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Biomedical subjects

L Iyer

Publications and source records attributed to L Iyer.

At least 19 recordsLinked to original sources
PubMed2006

Diagnosis, treatment and follow up of women undergoing conscious pain mapping for chronic pelvic pain: a prospective cohort study.

OBJECTIVE: To assess the efficacy of conscious pain mapping in diagnosing and treating chronic pelvic pain (CPP). DESIGN: Prospective cohort study. Setting Gynaecology Department, UK District General Hospital. POPULATION: Forty-three women diagnosed with CPP. METHODS: The cohort was followed up for 18-24 months after diagnosis and treatment based on conscious pain mapping. MAIN OUTCOME MEASURES: Improvement of pain assessed by using visual analogue scale (VAS) pain scores at 6-month follow up. RESULTS: Thirty-nine women had successful conscious pain mapping. Pelvic pathology was identified in 18, pelvic congestion in 13 and 8 women had normal pelvic organs. In 35 women (90%), conscious pain mapping identified the cause of pain. Five out of eight women (63%) who were judged to have a normal pelvis had positive findings at pain mapping. VAS scores fell significantly from pre-treatment to post-treatment values at 6-month follow up (P < 0.01). Overall, 26 women (74%) felt that their symptoms had improved after treatment based on findings at pain mapping. However, we concluded that pain mapping only contributed to the diagnosis and treatment in seven women (27%), who may not have received appropriate diagnosis and treatment if they had a laparoscopy under general anaesthetic. Conclusions CONSCIOUS: pain mapping is a useful additional investigation in the management of women with CPP. It can be employed in women with a negative laparoscopy or with visible pathology where the conventional treatment has failed.

Adult↗
PubMed2006

Molecular analysis of vibrio cholerae strains isolated in Malaysia: public health implications.

The genetic diversity or clonality among Vibrio cholerae O1, O139 and non-O1/ non-O139 of clinical and environmental origin using ribotyping and PFGE was performed in order to ascertain the public health implications of the different genotypes circulating within the Malaysian environment. Using an in-house typing scheme, of the 214 strains included, 202 strains were isolated locally between 1992 and 1998, seven were obtained from Bangladesh and five were reference strains. Amongst the 176 El Tor O1 strains, 152 clinical strains demonstrated five ribotypes--E1a, E1b, E2a, E3 and E1c. E1b was the most predominant ribotype demonstrated by 84% of the El Tor O1 strains and was present in all years demonstrating that this strain was intrinsic to Malaysia. PFGE analysis of these strains demonstrated minimal variation amongst the 15 PFGE profiles obtained. Ribotpye E2a amongst five clinical and two environmental O1 strains, were from one location and had previously been reported in Indonesia and the Philippines, thus demonstrating strong evidence that these strains may have been imported into Malaysia. Among Vibrio cholerae O139 strains, 91.7% were of ribotype A1a similar to the original O139, while two others were of ribotype A1b and one of A1e, corresponding to ribotypes 1, 2 and 3 of Dalsgaard and colleagues' scheme for O139 strains. PFGE analysis demonstrated that 89% of ribotype A1a could be differentiated into three PFGE genotypes which were very closely related. The eight non-O1/non-O139 serogroup strains were heterogeneous in both ribotype and PFGE patterns.

DNA, Bacterial↗
PubMed2002

UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity.

