Robin M. Taylor

The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein.

P-glycoprotein (P-gp) in the brain capillary endothelial cell limits the entry of many drugs into the brain. Our previous in-vitro study using ATPase as a marker of P-gp activity suggested that risperidone might be effectively transported by P-gp. In the present study, we compared the concentrations of risperidone and its major pharmacologically active metabolite 9-hydroxyrisperidone (9-OH-risperidone), in plasma, brain and various other tissues between abcb1ab-/- knockout mice which are functionally devoid of P-gp in their blood-brain barrier vs. FVB wild-type mice. One hour after intraperitoneal injection of 4 microg/g risperidone, the brain concentrations and ratios of brain:plasma concentrations of risperidone (13.1-fold and 12-fold respectively, p<0.05) and 9-OH-risperidone (29.4-fold and 29-fold respectively, p<0.01) were significantly higher in the abcb1ab-/- mice than those in the FVB mice. These results indicate that P-gp in the blood-brain barrier significantly influences the brain concentrations of risperidone and 9-OH-risperidone by limiting their CNS access.

Effects of garlic (Allium sativum L.) supplementation on cytochrome P450 2D6 and 3A4 activity in healthy volunteers.

Garlic (Allium sativum L.) is a commonly used food and herbal supplement. The objective of this study was to assess in healthy volunteers (N = 14) the influence of a garlic extract on the activity of cytochrome P450 (CYP) 2D6 and 3A4. Probe substrates dextromethorphan (CYP2D6) and alprazolam (CYP3A4) were administered orally at baseline and again after treatment with garlic extract (3 × 600 mg twice daily) for 14 days. Urinary dextromethorphan/dextrorphan ratios and alprazolam plasma concentrations were determined by HPLC at baseline and after garlic extract treatment. The ratio of dextromethorphan to its metabolite was 0.044 ± 0.48 at baseline and 0.052 ± 0.095 after garlic supplementation. There were no significant differences between the baseline and garlic phases (P ≥ .05). For alprazolam, there were no significant differences in pharmacokinetic parameters at baseline and after garlic extract treatment (all P values ≥ .05; maximum concentration in plasma, 27.3 ± 2.6 ng/mL versus 27.3 ± 4.8 ng/mL; time to reach maximum concentration in plasma, 1.9 ± 1.4 h versus 2.4 ± 1.8 h; area under the time‐versus‐concentration curve, 537 ± 94 h · ng · mL−1 versus 548 ± 159 h · ng · mL−1; half‐life of elimination, 13.7 ± 4.4 h versus 14.5 ± 4.3 h). Our results indicate that garlic extracts are unlikely to alter the disposition of coadministered medications primarily dependent on the CYP2D6 or CYP3A4 pathway of metabolism.

Multiple doses of saw palmetto (Serenoa repens) did not alter cytochrome P450 2D6 and 3A4 activity in normal volunteers.

Saw palmetto (Serenoa repens) is the most commonly used herbal preparation in the treatment of benign prostatic hyperplasia. The objective of this study was to determine whether a characterized saw palmetto product affects the activity of cytochrome P450 (CYP) 2D6 or 3A4 in healthy volunteers (6 men and 6 women). The probe substrates dextromethorphan (CYP2D6 activity) and alprazolam (CYP3A4 activity) were administered orally at baseline and again after exposure to saw palmetto (320‐mg capsule once daily) for 14 days. Dextromethorphan metabolic ratios and alprazolam pharmacokinetics were determined at baseline and after saw palmetto treatment. The mean ratio of dextromethorphan to its metabolite was 0.038 ± 0.044 at baseline and 0.048 ± 0.080 after 14 days of saw palmetto administration (P = .704, not significant [NS]), indicating a lack of effect on CYP2D6 activity. The area underthe plasma alprazolam concentration versus time curve was 476 ± 178 h · ng · mL−1 at baseline and 479 ± 125 h · ng · mL−1 after saw palmetto treatment (P = .923, NS), indicating a lack of effect on CYP3A4 activity. The elimination half‐life of alprazolam was 11.4± 3.1 hours at baseline and 11.6 ± 2.7 hours after saw palmetto treatment (P = .770, NS), also indicating a lack of effect on CYP3A4 activity. Our results indicate that extracts of saw palmetto at generally recommended doses are unlikely to alter the disposition of coadministered medications primarily dependent on the CYP2D6 or CYP3A4 pathways for elimination. These conclusions must be weighed in the context of the studys limited assessments and regarded as only the initial investigation into the drug interaction potential of saw palmetto.

Olanzapine penetration into brain is greater in transgenic Abcb1a P-glycoprotein-deficient mice than FVB1 (wild-type) animals.

The transmembrane energy-dependent efflux transporter P-glycoprotein (P-gp) limits a range of drugs from penetrating cells and deposits them into the extracellular space. P-gp is highly expressed in several normal tissues, including the luminal surface of capillary endothelial cells in the brain of humans. In this study, we tested whether olanzapine distribution to tissues highly expressing P-gp or devoid of this transporter was similar in Abcb1a (−/−) mice lacking P-gp and control animals. At 1 h following the intraperitoneal injection of 2.5 μg olanzapine/g mouse, olanzapine concentrations were statistically and significantly higher in brain (three-fold), liver (2.6-fold), and kidney (1.8-fold) of Abcb1a (−/−) mice than those of the control FVB Abcb1a (+/+) mice, and not statistically different in plasma, spleen, or penile tissue. Similar differences were also found for the ratios of organ:plasma and organ:spleen between the two groups. This is the first report that the presence of the Abcb1a gene is an important factor controlling brain access to olanzapine. The finding that the brain penetration of olanzapine is limited by P-gp implies that the highly prevalent functional polymorphisms of ABCB1 in humans may be a factor contributing to variability in dose requirements for this antipsychotic drug.

