P J Wedlund

The ability of normal subjects to hydroxylate mephenytoin (100 mg) or debrisoquine (10 mg) after oral dosing was investigated in 156 unrelated Caucasians living in middle Tennessee. Urinary recovery of 4-hydroxymephenytoin (4-OH-M) and the urinary S:R enantiomeric ratio of mephenytoin measured in an 8-hr urine sample were investigated as phenotypic traits for mephenytoin, and the urinary metabolic ratio of debrisoquine was used to determine the debrisoquine hydroxylase phenotype. Both urinary 4-OH-M and the S:R ratio of mephenytoin discriminated between extensive (EM) and poor (PM) metabolizers of mephenytoin. The frequencies of PMs for mephenytoin and debrisoquine hydroxylation activity were 2.6% and 7.0%. These two defects in oxidative metabolism were not observed in the same subjects, which suggests that 4-hydroxylation of mephenytoin is a new polymorphism independent of that for debrisoquine.

Plasma urine, and cerebrospinal fluid etoposide concentrations have been measured in 12 adult patients after administration of high-dose (400 to 800 mg/sq m) etoposide in order to determine the pharmacokinetics of this drug at these elevated dosages. Increasing the drug dosage produced proportionally higher peak plasma etoposide concentrations (27 to 114 micrograms/ml) and total areas under the concentration-time curve (9,200 to 48,000 micrograms/ml X min). The etoposide mean (+/- S.D.) terminal half-life of 8.05 +/- 4.3 hr and plasma clearance of 28.0 +/- 9.7 ml/min/sq m, however, were independent of the dosage given. The mean etoposide renal clearance in 5 patients was 10.0 +/- 4.3 ml/min/sq m, representing from 35 to 40% of the total clearance of this drug from plasma. Cerebrospinal fluid etoposide concentrations ranged from 0.1 to 1.4 micrograms/ml, as measured in 6 patients at 1 to 8 hr after high-dose etoposide therapy, and were 1.8 +/- 1.7% of the simultaneously measured plasma levels. Pleural fluid removed from one patient at 18 hr posttherapy contained etoposide at 1.8 micrograms/ml. Our data, combined with data published previously, indicate that the pharmacokinetics of high-dose etoposide is linear within the dosage range tested and similar to that seen with lower drug doses. They also suggest that etoposide penetrates poorly into the cerebrospinal fluid.

BACKGROUND: The limited available information on plasma risperidone levels shows a stable relationship between daily doses of risperidone and total plasma concentration (risperidone plus its active metabolite 9-hydroxyrisperidone). The ratio between risperidone and 9-hydroxyrisperidone characterizes cytochrome P450 2D6 (CYP2D6) status. According to the manufacturer, the CYP2D6 genotype or drugs that influence CYP2D6 or other cytochrome P450 isoenzyme activity are not expected to be clinically significant. One case report suggests that CYP3A participates in the metabolism of risperidone. METHOD: A case series of 13 risperidone patients (the initial case and 12 new cases) who were genotyped for CYP2D6 were followed, and another 20 risperidone patients from a case-control study for the CYP2D6 genotype were reviewed. RESULTS: The CYP2D6 poor metabolizers, who are enzyme deficient (2/13 in the case series and 3/20 in the case-control study), did not appear to tolerate risperidone well. Drugs affecting CYP3A, in particular powerful inducers and inhibitors, resulted in at least a 2-fold decrease or increase in plasma risperidone levels. CONCLUSION: The anecdotal nature of this study is clearly a limitation. Drugs influencing CYP3A and CYP2D6 metabolic activity may significantly affect risperidone levels. Thus, plasma level monitoring of risperidone in a clinical setting may be useful, especially if patients are taking multiple medications or a CYP2D6 deficiency is suspected. New prospective studies under more controlled conditions are needed to verify these hypotheses.

Risperidone (R) is metabolized to 9-hydroxyrisperidone (9-OHR) by cytochrome P450 2D6 (CYP2D6). The main objective of this naturalistic study was to investigate the variables associated with two plasma ratios: the plasma R:9-OHR concentration ratio and the total concentration-to-dose (C:D) ratio. These ratios were studied as continuous measures by linear regression analyses and as three dichotomous variables in logistic regression analyses: R:9-OHR ratio >1 (indicative of lack of CYP2D6 activity), C:D ratio >14 (indicative of diminished R elimination), and C:D ratio <3.5 (indicative of increased R elimination). Plasma R levels; genotypes for CYP2D6, CYP3A5; and ABCB1 genes, and co-medication, including CYP inhibitors and CYP3A inducers, were studied in 277 patients. Almost all CYP2D6 poor metabolizers (PMs) had an inverted R:9-OHR ratio (>1). Having a CYP2D6 PM phenotype was strongly associated with a C:D ratio >14 (OR=8.2; 95% confidence interval [CI]=2.0-32.7), indicating diminished R elimination. CYP2D6 ultrarapid metabolizers (UMs) did not exhibit an increased R elimination. Some ABCB1 (or MDR1) variants were significantly associated with increased R:9-OHR ratios and decreased C:D ratios, but the results were neither consistent nor robust. Taking CYP inhibitors was significantly associated with a C:D ratio >14 (OR=3.8; CI=1.7-8.7) and with an inverted R:9-OHR ratio. Taking CYP3A inducers was significantly associated with a C:D ratio <3.5 (OR=41.8; CI=12.7-138), indicating increased R elimination. Female gender and old age appeared to be associated with a lower R elimination. Our study indicated that the CYP2D6 PM phenotype may have a major role in personalizing R doses, whereas the CYP3A5 PM phenotype probably has no role. CYP inducers and inhibitors appear to be relevant to R dosing. New studies are needed, particularly to further assess the role of the CYP2D6 UM phenotype and ABCB1 variants in R pharmacokinetics.