The metabolism of irinotecan (CPT-11) involves sequential activation to SN-38 and detoxification to the pharmacologically inactive SN-38 glucuronide (SN-38G). We have previously demonstrated the role of UGT1A1 enzyme in the glucuronidation of SN-38 and a significant correlation between in vitro glucuronidation of SN-38 and UGT1A1 gene promoter polymorphism. This polymorphism (UGT1A1*28) is characterized by the presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter, ((TA)7TAA, instead of (TA)6TAA). Here we report the results from a prospective clinical pharmacogenetic study to determine the significance of UGT1A1*28 polymorphism on irinotecan disposition and toxicity in patients with cancer. Twenty patients with solid tumors were treated with a 90 min i.v. infusion of irinotecan (300 mg m(-2)) once every 3 weeks. The frequency of UGT1A1 genotypes was as follows: 6/6--45%, 6/7--35% and 7/7--20%, with allele frequencies of 0.375 and 0.625 for (TA)7TAA and (TA)6TAA, respectively. Patients with the (TA)7TAA polymorphism had significantly lower SN-38 glucuronidation rates than those with the normal allele (6/6>6/7>7/7, P = 0.001). More severe grades of diarrhea and neutropenia were observed only in patients heterozygous (grade 4 diarrhea, n = 1) or homozygous (grade 3 diarrhea/grade 4 neutropenia, n = 1 and grade 3 neutropenia, n = 1) for the (TA)7TAA sequence. The results suggest that screening for UGT1A1*28 polymorphism may identify patients with lower SN-38 glucuronidation rates and greater susceptibility to irinotecan induced gastrointestinal and bone marrow toxicity.

Adult↗
PubMed2001

Phase I clinical and pharmacogenetic study of weekly TAS-103 in patients with advanced cancer.

PURPOSE: TAS-103 is an inhibitor of both topoisomerase I and II enzymes with broad antitumor activity. It is metabolized to TAS-103-glucuronide (TAS-103-G) predominantly by uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1). We conducted a phase I study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of TAS-103 when administered on a weekly schedule to patients with advanced cancer. In addition, we evaluated the influence of UGT1A1 genotype on the pharmacokinetics and toxicity of TAS-103. PATIENTS AND METHODS: Thirty-two patients were treated with escalating doses (50 to 200 mg/m(2)) of TAS-103, administered intravenously over 1 hour each week for 3 weeks. Pharmacokinetic analysis was performed at the 130-, 160-, and 200-mg/m(2) dose levels. UGT1A1 genotypes were determined using reverse-transcription polymerase chain reaction techniques. RESULTS: DLT (grade 3 neutropenia) was observed in 5 of 12 patients at 160 mg/m(2) and in 3 of 6 patients at 200 mg/m(2). At 160 mg/m(2), there was a significant correlation between areas under the curve (AUCs) for TAS-103 and TAS-103-G (r = 0.76, P <.05) and an apparent relationship between TAS-103 AUC and D 15 absolute neutrophil count (r = -0.63, P <.05, n = 11, one outlier excluded). UGT1A1 genotype did not influence clearance of TAS-103. CONCLUSION: We recommend a dose of 130 to 160 mg/m(2), or 250 to 300 mg administered using the above weekly schedule for phase II studies. Further studies to characterize the pharmacodynamics and pharmacogenetics of TAS-103 are warranted.

Adult↗
PubMed2001

Platelet APP isoform ratios in asymptomatic young adults expressing an AD-related presenilin-1 mutation.

The Alzheimer's disease (AD) related amyloid precursor protein (APP) is stored, cleaved and released similarly from neurons and from platelets. We have reported that the proportion of 120-130 to 110 kDa carboxyl-cleaved APP present in the platelets of AD patients is significantly lower than that of platelets of age-matched controls. This reduced APP isoform ratio, not seen in several other disease groups, is further reduced as the severity of AD increases. Since the neuropathology of AD is believed to begin many years before the onset of cognitive loss, we have also compared platelet APP ratios of four pre-symptomatic young adults carrying a presenilin-1 mutation to seven siblings homozygous for the normal PS-1 gene in an effort to determine whether reduced APP ratios are present before apparent cognitive loss in familial AD. Decreased platelet APP ratios were not seen in any of these subjects at this time. We will continue to monitor these subjects as they near the mean age of AD onset in these families. As the magnitude of the APP ratio reduction is proportional to the severity of cognitive loss in sporadic AD, these cognitively normal incipient AD subjects would not be expected to present significant reductions in this AD severity index at this time. Alternatively, the absence of platelet APP ratio reductions may result from a failure of platelets from familial PS-1 AD subjects to manifest altered APPs, as has been reported for PS-2 AD subjects, unlike those of sporadic AD patients. Continued monitoring of cognitive status in our sub-set of controls with AD-like low APP ratios may yet validate the ability of this assay to detect incipient sporadic AD.

