkin/metabolism , Male , Metabolic Clearance Rate , Middle Aged , Sex Characteristics
15.
Drug Metab Dispos ; 27(1): 133-7, 1999 Jan.
Article in English | MEDLINE | ID: mdl-9884322

ABSTRACT

In a previous study, we observed that the elimination clearance of 4-hydroxycyclophosphamide (HCY) in patients receiving cyclophosphamide (CY) 60 mg/kg/day by 1-h i.v. infusion for 2 consecutive days decreased from day 1 to day 2 due to an apparent decrease in human aldehyde dehydrogenase 1 (ALDH1) activity. Here, the mechanism for the decrease in ALDH1 activity after CY administration was investigated. In human liver cytosol incubations, HCY inhibited ALDH activity mainly through its degradation product acrolein, whereas carboxyethylphosphoramide mustard inhibited ALDH activity only at supraclinical concentrations. Other CY metabolites evaluated, phosphoramide mustard and chloroacetaldehyde, did not inhibit ALDH. The inhibition of ALDH1 activity by acrolein in incubations with human erythrocyte ALDH1 was competitive with a Ki of 0.646 microM. The inhibition was independent of preincubation time and reversible by dialysis. The percentage of inhibition of ALDH1 activity in vivo by acrolein in patients receiving CY was calculated based on the in vitro Ki of acrolein, the in vitro Km of HCY, and the in vivo peak blood concentrations of HCY and acrolein. The calculations indicated that the activity of ALDH1 was inhibited by 85, 88, and 91% on days 1, 2, and 3 (24 h after the dose on day 2) of CY administration, respectively. The increase in ALDH1 inhibition with time is consistent with the decrease in HCY elimination clearance and the increase in HCY area under the plasma concentration time curve with time.


Subject(s)
Acrolein/pharmacology , Aldehyde Dehydrogenase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Isoenzymes/antagonists & inhibitors , Liver/drug effects , Liver/enzymology , Acrolein/metabolism , Aldehyde Dehydrogenase 1 Family , Cyclophosphamide/analogs & derivatives , Cyclophosphamide/metabolism , Cytosol/drug effects , Cytosol/enzymology , Enzyme Inhibitors/metabolism , Humans , Retinal Dehydrogenase
16.
Ther Drug Monit ; 20(5): 543-9, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9780133

ABSTRACT

Busulfan is an alkylating agent commonly used to ablate marrow before hematopoietic stem cell transplantation. High levels have been shown to increase the chance for severe hepatic veno-occlusive disease, for which there is no treatment and which can be fatal. Low levels are associated with recurrence of chronic myeloid leukemia, whereas even lower levels are associated with graft rejection. The therapeutic window for busulfan is narrow and disease and graft-source dependent. Busulfan concentration in plasma is readily assayed by gas chromatography. In the authors' center, busulfan levels determined from the first dose of the drug are used to adjust the dose to that selected to achieve the desired therapeutic outcome by the third dose of the 16-dose regimen. Thus, turnaround time is less than 6 hours. Analytical and pharmacokinetic aspects of busulfan therapeutic monitoring are described. The cost of pharmacokinetically targeting busulfan concentration is < or = 1% of the cost of hematopoietic stem cell transplantation.


Subject(s)
Antineoplastic Agents, Alkylating/pharmacokinetics , Busulfan/pharmacokinetics , Drug Monitoring , Hematopoietic Stem Cell Transplantation , Transplantation Conditioning , Adult , Antineoplastic Agents, Alkylating/blood , Busulfan/blood , Female , Humans , Infant , Male
17.
Clin Pharmacol Ther ; 64(3): 289-301, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9757153

ABSTRACT

OBJECTIVES: To characterize the pharmacokinetics of cyclophosphamide and 5 of its metabolites in bone marrow transplant patients and to identify the mechanism of the increase in 4-hydroxycyclophosphamide area under the plasma concentration-time curve (AUC) from day 1 to day 2 of cyclophosphamide administration. METHODS: Cyclophosphamide was administered by intravenous infusion (60 mg/kg over 1 hour, once a day) for 2 consecutive days to 18 patients. Cyclophosphamide and 4-hydroxycyclophosphamide concentration time data on day 1 and day 2 were fitted to a model to estimate 4-hydroxycyclophosphamide formation (CLf) and elimination (CLm) clearances. Erythrocyte aldehyde dehydrogenase-1 activity was measured ex vivo just before the first cyclophosphamide infusion was started (0 hours) and 24 hours after the second cyclophosphamide infusion (48 hours). RESULTS: From day 1 to day 2, the AUC of cyclophosphamide, deschloroethyl cyclophosphamide and phosphoramide mustard decreased 24.8%, 51%, and 29.4% (P < .02), the AUC of 4-hydroxycyclophosphamide and carboxyethylphosphoramide mustard increased 54.7% and 25% (P < .01), whereas the AUC of phosphoramide mustard was not significantly changed (P > .3). The CLf of 4-hydroxycyclophosphamide increased 60% (P < .001), its CLm decreased 27.7% (P < .001), and the fraction of cyclophosphamide dose converted to 4-hydroxycyclophosphamide increased 16% (P < .001) from day 1 to day 2. The activity of patient erythrocyte aldehyde dehydrogenase-1 decreased 23.3% (P < .02) from 0 hours to 48 hours. CONCLUSIONS: The AUC of 4-hydroxycyclophosphamide increased from day 1 to day 2 as a result of increased formation and decreased elimination clearances of 4-hydroxycyclophosphamide. Aldehyde dehydrogenase-1 activity appears to decline as a consequence of cyclophosphamide administration.


