Pharmacogenetics in the treatment of breast cancer.
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Antineoplastic Agents↗
Biomedical subjects
D A Flockhart
Publications and source records attributed to D A Flockhart.
Cytochrome P450 3A pharmacogenetics: the road that needs traveled.
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Cytochrome P-450 CYP3A↗
Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6.
We studied the pharmacokinetics and QT interval pharmacodynamics of a single 10 mg dose of oral haloperidol in a randomized, double-blind, placebo-controlled, crossover trial of healthy poor (PMs) and extensive (EMs) metabolizers of CYP2D6. There was a statistically significant greater mean QT(c) on haloperidol (421.6+/-20.1 ms) than on placebo (408.4+/-18.5 ms, P=0.0053) occurring 10 h post haloperidol/placebo administration. Men and women had similar ranges of QT(c) changes from placebo. Despite a statistically significant greater mean elimination half-life (19.1+/-3.6 vs 12.9+/-4.0 h, P=0.04) and lower mean apparent oral clearance (12.8+/-4.1 vs 27.0+/-11.3 ml/min/kg, P=0.02) of haloperidol in CYP2D6 PMs than in EMs, this exposure change did not translate into marked QT(c) changes from baseline that could be considered clinically important. Although the magnitude of the mean QT(c) prolongation on haloperidol relative to placebo is relatively small, it may assume significance in the presence of other risk factors for QT prolongation.
Adult↗
Pharmacokinetics and biochemical effects of hepapoietin in patients with chronic liver disease.
BACKGROUND: Hepapoietin is a naturally occurring cytokine that promotes hepatocyte growth. Animal studies have suggested that hepapoietin and hepatocyte growth factor have a potential role in the prevention and management of liver diseases. However, human studies have been lacking. AIM: To evaluate the safety and pharmacokinetics of single escalating doses of hepapoietin in patients with chronic liver disease. METHODS: An open-label, single escalating dose trial with five different doses of hepapoietin (1, 3, 10, 30 and 100 mg) was performed. Adults with chronic, compensated, non-viral liver disease were included. Liver function tests were obtained before dosing, 24 h after hepapoietin administration and on days 4, 7, 30 and 45. All patients were followed for 45 days. RESULTS: Twenty-five subjects received hepapoietin, with five subjects each at 1, 3, 10, 30 and 100 mg of hepapoietin. Significant decreases occurred in total bilirubin, ammonia, partial thromboplastin time and cholesterol levels overall, and both high-density and low-density lipoprotein cholesterol showed a downward trend. An increase in albumin was observed at the 30 mg dose level. Slight decreases in haemoglobin and red blood cell levels were observed at day 4, but returned to normal levels immediately thereafter. Child-Pugh scores from day 0 to day 7 were improved in 24%, stable in 64% and worse in 12% of patients. Hepatic encephalopathy displayed changes from day 0 to day 45 with improvement in 16%, no change in 80% and worsening in 4%. CONCLUSIONS: Hepapoietin in doses up to 100 mg is safe for use in humans. Potential benefits are suggested by significant decreases in bilirubin, ammonia, partial thromboplastin time and cholesterol levels and an increase in albumin. Further studies with multiple dosing regimens are needed to identify the clinical utility of hepapoietin in the management of chronic liver disease.
Area Under Curve↗
The gastroprokinetic and antiemetic drug metoclopramide is a substrate and inhibitor of cytochrome P450 2D6.