Adult↗
PubMed2001

Pharmacogenetics of anticancer agents: lessons from amonafide and irinotecan.

Amonafide and irinotecan are anticancer drugs representative of the clinical relevance of N-acetyltransferase (NAT) and uridine diphosphate glucuronosyltransferase (UGT) polymorphisms in cancer chemotherapy, respectively. Amonafide, a substrate for the polymorphic NAT2, has an active metabolite, N-acetyl-amonafide. Using caffeine as a probe, slow and rapid acetylators of amonafide were identified. Fast acetylators experienced greater myelosuppression than did slow acetylators, and a reduced dose of amonafide for fast acetylators has been recommended. A pharmacodynamic model based on acetylator phenotype, pretreatment white blood cell count, and gender has been proposed for dose individualization. The strategy adopted for amonafide is a model for future investigations in pharmacogenetics, although amonafide is no longer in clinical development. SN-38, the active metabolite of irinotecan, is glucuronidated to the inactive SN-38 glucuronide by UGT1A1, the isoform catalyzing bilirubin glucuronidation. Genetic defects in UGT1A1 determine Crigler-Najjar and Gilbert's syndromes characterized by unconjugated hyperbilirubinemia. Gilbert's syndrome often remains undiagnosed and occurs in up to 19% of individuals. Gilbert's syndrome is due to a homozygous TA insertion in the TATAA promoter of UGT1A1, leading to the mutated (TA)(7) allele. Irinotecan toxicity depends on the individual glucuronidation rate of SN-38. Decreased SN-38 glucuronidating activity has been found in livers obtained from individuals carrying the (TA)(7) allele. A phenotyping procedure for UGT1A1 has not been identified and genotyping of the UGT1A1 promoter in patients receiving irinotecan may identify patients at increased risk of toxicity. A clinical trial at the University of Chicago is ongoing to demonstrate the predictive significance of UGT1A1 genotyping for irinotecan pharmacodynamics.

Adenine↗
PubMed2001

Epirubicin glucuronidation is catalyzed by human UDP-glucuronosyltransferase 2B7.

Epirubicin is one of the most active agents for breast cancer. The formation of epirubicin glucuronide by liver UDP-glucuronosyltransferase (UGT) is its main inactivating pathway. This study aimed to investigate epirubicin glucuronidation in human liver microsomes, to identify the specific UGT isoform for this reaction, and to correlate epirubicin glucuronidation with other UGT substrates. Microsomes from human livers were used. UGTs specifically expressed in cellular systems, as well as two UGT2B7 variants, were screened for epirubicin glucuronidation. Epirubicin, morphine, and SN-38 glucuronides were measured by high-pressure liquid chromatography. The mean +/- S.D. formation rate of epirubicin glucuronide in human liver microsomes (n = 47) was 138 +/- 37 pmol/min/mg (coefficient of variation, 24%). This phenotype was normally distributed. We screened commercially available UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 for epirubicin glucuronidation. Only UGT2B7 converted epirubicin to its glucuronide. No differences in epirubicin glucuronidation were found in HK293 cells expressing the two UGT2B7 variants at position 268. Catalytic efficiency (V(max)/K(m)) of epirubicin glucuronidation was 1.4 microl/min/mg, a value higher than that observed for morphine, a substrate of UGT2B7. Formation of epirubicin glucuronide was significantly related to that of morphine-3-glucuronide (r = 0.76, p < 0.001) and morphine-6-glucuronide (r = 0.73, p < 0.001). No correlation was found with SN-38, a substrate of UGT1A1 (r = 0.04). UGT2B7 is the major human UGT catalyzing epirubicin glucuronidation, and UGT2B7 is the candidate gene for this phenotype. The reported tyrosine to histidine polymorphism in UGT2B7 does not alter the formation rate of epirubicin glucuronide, and undiscovered genetic polymorphisms in UGT2B7 might change the metabolic fate of this important anticancer agent.