Subject(s)
Bone Marrow Transplantation , Cyclophosphamide/pharmacokinetics , Immunosuppressive Agents/pharmacokinetics , Aldehyde Dehydrogenase/metabolism , Area Under Curve , Cyclophosphamide/blood , Cyclophosphamide/urine , Erythrocytes/enzymology , Humans , Hydroxylation , Immunosuppressive Agents/blood , Immunosuppressive Agents/urine , Time Factors
18.
J Pharm Sci ; 87(3): 390-3, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9523995

ABSTRACT

The cytochrome P450s responsible for the conversion of lisofylline, a drug being developed to prevent the complications of high-dose chemotherapy, to lisofylline 4,5-diol, one of two principal metabolites in human liver microsomes, were evaluated. Lisofylline diol formation in microsomes prepared from five adult human livers was biphasic, with respective Km values of 0.0230+/-0.015 and 4.23+/-2.8 mM (mean +/- SD) and respective Vmax values of 0.0565+/-0.052 and 0.429+/-0.15 nmol/min/mg of protein. Through studies with isoform selective chemical inhibitors, CYP3A4 was implicated as the low Km enzyme from 89.0+/-11.2% inhibition of lisofylline 4,5-diol formation by troleandomycin at 50 microM substrate and CYP2A6 was implicated as the high Km enzyme. The formation of lisofylline 4,5-diol by these enzymes was confirmed with cDNA-expressed human CYP3A4 and CYP2A6.


Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Microsomes, Liver/metabolism , Mixed Function Oxygenases/metabolism , Pentoxifylline/analogs & derivatives , Adult , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors , Enzyme Inhibitors/pharmacology , Humans , Mixed Function Oxygenases/antagonists & inhibitors , Oxidation-Reduction , Pentoxifylline/metabolism
19.
Drug Metab Dispos ; 26(1): 52-5, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9443852

ABSTRACT

The apparent oral clearance of busulfan has been observed to vary as much as 10-fold in the population of children and adults receiving high-dose busulfan. The only identified elimination pathway for busulfan involves glutathione conjugation. The reaction is predominantly catalyzed by glutathione S-transferase (GST) A1-1, which is present in both liver and intestine. The purpose of this study was to compare busulfan Vmax/Km in cytosol prepared from adult human liver and small intestine. Tetrahydrothiophenium ion formation rate per milligram of cytosolic protein was constant along the length (assessed in 30-cm segments) of three individual small intestines. A 30-cm-long intestinal segment 90-180 cm from the pylorus was chosen to be representative of intestinal cytosolic busulfan conjugating activity. Busulfan Vmax/Km (mean +/- SD) in cytosol prepared from 23 livers and 12 small intestines was 0.166 +/- 0.066 and 0.176 +/- 0.085 microl/min/mg cytosolic protein, respectively, in incubations with 5 microM busulfan, 1 mM glutathione, and 2 mg of cytosolic protein. The relative content of GSTalpha (A1-1, A1-2, and A2-2) was compared for human liver and intestinal cytosol using Western blot. The levels of GSTalpha in liver and intestinal cytosol were 1.12 +/- 0.56 and 1.36 +/- 0.32 integrated optimal density units/5 microg cytosolic protein, respectively. Busulfan conjugation in vitro was comparable per milligram of cytosolic protein in liver and intestinal cytosol.


Subject(s)
Busulfan/metabolism , Intestine, Small/enzymology , Liver/enzymology , Busulfan/chemistry , Catalysis , Cytosol/drug effects , Cytosol/metabolism , Dinitrobenzenes/metabolism , Glutathione Transferase/metabolism , Glutathione Transferase/pharmacology , Humans , Intestine, Small/chemistry , Kinetics , Liver/chemistry , Proteins/chemistry , Proteins/metabolism , Thiophenes/metabolism
20.
Drug Metab Dispos ; 25(10): 1150-6, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9321518

ABSTRACT

Caffeine and 7,8-benzoflavone activate CYP3A2 in rat liver microsomes. Both activators appear to enhance enzyme activity by an increase in Vmax and to a lesser extent a decrease in Km. Additive effect studies demonstrated that the two activators oppose one another's effect. Electron transfer steps in the cytochrome P450 cycle are involved in the mechanism of cytochrome P450 activation, as indicated by the lack of effect of caffeine or 7,8-benzoflavone on cumene hydroperoxide-supported oxidation of acetaminophen by cytochrome P450. The involvement of cytochrome b5 in the formation of N-acetyl-p-benzoquinone imine (NAPQI) was implicated through a synergistic effect of NADH on the NADPH-supported reaction. Anti-cytochrome b5, but not anti-cytochrome P450 reductase IgG, diminished the activation effect of caffeine on NAPQI formation. Neither antibody altered the effect of 7,8-benzoflavone on NAPQI formation. The impairment of NAPQI formation by cytochrome b5 antibody suggests that cytochrome P450 activation by caffeine but not 7,8-benzoflavone is mediated in part through enhancement of the transfer of the second electron to cytochrome P450 from cytochrome b5.


Subject(s)
Benzoflavones/pharmacology , Caffeine/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Cytochromes b5/metabolism , Microsomes, Liver/drug effects , NADH, NADPH Oxidoreductases/metabolism , Animals , Benzoquinones/metabolism , Electron Transport , Enzyme Activation , Imines/metabolism , Male , Microsomes, Liver/metabolism , NADPH-Ferrihemoprotein Reductase , Rats , Rats, Sprague-Dawley
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