Amar Pinto

The Effect of Echinacea (Echinacea purpurea Root) on Cytochrome P450 Activity in Vivo

Echinacea is a widely available over‐the‐counter herbal remedy. Tinctures of echinacea have been shown to inhibit cytochrome P450 (CYP) in vitro. The effect of echinacea (Echinacea purpurea root) on CYP activity in vivo was assessed by use of the CYP probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), dextromethorphan (CYP2D6), and midazolam (hepatic and intestinal CYP3A).

Association Between the CYP3A5 Genotype and Blood Pressure

We tested the hypothesis that the presence of a CYP3A5*1 allele is associated with increases in blood pressure in 2 studies of subjects with a total of 683 participants. The first study involving 271 subjects was part of a longitudinal study conducted at Indiana University Medical Center that consisted of 2 phases. The first phase studied the relationship of salt sensitivity with blood pressure, whereas the second phase, conducted ≈26 years later, studied the relationship between blood pressure, carbohydrate intolerance, and vascular compliance in the same subjects. The second study was a cross-sectional evaluation of 412 normotensive and hypertensive subjects conducted at the University of California San Diego. The second study (Mantel–Haenszel &khgr;2 test; P=0.05) showed that a greater proportion of black participants with poor blood pressure control had CYP3A5*1/*1 genotype. Evaluation of the untreated blood pressure from phase 1 of the first study showed that the blacks with CYP3A5*3/*3 (146±35 mm Hg) had a higher systolic blood pressure than those with the *1/*3 (119±14.1 mm Hg; P=0.0006) and *1/*1 (125±17.4 mm Hg; P=0.009) genotypes. For blacks in study 2, the CYP3A5*1 allele was more common in hypertensives (Fisher exact test; P=0.025) than normotensives. In whites there was no association between CYP3A5 genotype and blood pressure in either study. We conclude that although untreated blood pressure may be higher in blacks with the CYP3A5*3/*3 genotype, the CYP3A5*1 allele may be associated with hypertension that is more refractory to treatment in this ethnic group.

Inhibition of human intestinal wall metabolism by macrolide antibiotics: effect of clarithromycin on cytochrome P450 3A4/5 activity and expression.

Clarithromycin increases both hepatic and intestinal availability of the selective cytochrome P450 (CYP) 3A probe midazolam. This study was designed to identify determinants of variability in the extent of intestinal wall CYP3A inhibition by clarithromycin, such as CYP3A5 genotype, and the mechanism of inhibition.

Activity of CYP2E1 and CYP3A enzymes in adults with moderate alcohol consumption: A comparison with nonalcoholics

Alcohol consumption is known to induce hepatic CYP2E1 activity, but its effect on hepatic and intestinal CYP3A in humans is not known. We have conducted a study to compare the CYP2E1 and CYP3A activities in 20 individuals with moderate alcohol consumption and 20 gender‐, race‐. and body mass index (BMI)‐matched nonalcoholics. Intravenous and oral midazolam (MDZ) clearances were used to measure the in vivo CYP3A activity, and chlorzoxazone (CHZ) oral clearance was used to assess in vivo CYP2E1 activity. Furthermore, we assessed the relationship between hepatic CYP2E1 and CYP3A activities and their messenger RNA (mRNA) expression in the peripheral lymphocytes. The systemic clearance (CL) of MDZ was not different between alcoholics (36.9 ± 12 L/hr) and nonalcoholics (36.6 ± 14.1; P = .9). The oral availability of MDZ was significantly lower in alcoholics than in the nonalcoholics (0.28 ± .09 vs. 0.38 ± .17, respectively, P = .03). The maximum serum concentration after oral midazolam dosing was significantly different between the 2 groups. CHZ CL was significantly higher in alcoholics than in nonalcoholics (31.5 ± 11.9 vs. 23.4 ± 8.7 L/hr, P < 0.05). CYP3A4 and CYP2E1 mRNA levels were not significantly different between the groups, and no correlation was observed between lymphocyte CYP mRNA and in vivo CYP activity. In conclusion, in individuals with moderate alcohol consumption, there was no alteration in the hepatic CYP3A activity, but the reduced midazolam oral bioavailability suggests that moderate alcohol consumption may cause intestinal CYP3A induction. Lymphocyte CYP2E1 and CYP3A4 mRNA levels did not correlate with CYP2E1 and CYP3A activities. (HEPATOLOGY 2005;41:1144–1150.)