Catalysis↗
PubMed2000

Platelet APP isoform ratios correlate with declining cognition in AD.

BACKGROUND: Platelets and neurons both contain large quantities of two carboxyl-truncated 120 to 130 and 110 kDa Alzheimer amyloid precursor proteins (APPs). Platelets taken from patients with AD have been reported to contain a reduced ratio of these APPs. OBJECTIVE: To further study the AD specificity of reduced platelet APP ratios and to determine whether, after 3 years, cognitive losses in AD are accompanied by similarly reduced platelet APP ratios. METHODS: To test the AD specificity of reduced platelet APP ratios, we quantitated these APPs in eight patients with PD and six patients with hemorrhagic stroke (HS). To determine whether further cognitive losses correlate with platelet APP ratio reductions in patients with AD, the authors re-examined platelet APPs and Mini-Mental State Examination (MMSE) scores of 10 patients with AD and 11 controls, who were tested 3 years ago. APP ratios were determined by the average of six assays using Western blotting with m22C11 monoclonal antibody, enhanced chemoluminescence, and digital scanning of autoradiographs. RESULTS: APP ratios were normal in the patients with PD and HS, further supporting the AD specificity of this assay. After 3 years, the MMSE scores and APP ratios of our control subjects changed by <4%. However, the average MMSE scores of our patients with AD declined from 16.4 to 8.3, and their average 120 to 130/110 kDa APP ratios declined from 5.8 to 3.6. The difference between AD and control APP ratios, with no overlap, is significant and the correlation between the 3-year decline in AD MMSE scores and reduced APP ratios (r = 0.69) was significant. CONCLUSIONS: Although the number of subjects analyzed was limited, reduced platelet APP ratios appear to be a specific biological marker of AD and a biological index of the severity of cognitive loss in AD.

Aged↗
PubMed2000

Epidemiology and molecular characterization of nosocomially transmitted multidrug-resistant Klebsiella pneumoniae.

OBJECTIVES: To describe the epidemiology, antimicrobial susceptibility, genomic profiles, and control of a nosocomial outbreak of multidrug-resistant Klebsiella pneumoniae (MRKP) that occurred in the pediatric oncology unit of the University of Malaya Medical Centre in Kuala Lumpur. MATERIALS AND METHODS: A prospective epidemiologic and microbiologic study was conducted of MRKP isolated from the blood and wound of a boy with necrotizing fasciitis after a 7-day course of ceftazidime and amikacin. In the following 2 weeks, phenotypically similar MRKP were isolated from the blood cultures of four other patients and rectal swabs of another three patients and two liquid soap samples located in the same ward. RESULTS: Antimicrobial profiles demonstrated that all the isolates were resistant to ceftazidime, sensitive to imipenem and ciprofloxacin, and confirmed to be extended-spectrum beta-lactamase producers. Plasmids of varying molecular weights were present in all isolates. In eight of these isolates, which included four from blood, there were common large molecular weight plasmids ranging from 80 kb to 100 kb. Pulsed-field gel electrophoresis analysis using XbaI demonstrated six different DNA profiles, A to F. Profile A was shared by two blood culture isolates and were related by 91%. Profile B was found in one rectal swab isolate and one isolate from liquid soap and were related by 94%. Profile C was shared by one blood isolate and one liquid soap isolate and showed 100% relatedness. Profiles D, E, and F each were demonstrated by one blood isolate and two rectal swab isolates, respectively. These showed only 65% relatedness. CONCLUSIONS: The MRKP strains in this outbreak were not clonal in origin. The decline of the outbreak after 4 weeks was attributed to the reemphasis of standard infection control procedures and the implementation of a program that addressed sites of environmental contamination.