Metoclopramide is increasingly prescribed for conditions previously treated with cisapride, but its metabolic enzymology and drug interactions are poorly understood. Using human liver microsomes (HLMs) and recombinant human cytochromes P450 (P450), we identified the major route of metoclopramide oxidation and the P450 isoforms involved. We also documented the ability of metoclopramide to inhibit the P450 system, using isoform-specific substrate reaction probes of CYP1A2, 2C19, 2C9, 2D6, 2E1, and 3A4. Metoclopramide was predominantly N-dealkylated to monodeethylmetoclopramide, a metabolite that has not so far been described in humans. Formation rate of this metabolite followed Michaelis-Menten kinetics (K(m), 68 +/- 16 microM; V(max), 183 +/- 57 pmol/min/mg of protein; n = 3 HLMs). Of the isoform-specific inhibitors tested, 1 microM quinidine was a potent inhibitor of metoclopramide (25 microM) monodeethylation [by an average of 58.2%; range, approximately 38% (HL09-14-99) to 78.7% (HL161)] with K(i) values highly variable among the HLMs tested (K(i), mean +/- S.D., 2.7 +/- 2.8 microM; range, 0.15 microM in HL66, 2.4 microM in HL09-14-99, and 5.7 microM in HLD). Except troleandomycin, which inhibited metoclopramide metabolism in only one HLM (by approximately 23% in HL09-14-99), the effect of other inhibitors was minimal. Among the recombinant human P450 isoforms examined, monodeethylmetoclopramide was formed at the highest rate by CYP2D6 (V = 4.5 +/- 0.3 pmol/min/pmol of P450) and to a lesser extent by CYP1A2 (0.97 +/- 0.15 pmol/min/pmol of P450). The K(m) value derived (approximately 53 microM) was close to that from HLMs (68 microM). Metoclopramide is a potent inhibitor of CYP2D6 at therapeutically relevant concentrations (K(i) = 4.7 +/- 1.3 microM), with negligible effect on other isoforms tested. Further inhibition of CYP2D6 was observed when metoclopramide was preincubated with HLMs and NADPH-generating system before the substrate probe was added (maximum rate of inactivation, K(inact) = 0.02 min(-1), and the concentration required to achieve the half-maximal rate of inactivation, K'(i) = 0.96 microM), suggesting mechanism-based inhibition. Metoclopramide elimination is likely to be slowed in poor metabolizers of CYP2D6 or in patients taking inhibitors of this isoform, whereas metoclopramide itself could reduce the clearance of CYP2D6 substrate drugs.
Animals↗
Formal education about medication errors in internal medicine clerkships.
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Clinical Clerkship↗
Stereoselective pharmacokinetics of cisapride in healthy volunteers and the effect of repeated administration of grapefruit juice.
AIMS: To determine whether the pharmacokinetics of cisapride and its interaction with grapefruit juice are stereoselective. METHODS: The study was a randomized, two-phase cross over design with a washout period of 2 weeks. Ten healthy volunteers were pretreated with either water or 200 ml double strength grapefruit juice three times a day for 2 days. On the 3rd each subject ingested a single 10 mg dose of rac-cisapride tablet. Double strength grapefruit juice (200 ml) or water was administered during cisapride dosing and 0.5 and 1.5 h thereafter. Blood samples were collected before and for 32 h after cisapride administration. Plasma concentrations of cisapride enantiomers were measured by a chiral h.p.l.c. method. A standard 12-lead ECG was recorded before cisapride administration (baseline) and 2, 5, 8, and 12 h later. RESULTS: This study showed that cisapride pharmacokinetics are stereoselective. In control (water treated) subjects, the mean Cmax (30 +/- 13.6 ng ml-1; P = 0.0008) and AUC(0, infinity) (201 +/- 161 ng ml-1 h; P = 0.029) of (-)-cisapride were significantly higher than the Cmax (10.5 +/- 3.4 ng ml-1) and AUC(0, infinity) (70 +/- 51.5 ng ml-1 h) of (+)-cisapride. There was no marked difference in elimination half-life between (-)-cisapride (4.7 +/- 2.7 h) and (+)-cisapride (4.8 +/- 3 h). Compared with the water treated group, grapefruit juice significantly increased the mean Cmax of (-)-cisapride from 30 +/- 13.6-55.5 +/- 18 ng ml-1 (95% CI on mean difference, -33, -17; P = 0.00005) and of (+)-cisapride from 10.5 +/- 3.4 to 18.4 +/- 6.2 ng ml-1 (95% CI on mean difference, -11.8, -3.9, P = 0.00015). The mean AUC(0, infinity) of (-)-cisapride was increased from 201 +/- 161 to 521.6 +/- 303 ng ml-1 h (95% CI on mean difference, -439, -202; P = 0.0002) and that of (+)-cisapride from 70 +/- 51.5 to 170 +/- 91 ng ml-1 h (95% CI on mean difference, -143, -53; P = 0.0005). The tmax was also significantly increased for both enantiomers (from 1.35 to 2.8 h for (-)-cisapride and from 1.75 to 2.9 h for (+)-cisapride in the control and grapefruit juice group, respectively; P < 0.05). The t(1/2) of (-)-cisapride was significantly increased by grapefruit juice, while this change did not reach significant level for (+)-cisapride. The proportion of pharmacokinetic changes brought about by grapefruit juice was similar for both enantiomers, suggesting non-stereoselective interaction. We found no significant difference in mean QTc intervals between the water and grapefruit juice treated groups. CONCLUSIONS: The pharmacokinetics of cisapride is stereoselective. Grapefruit juice elevates plasma concentrations of both (-)- and (+)-cisapride, probably through inhibition of CYP3A in the intestine. At present, there are no data on whether the enantiomers exhibit stereoselective pharmacodynamic actions. If they do, determination of plasma concentrations of the individual enantiomers as opposed to those of racemic cisapride may better predict the degree of drug interaction, cardiac safety and prokinetic efficacy of cisapride.