Modafinil influences the pharmacokinetics of intravenous cocaine in healthy cocaine-dependent volunteers.

AbstractObjective: To determine if modafinil, a putative treatment for cocaine dependence, influences the pharmacokinetics of intravenous cocaine in otherwise healthy cocaine-dependent volunteers. Methods: Cocaine 20 or 40mg was administered intravenously on consecutive days over 1 minute at baseline and after modafinil administration at each of two dosages of 400 and 800 mg/day for 7 days. Results: Twelve subjects completed the clinical protocol. Compared with baseline, the cocaine peak plasma concentration was decreased after both the 20 and 40mg cocaine infusions, but the reduction was only statistically significant after the 40mg cocaine infusion (p < 0.01 after modafinil 400 mg/day; p < 0.05 after modafinil 800 mg/day). The area under the cocaine plasma concentration-time curve from 0 to 180 minutes (AUC180) was significantly decreased by modafinil administration (p < 0.01 and p < 0.001 for modafinil 400 and 800 mg/day, respectively, for the cocaine 20mg dose; p < 0.001 for the cocaine 40mg dose at both modafinil levels). There were no significant changes in total AUC, clearance or elimination half-life of cocaine. Conclusion: This study did not find evidence for a harmful pharmacokinetic interaction between modafinil and cocaine. In contrast, long-term administration of modafinil significantly decreased systemic exposure to cocaine during the first 180 minutes following intravenous cocaine administration.

Personality characteristics of patients showing suboptimal cognitive effort.

This study examined the relationship between performance on the Portland Digit Recognition Test (PDRT) and the MMPI-2 in a group of veterans who were suspected of having motivation to exaggerate cognitive and/or psychiatric symptoms. Number correct on “easy” trials on the PDRT correlated inversely with MMPI-2 measures of psychopathology, whereas number correct on “hard” trials positively correlated with the same scales. Some individuals performed poorly across both types of PDRT trials and had significant MMPI-2 elevations, whereas others performed poorly only on “hard” PDRT trials and had less extreme MMPI-2 elevations. This study reinforces the need to assess the validity of both cognitive and psychiatric symptom complaints.

Effect of St. John’s Wort on Drug Metabolism by Induction of Cytochrome P450 3A4 Enzyme

CONTEXT St Johns wort is a popular herbal product used to treat depression but it has been implicated in drug interactions. OBJECTIVE To assess the potential of St Johns wort administration to alter the activity of the cytochrome P450 (CYP) enzymes extensively involved in drug metabolism. DESIGN, SETTING, AND PARTICIPANTS Open-label crossover study with fixed treatment order conducted March 2002 to February 2003 in a US general clinical research center involving 12 healthy volunteers (6 men and 6 women) aged 22 to 38 years before and after 14 days of administration of St Johns wort. INTERVENTION Participants were given probe drugs (30 mg of dextromethorphan and 2 mg of alprazolam) to establish baseline CYP 3A4 and CYP 2D6 activity. After a minimum 7-day washout period, participants began taking one 300-mg tablet 3 times per day. After 14 days of St Johns wort administration, participants were given the probe drugs along with 1 St Johns wort tablet to establish postadministration CYP activity; the St Johns wort dosing regimen was continued for 48 hours. MAIN OUTCOME MEASURES Changes in plasma pharmacokinetics of alprazolam as a probe for CYP 3A4 activity and the ratio of dextromethorphan to its metabolite, dextrorphan, in urine as a probe for CYP 2D6 activity. RESULTS A 2-fold decrease in the area under the curve for alprazolam plasma concentration vs time (P<.001) and a 2-fold increase in alprazolam clearance (P<.001) were observed following St Johns wort administration. Alprazolam elimination half-life was shortened from a mean (SD) of 12.4 (3.9) hours to 6.0 (2.4) hours (P<.001). The mean (SD) urinary ratio of dextromethorphan to its metabolite was 0.006 (0.010) at baseline and 0.014 (0.025) after St Johns wort administration (P =.26). CONCLUSIONS A 14-day course of St Johns wort administration significantly induced the activity of CYP 3A4 as measured by changes in alprazolam pharmacokinetics. This suggests that long-term administration of St Johns wort may result in diminished clinical effectiveness or increased dosage requirements for all CYP 3A4 substrates, which represent at least 50% of all marketed medications.

BRIEF REPORT Relationship of MMPI‐2 anxiety and defensiveness to neuropsychological test performance and psychotropic medication use

Research has suggested an adverse effect of anxiety on cognitive functioning, and high defensive individuals may have poorer control of their anxiety than low defensive individuals. Thus, these individuals may be more likely to have a prescription for psychotropic medication. The purpose of this study was to further delineate the effects of anxiety and defensiveness on neuropsychological test performance and psychotropic medication use. Participants were 143 US veterans referred for neuropsychological evaluation. Four groups were established based on median splits on MMPI‐2 approximations of anxiety and defensiveness. Anxiety and defensiveness were unrelated to neuropsychological test performance. Defensive high anxious individuals were more likely than truly high anxious individuals to have anxiolytic and narcotic prescriptions. There was also a trend toward truly low anxious participants being more likely to be prescribed anxiolytics than repressor participants. Thus, defensiveness appears to attenuate the experience of anxiety in individuals who are low, but not high, in self‐reported anxiety.