Anti-Bacterial Agents↗
PubMed2000

Molecular evidence of clonality amongst Vibrio cholerae O1 biotype El Tor during an outbreak in Malaysia.

Forty-three clinical strains of V. cholerae O1 biotype E1 Tor were isolated between 3 May and 10 June 1998 during an outbreak in the metropolitan area of Kuala Lumpur and its suburbs. With the exception of three Inaba strains that were restricted to three members of a family, all the others belonged to the Ogawa serotype. The strains were analysed for clonality using ribotyping and pulsed-field gel electrophoresis (PFGE). Two ribotypes, V/B21a and B27, were identified among 40 Ogawa isolates using BglI restriction endonuclease. Ribotype V/B21a has been described previously from Taiwan and Colombia and several Asian countries while B27 has been reported among isolates from Senegal. The three Inaba strains belonged to one ribotype, designated type A, not previously reported. PFGE analysis using NotI revealed that all isolates within a ribotype had identical profiles demonstrating clonality amongst the strains. Dice coefficient analysis of the two Ogawa genotypes revealed 89% similarity on ribotype patterns and 91.3% on PFGE profiles. Ribotype V/B21a isolates were associated with cases from dispersed areas of Kuala Lumpur and its suburbs while ribotype B27 was restricted to cases from one particular area suggesting a common-source outbreak.

Bacterial Typing Techniques↗
PubMed2000

Detection of virulence associated genes, haemolysin and protease amongst Vibrio cholerae isolated in Malaysia.

Eighty-four strains of Vibrio cholerae O1, O139 and non-O1/non-O139 from clinical and environmental sources were investigated for the presence of the toxin co-regulated pilus gene, tcpA, the virulence cassette genes ctxA, zot, ace and cep and also for their ability to elaborate haemolysin and protease. The ctxA and zot genes were detected using DNA-DNA hybridization while the ace, cep and tcpA genes were detected using PCR. Production of haemolysin and protease was detected using mammalian erythrocytes and an agar diffusion assay respectively. Analysis of their virulence profiles showed six different groups designated Type I to Type VI and the major distinguishing factor among these profiles was in the in vitro production of haemolysin and/or protease. Clinical O1, O139 and environmental O1 strains were similar with regard to presence of the virulence cassette genes. All environmental O1 strains with the exception of one were found to possess ctxA, zot and ace giving rise to the probability that these strains may actually be of clinical origin. One strain which had only cep but none of the toxin genes may be a true environmental isolate. The virulence cassette and colonization factor genes were absent in all non-O1/non-O139 environmental strains but production of both the haemolysin and protease was present, indicating that these may be putative virulence factors. These findings suggest that with regard to its pathogenic potential, only strains of the O1 and O139 serogroup that possess the tcpA gene which encodes the phage receptor, have the potential to acquire the CTX genetic element and become choleragenic.

Cholera↗
PubMed2000

Pharmacogenetics: a tool for individualizing antineoplastic therapy.

This article reviews the clinical relevance of pharmacogenetics in cancer chemotherapy, with emphasis on drugs for which genetic differences in enzyme metabolism have been demonstrated to affect patient outcome. About 10% of children with leukaemia are intolerant to mercaptopurine (6-mercaptopurine) because of genetic defects in mercaptopurine inactivation by thiopurine S-methyltransferase. However, mercaptopurine dose intensity, a critical factor for outcome in patients deficient in thiopurine S-methyltransferase, can be maintained by means of thiopurine S-methyltransferase phenotyping or genotyping. Patients with reduced fluorouracil (5-fluorouracil) catabolism are more likely to be exposed to severe toxicity. The measurement of dihydropyrimidine dehydrogenase activity in patients cannot be considered fully predictive, and the role of dihydropyrimidine dehydrogenase gene variants in this syndrome has yet to be clarified. With regard to irinotecan, patients with Gilbert's syndrome phenotype have reduced inactivation of the active topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin (SN-38) caused by a mutation in the UDP-glucuronosyltransferase 1A1 gene promoter. This subset of patients is more likely to be exposed to irinotecan toxicity and could be identified by genotyping for gene promoter variants. Finally, the experience with amonafide represents a model for dose individualization approaches that use simple phenotypic probes.