Administration, Oral↗
Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced haloperidol.
AIMS: We evaluated the inhibitory effect of haloperidol and its metabolites on CYP2D6 activity in order to better understand the potential role of these metabolites in drug interactions involving haloperidol. METHODS: The inhibitory effects of haloperidol and five of its metabolites on dextrorphan formation from dextromethorphan, a marker probe of CYP2D6 activity, were measured in human liver microsomal preparations. Apparent kinetic parameters for enzyme inhibition were determined by nonlinear regression analysis of the data. RESULTS: Racemic reduced haloperidol and its metabolite, RHPTP competitively inhibited dextromethorphan O-demethylation with estimated Ki values (0.24 microM and 0.09 microM, respectively) that were substantially lower than that of haloperidol (0.89 microM). The inhibitory effect of S(-)-reduced haloperidol was more potent than the R(+)-enantiomer, with estimated Ki values of 0.11 microM and 1.1 microM, respectively. The pyridinium metabolite of haloperidol, HPP+ inhibited the enzyme activity noncompetitively with a Ki value of 0.79 microM. The N-dealkylated metabolites of haloperidol (FBPA and CPHP) had a diminished inhibitory potency. While FBPA showed no notable inhibitory effect on dextrorphan formation, CPHP showed moderate competitive inhibition with a Ki value of 20.9 microM. CONCLUSIONS: The principal metabolites of haloperidol inhibit CYP2D6, suggesting that they might contribute to the inhibitory effects of the drug. Reduced haloperidol seems to inhibit CYP2D6 activity in an enantioselective manner with the physiologically occurring S(-) enantiomer being more potent.
Binding, Competitive↗
Effects of ethnicity on the distribution of clinically relevant endothelial nitric oxide variants.
Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene have been associated inconsistently with cardiovascular diseases. A maldistribution of eNOS variants among ethnic groups may explain interethnic differences in nitric oxide (NO)-mediated vasodilation and response to drugs. To test this possibility, we examined the distribution of genetic variants of three clinically relevant eNOS polymorphisms (T-786C in the promoter, the variable number of tandem repeats (VNTR) in intron 4, and the Glu298Asp variant in exon 7) in 305 ethnically well-characterized DNA samples (100 Caucasians, 100 African-Americans, and 105 Asians). We estimated the haplotype frequency, and evaluated associations between these variants. The Asp298 variant was more common in Caucasians (34.5%) than in African-Americans (15.5%) or Asians (8.6%)(P < 0.0001). The C-786 variant was also more common in Caucasians (42.0%) than in African-Americans (17.5%) or Asians (13.8%) (P < 0.0001). The 4a variant in intron 4 was more common in African-Americans (26.5%) than in Caucasians (16.0%) or Asians (12.9%) (P < 0.0001). The most common predicted haplotype in the three groups combined only wild-type variants. Asians had the highest frequency of this haplotype (77% in Asians v. 46% in the other groups). In Caucasians, the Asp298 and C-786variants were associated, and this haplotype was predicted to have a frequency of 24%. In African-Americans, the second most common haplotype included the variant 4a and wild-type variants; the Asp298 and 4a variants were associated negatively in this group. The C-786 and 4a variants were associated in Asians (P < 0.0001). The marked interethnic differences that we found in the distribution of eNOS variants, in the estimated haplotype frequency, and in the association between variants may help us to understand how the combination of these genetic variants may influence cardiovascular diseases.
Alleles↗
Inhibition of cytochrome P450 (CYP450) isoforms by isoniazid: potent inhibition of CYP2C19 and CYP3A.