Severe thrombocytopenia due to hypersplenism successfully treated with partial splenic embolization in preoperative management.

Hypersplenism is a known complication of portal hypertension secondary to cirrhosis of the liver. Although thrombocytopenia secondary to hypersplenism does not cause clinically significant hemostatic defect, it may need to be addressed in selective circumstances, such as preoperative preparation for a surgery. This report describes a 30-year-old male with a history of cirrhosis of the liver and hypersplenism who had a recurrence of craniopharyngioma. A platelet count of 40 × 10 9/L limited his treatment options. A stereotactic injection of radioactive P32 into the tumor was planned but was thought not to be feasible because of the thrombocytopenia. The thrombocytopenia responded favorably to partial splenic embolization, and the patient underwent successful stereotactic injection of radioactive P32 into the tumor.

Altered first-pass effects in a liver transplant recipient explained intraindividual variation in calcineurin inhibitor concentrations: a case report.

BACKGROUND The significant interindividual and intraindividual variability in the blood concentrations of the most commonly used calcineurin inhibitors such as tacrolimus and cyclosporine makes the exact dosing of these agents in transplant recipients very challenging. As both of these drugs have narrow therapeutic index and are metabolized by hepatic and intestinal cytochrome P450 3A, we tested the hypothesis that these variations are secondary to varying first-pass effects in the gut and the liver over a period of time. CASE REPORT A liver transplant recipient, who had previously presented with tacrolimus toxicity on his usual dosing regimen and intolerant to standard doses of cyclosporine, was selected to undergo the study. Oral and intravenous midazolam was used as the probe to measure hepatic and intestinal CYP3A4 activities at two different time points (phases one and two). Small intestinal biopsies were also obtained for measuring CYP3A4 activity for in vitro studies. On serially determining the patients hepatic and intestinal CYP3A activities, we concluded that the variability in the dosing requirements is due to altered first-pass effects in the intestine. DISCUSSION Transplant recipients receive multiple medications that may inhibit or induce these metabolizing enzymes, which eventually determine the concentrations of these narrow therapeutic agents. If no obvious etiology of intolerance to calcineurin inhibitors in a transplant recipient is identified, one should consider altered first-pass effects in the gut and the liver contributing to intraindividual variations in the blood concentrations.

The association between the CYP3A5 genotype and blood pressure

A previous report indicated that the CYP3A5 *1 allele was associated with elevated blood pressure in young African Americans. We determined the frequency of the CYP3A5 *3 allele in 271 subjects (73.4% Caucasian, 34.3% hypertensives, 51.3% men) using the real time polymerase chain reaction. These subjects were part of a longitudinal study of salt sensitivity (initial mean age was 34 years). Demographics and blood pressure (BP), creatinine clearance, urine microalbumin excretion, vascular reactivity measurements and insulin sensitivity indices were recorded during the mean follow‐up of 26 years. Using Wilcoxon paired tests, we found that among Caucasians, initial BMI was higher for *1/*3 (27.2±6.0) when compared with *3/*3 (25.1±5.1) (p=0.04) and Homeostasis Model Assessment taken during follow‐up was also higher for *1/*3 (9.6±14.1) when compared with *3/*3 (5.7±8.4) (p=0.05). For African Americans, baseline systolic BP taken during the initial study was significantly higher in those with the *3/*3 genotype (146±35 mm Hg) than those with the *1/*1 (125±17.4 mm Hg, p=0.009) and the *1/*3 (119±14.1 mm Hg, p=0.0006) genotypes. Other variables tested showed no significant association with the CYP3A5 genotype. We conclude that the CYP3A5 gene may be associated with effects on BP and insulin sensitivity in a race selective manner.