Adenine↗
PubMed2000

Flavopiridol metabolism in cancer patients is associated with the occurrence of diarrhea.

Flavopiridol, a cyclin-dependent kinase inhibitor currently undergoing clinical evaluation, has a dose-limiting toxicity of diarrhea. Preclinical data on flavopiridol metabolism indicate that flavopiridol undergoes hepatic glucuronidation. The purpose of this study is to evaluate whether the occurrence of diarrhea is related to the systemic glucuronidation of flavopiridol. Parent drug and metabolite concentrations in plasma were measured by high-pressure liquid chromatography in 22 metastatic renal cancer patients treated on a Phase II trial of 50 mg/m2/day of flavopiridol administered every 2 weeks as a 72-h continuous infusion. Pharmacokinetics of flavopiridol and its glucuronide were assessed during the first cycle at 23, 47, and 71 h during the infusion. Flavopiridol concentrations at 23, 47, and 71 h were 389 nM (296-567 nM), 412 nM (297-566 nM), and 397 nM (303-597 nM) [median (interquartile range)], respectively. Flavopiridol glucuronide reached a plateau of 358 nM (196-553 nM) at 47 h. Metabolic ratios of flavopiridol glucuronide:flavopiridol at 71 h showed an apparent bimodal distribution with an antimode of 1.2. Thirteen patients experienced diarrhea and had lower metabolic ratios [0.72 (0.53-0.86)] than patients without diarrhea [2.24 (1.76-2.3); P = 0.002]. Eight of 11 extensive glucuronidators (ratio > 1.2) did not develop diarrhea, whereas 10 of 11 poor glucuronidators (ratio < 1.2) developed diarrhea (P = 0.008). The glucuronidation of flavopiridol is apparently polymorphic, suggesting a genetic etiology. The systemic glucuronidation of flavopiridol is inversely associated with the risk of developing diarrhea.

Antineoplastic Agents↗
PubMed1999

Phenotype-genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism.

BACKGROUND: Hepatic uridine diphosphate glucuronosyltransferase (UGT) isoform 1A1 (UGT1A1) is primarily responsible for the glucuronidation of SN-38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of the anticancer agent irinotecan. UGT1A1, also catalyzing the glucuronidation of bilirubin, has been shown to have reduced activity in Gilbert's syndrome. The presence of an additional TA repeat [(TA)7TAA] in the TATA sequence of UGT1A1 has been associated with Gilbert's syndrome. OBJECTIVE: To evaluate the relationship between UGT1A1 phenotypic activity and UGT1A1 promoter polymorphism. METHODS: Phenotypic measurements included in vitro SN-38 and bilirubin glucuronidation in human liver microsomes (n = 44). A recently developed genotyping test was used to determine TATA sequence polymorphisms in UGT1A1. Genotypes were assigned as follows: 7/7, homozygous for the (TA)7TAA allele; 6/6, homozygous for the (TA)6TAA allele; and 6/7, heterozygous with 1 of each allele. RESULTS: Nine percent of screened liver samples were found to be homozygous for allele 7 (7/7), 43% were homozygous for allele 6 (6/6), and 48% were heterozygous (6/7). Frequencies of (TA)7TAA and (TA)6TAA alleles were 0.33 and 0.67, respectively. A significant trend toward a decrease in SN-38 and bilirubin glucuronidation rates was found as the number of TA repeats increased (6/6 > 6/7 > 7/7). Glucuronidation rates of both substrates were significantly lower in the 7/7 and 6/7 groups compared with the 6/6 group. CONCLUSIONS: The results indicate a significant association of UGT1A1 phenotype and genotype based on in vitro phenotypic measurements. The clinical significance of our finding remains to be established.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Inherited variations in drug-metabolizing enzymes: significance in clinical oncology.