Isoniazid (INH) remains the most safe and cost-effective drug for the treatment and prophylaxis of tuberculosis. The use of INH has increased over the past years, largely as a result of the coepidemic of human immunodeficiency virus infection. It is frequently given chronically to critically ill patients who are coprescribed multiple medications. The ability of INH to elevate the concentrations in plasma and/or toxicity of coadministered drugs, including those of narrow therapeutic range (e.g., phenytoin), has been documented in humans, but the mechanisms involved are not well understood. Using human liver microsomes (HLMs), we tested the inhibitory effect of INH on the activity of common drug-metabolizing human cytochrome P450 (CYP450) isoforms using isoform-specific substrate probe reactions. Incubation experiments were performed at a single concentration of each substrate probe at its K(m) value with a range of INH concentrations. CYP2C19 and CYP3A were inhibited potently by INH in a concentration-dependent manner. At 50 microM INH (approximately 6.86 microg/ml), the activities of these isoforms decreased by approximately 40%. INH did not show significant inhibition (<10% at 50 microM) of other isoforms (CYP2C9, CYP1A2, and CYP2D6). To accurately estimate the inhibition constants (K(i) values) for each isoform, four concentrations of INH were incubated across a range of five concentrations of specific substrate probes. The mean K(i) values (+/- standard deviation) for the inhibition of CYP2C19 by INH in HLMs and recombinant human CYP2C19 were 25.4 +/- 6.2 and 13 +/- 2.4 microM, respectively. INH showed potent noncompetitive inhibition of CYP3A (K(i) = 51.8 +/- 2.5 to 75.9 +/- 7.8 microM, depending on the substrate used). INH was a weak noncompetitive inhibitor of CYP2E1 (K(i) = 110 +/- 33 microM) and a competitive inhibitor of CYP2D6 (K(i) = 126 +/- 23 microM), but the mean K(i) values for the inhibition of CYP2C9 and CYP1A2 were above 500 microM. Inhibition of one or both CYP2C19 and CYP3A isoforms is the likely mechanism by which INH slows the elimination of coadministered drugs, including phenytoin, carbamazepine, diazepam, triazolam, and primidone. Slow acetylators of INH may be at greater risk for adverse drug interactions, as the degree of inhibition was concentration dependent. These data provide a rational basis for understanding drug interaction with INH and predict that other drugs metabolized by these two enzymes may also interact.
Algorithms↗
Visual hallucination and tremor induced by sertraline and oxycodone in a bone marrow transplant patient.
The authors report a case of probable serotonin syndrome caused by the coadministration of sertraline and oxycodone. A 34 year-old male patient experienced visual hallucinations and severe tremor after dramatically increasing his dosage of oxycodone while on stable amounts of sertraline and cyclosporin. Discontinuation of cyclosporin did not result in resolution of his symptoms. Consideration of a possible sertraline-oxycodone interaction led to withholding sertraline, which resulted in symptom resolution. Serotonin syndrome has been noted with sertraline in combination with other drugs, but this is the first report in combination with a narcotic analgesic. Possible pharmacological mechanisms are discussed. In complicated patients that are taking multiple medications, physicians should be aware of this possible interaction to avoid delay in the diagnosis of serotonin syndrome.
Adult↗
Olanzapine-induced rhabdomyolysis.
OBJECTIVE: To report a possible case of olanzapine-induced rhabdomyolysis with concomitant lithium-induced pseudo-infarction electrocardiogram changes. CASE SUMMARY: A 13-year-old white boy was admitted to the hospital with profound weakness and electrocardiogram (EGG) changes suggestive of myocardial damage after starting olanzapine and lithium. An adverse medication effect was not considered at the time of the patient's admission. The time course of onset of weakness was coincident with administration of olanzapine. ECG abnormalities are a known manifestation of lithium therapy DISCUSSION: This is a case description of olanzapine-induced rhabdomyolysis. Although other antipsychotic agents have been reported to cause rhabdomyolysis, an adverse drug reaction was not initially part of this patient's differential diagnosis. The patient had begun reporting rnyalgias six days after starting olanzapine. Fourteen days later, these symptoms forced him to bed rest; lithium was added for behavior misinterpreted as disobedience and oppositional disorder. Only when medications were considered as cause of the weakness and EGG changes, was the true nature of the patient's illness discovered. CONCLUSIONS: Olanzapine, like other neuroleptic agents, can cause rhabdomyolysis. Lithium can cause multiple EGG changes that can be misinterpreted as myocardial damage. Medication effects and adverse effects must always be considered in any disease complex.