Pharmacogenetics has emerged as a novel and challenging area of interest in oncology. Cancer chemotherapy is characterized by major intersubject variability in tumor responses and host toxicity. This variation may be caused by genetic differences in the enzymes involved in the metabolism of anticancer agents. Anticancer agents, such as 6-mercaptopurine, 5-fluorouracil, and irinotecan, have a narrow therapeutic index that can sometimes result in severe life-threatening toxicities. The impact of polymorphisms in metabolizing enzymes (thiopurine S-methyltransferase, dihydropyrimidine dehydrogenase, and uridine diphosphate glucuronosyltransferase) that participate significantly in the disposition of these anticancer agents is discussed.

Alleles↗
PubMed1998

Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes.

Irinotecan (CPT-11) is a promising antitumor agent, recently approved for use in patients with metastatic colorectal cancer. Its active metabolite, SN-38, is glucuronidated by hepatic uridine diphosphate glucuronosyltransferases (UGTs). The major dose-limiting toxicity of irinotecan therapy is diarrhea, which is believed to be secondary to the biliary excretion of SN-38, the extent of which is determined by SN-38 glucuronidation. The purpose of this study was to identify the specific isoform of UGT involved in SN-38 glucuronidation. In vitro glucuronidation of SN-38 was screened in hepatic microsomes from normal rats (n = 4), normal humans (n = 25), Gunn rats (n = 3), and patients (n = 4) with Crigler-Najjar type I (CN-I) syndrome. A wide intersubject variability in in vitro SN-38 glucuronide formation rates was found in humans. Gunn rats and CN-I patients lacked SN-38 glucuronidating activity, indicating the role of UGT1 isoform in SN-38 glucuronidation. A significant correlation was observed between SN-38 and bilirubin glucuronidation (r = 0.89; P = 0.001), whereas there was a poor relationship between para-nitrophenol and SN-38 glucuronidation (r = 0.08; P = 0.703). Intact SN-38 glucuronidation was observed only in HK293 cells transfected with the UGT1A1 isozyme. These results demonstrate that UGT1A1 is the isoform responsible for SN-38 glucuronidation. These findings indicate a genetic predisposition to the metabolism of irinotecan, suggesting that patients with low UGT1A1 activity, such as those with Gilbert's syndrome, may be at an increased risk for irinotecan toxicity.

Animals↗
PubMed1998

Phase I clinical and pharmacokinetic study of oral 9-aminocamptothecin (NSC-603071).

PURPOSE: 9-Aminocamptothecin (9-AC) is a topoisomerase I inhibitor with high antitumor activity but poor solubility in conventional vehicles. The purpose of this study was to evaluate the toxicities and pharmacokinetics of a colloidal dispersion (CD) formulation of 9-AC when administered orally on a 5 days per week every 2 weeks schedule. METHOD: This formulation, which was developed for intravenous administration, was orally administered in 20 ml orange juice. A group of 16 cancer patients were treated at doses of 0.2-0.68 mg/m2 daily. RESULTS: Grade 1-2 nausea (n = 9) was common, usually occurring during the last 2 days of dosing. No objective responses or cumulative toxicities were observed. Pharmacokinetic analysis of total 9-AC showed highly variable apparent oral 9-AC clearance and half-life. There was marked interpatient variability at each dose level in the 9-AC AUC and Cmax, and these parameters showed a poor correlation with dose (r2 = 0.07 and 0.38, respectively). CONCLUSIONS: We conclude that this formulation is not suitable for further clinical development because of poor bioavailability and highly variable and/or saturable absorption or elimination. Another formulation developed for oral administration is under study elsewhere.

Adult↗