Adolescent↗
Stereoselective metabolism of cisapride and enantiomer-enantiomer interaction in human cytochrome P450 enzymes: major role of CYP3A.
Cisapride is a chiral molecule that is marketed as a racemate consisting of two optical isomers, but little is known about its stereoselective metabolism. Studies with (-)-, (+)-, and (+/-)-cisapride were undertaken in human liver microsomes (HLMs) and recombinant cytochrome P450s (P450s) to determine the stereoselective metabolism and enantiomer-enantiomer interaction. Each enantiomer and racemic cisapride were N-dealkylated to norcisapride (NORCIS) and hydroxylated to 3-fluoro-4-hydroxycisapride (3-F-4-OHCIS) and 4-fluoro-2-hydroxycisapride (4-F-2-OHCIS). The kinetics for the formation of NORCIS from (-)-cisapride (Km = 11.9 +/- 4.8 microM; Vmax = 203 +/- 167 pmol/min/mg of protein) or (+)-cisapride (Km = 18.5 +/- 4.7 microM; Vmax = 364 +/- 284 pmol/min/mg of protein) in HLMs exhibited simple Michaelis-Menten kinetics, while a sigmoidal model characterized those of 3-F-4-OHCIS and 4-F-2-OHCIS. In vitro, NORCIS appears to be the major metabolite of both enantiomers. NORCIS and 3-F-4-OHCIS were preferentially formed from (+)-cisapride rather than (-)-cisapride, but that of 4-F-2-OHCIS was the reverse, suggesting regio- and stereoselective metabolism. The formation rate of each metabolite from each enantiomer (20 microM) in 18 HLMs was highly variable (e.g., NORCIS, >35-fold) and correlated with the activity of CYP3A (r = 0.6-0.85; p < 0.05). Coincubation of troleandomycin (50 microM) with cisapride enantiomers (15 microM) in HLMs resulted in potent inhibition of NORCIS formation (by 75-80%), while other inhibitors showed negligible effect. Of 10 recombinant human P450s tested, CYP3A4 catalyzed the formation of NORCIS, 3-F-4-OHCIS, and 4-F-2-OHCIS from each enantiomer and racemic cisapride (15 microM) with the highest specific activity (Km values close to those in HLMs). We noted that the rate of racemic cisapride metabolism by HLMs and recombinant human CYP3A4 is slower compared with equimolar concentrations of each enantiomer. When incubated simultaneously in HLMs, the enantiomers inhibit each other's metabolism. In conclusion, our data demonstrate for the first time the stereoselective metabolism and enantiomer-enantiomer interaction of cisapride. Provided that the potency or the response of the enantiomers differ, understanding the factors that control their disposition as opposed to that of racemic cisapride may better predict adverse drug interactions and the resulting prokinetic efficacy and cardiac safety of cisapride.
Aryl Hydrocarbon Hydroxylases↗
Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cDNA and oligonucleotide expression arrays.
We used expression microarrays to test the effects of rifampin on the overall pattern of mRNA expression of multiple metabolic enzymes in primary human hepatocytes. Two microarrays were utilized, a cDNA-based array and one that is oligonucleotide-based. The cDNA-based expression arrays showed that rifampin caused a 7.7 +/- 6.6-fold induction in CYP2A6 and a 4.0 +/- 2.0-fold increase in the CYP2C family of enzymes while having little effect on CYP2E1 or CYP2D6. Many non-P450 enzymes were also induced including FMO-4 and -5, UGT-1A, MAO-B, and GST-P1. The oligonucleotide-based array made it possible to detect different levels of induction within the CYP2C family, with rifampin causing a 6.5-fold increase in expression of CYP2C8 and a 3.7-fold increase in CYP2C9 while having no effect on the level of CYP2C18 mRNA. Rifampin also induced other CYP enzymes including CYP2B6 and all three members of the CYP3A family, with CYP3A4 showing the highest level of induction at 55.1-fold. RNase protection assays were used to validate results from the arrays and a comparison of all three methods of mRNA detection showed qualitatively similar results. These data make it clear that rifampin treatment brings about broad changes in the pattern of gene expression, rather than increased expression of a small number of metabolic enzymes. Clinicians and researchers who use and study rifampin and other drugs that induce drug metabolism should be alert to the possibility of multiple effects.
Antibiotics, Antitubercular↗
Stereoselective determination of cisapride, a prokinetic agent, in human plasma by chiral high-performance liquid chromatography with ultraviolet detection: application to pharmacokinetic study.
We have developed a simple, sensitive, specific and reproducible stereoselective high-performance liquid chromatography technique for analytical separation of cisapride enantiomers and measurement of cisapride enantiomers in human plasma. A chiral analytical column (ChiralCel OJ) was used with a mobile phase consisting of ethanol-hexane-diethylamine (35:64.5:0.5, v/v/v). This assay method was linear over a range of concentrations (5-125 ng/ml) of each enantiomer. The limit of quantification was 5 ng/ml in human plasma for both cisapride enantiomers, while the limit of detection was 1 ng/ml. Intra- and inter-day C.V.s did not exceed 15% for all concentrations except at 12.5 ng/ml for EII (+)-cisapride, which was approximately 20 and 19%, respectively. The clinical utility of the method was demonstrated in a pharmacokinetic study of normal volunteers who received a 20 mg single oral dose of racemic cisapride. The preliminary pharmacokinetic data obtained using the method we describe here provide evidence for the first time that cisapride exhibits stereoselective disposition.
Chromatography, High Pressure Liquid↗
Molecular basis of cardiovascular drug metabolism: implications for predicting clinically important drug interactions.
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ATP Binding Cassette Transporter, Subfamily B, Mem↗
In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6.
AIMS: To examine the potency of ticlopidine (TCL) as an inhibitor of cytochrome P450s (CYP450s) in vitro using human liver microsomes (HLMs) and recombinant human CYP450s. METHODS: Isoform-specific substrate probes of CYP1A2, 2C19, 2C9, 2D6, 2E1 and 3A4 were incubated in HLMs or recombinant CYPs with or without TCL. Preliminary data were generated to simulate an appropriate range of substrate and inhibitor concentrations to construct Dixon plots. In order to estimate accurately inhibition constants (Ki values) of TCL and determine the type of inhibition, data from experiments with three different HLMs for each isoform were fitted to relevant nonlinear regression enzyme inhibition models by WinNonlin. RESULTS: TCL was a potent, competitive inhibitor of CYP2C19 (Ki = 1.2 +/- 0.5 microM) and of CYP2D6 (Ki = 3.4 +/- 0.3 microM). These Ki values fell within the therapeutic steady-state plasma concentrations of TCL (1-3 microM). TCL was also a moderate inhibitor of CYP1A2 (Ki = 49 +/- 19 microM) and a weak inhibitor of CYP2C9 (Ki > 75 microM), but its effect on the activities of CYP2E1 (Ki = 584 +/- 48 microM) and CYP3A (> 1000 microM) was marginal. CONCLUSIONS: TCL appears to be a broad-spectrum inhibitor of the CYP isoforms, but clinically significant adverse drug interactions are most likely with drugs that are substrates of CYP2C19 or CYP2D6.
Anticonvulsants↗
A discordance of the cytochrome P450 2C19 genotype and phenotype in patients with advanced cancer.
AIMS: To examine the relationship between cytochrome P450 2C19 (CYP2C19) genotype and expressed metabolic activity in 16 patients with advanced metastatic cancer. METHODS: Individual CYP2C19 genotypes were determined by PCR-based amplification, followed by restriction fragment length analysis, and compared with observed CYP2C19 metabolic activity, as determined using the log hydroxylation index of omeprazole. RESULTS: All 16 patients had an extensive metabolizer genotype. However, based on the antimode in a distribution of log omeprazole hydroxylation indices from healthy volunteers, four of the patients had a poor metabolizer phenotype and there was a general shift of the remaining 12 patients towards a slower metabolic phenotype. This suggests a reduction in metabolic activity for all patients relative to healthy volunteers. A careful analysis of patient medical records failed to reveal any drug interactions or other source for the observed discordance between genotype and phenotype. CONCLUSIONS: There are no previous reports of a 'discordance' between genotype and expressed enzyme activity in cancer patients. Such a decrease in enzyme activity could have an impact on the efficacy and toxicity of chemotherapeutic agents and other drugs, used in standard oncology practice.
Aryl Hydrocarbon Hydroxylases↗