Efavirenz-mediated induction of omeprazole metabolism is CYP2C19 genotype dependent.

Efavirenz increases CYP2C19- and CYP3A-mediated omeprazole metabolism. We hypothesized that CYP2C19 and CYP2B6 genetic polymorphisms influence the extent of induction of omeprazole metabolism by efavirenz. Healthy subjects (n=57) were administered a single 20 mg oral dose of omeprazole on two occasions: with a single 600 mg efavirenz dose; and after a 17-day treatment with efavirenz (600 mg per day). DNA was genotyped for CYP2C19*2, *3 and *17 alleles and CYP2B6*6, *4 and *9 alleles using Taqman assays. Omeprazole, its enantiomers and metabolites were measured by liquid chromatography/tandem mass spectrometry. Our results showed that efavirenz increased omeprazole clearances in all CYP2C19 genotypes in non-stereoselective manner, but the magnitude of induction was genotype dependent. Metabolic ratios of 5-hydroxylation of omeprazole were reduced in extensive and intermediate metabolizers of CYP2C19 (P<0.05). No significant associations were observed between CYP2B6 genotypes and induction by efavirenz on omeprazole metabolism. Our data indicate how interplays between drug interactions and CYP2C19 genetic variations may influence systemic exposure of CYP2C19 substrates.

Objective comparison of physical dysfunction after neck dissection.

Thirty-five patients who underwent a total of 44 neck dissections of various types were prospectively studied to compare differences in postoperative shoulder function. Those who underwent a radical neck dissection suffered the greatest reduction in shoulder movement and had severely abnormal electromyograms. Those who underwent modified neck dissection with preservation of the spinal accessory nerve suffered less loss of shoulder function than the radical neck dissection group, but not to a significant degree at 16 weeks; however, the electromyograms of patients who underwent modified neck dissection were significantly better than those of the radical neck dissection group, which suggests that these patients may improve with time. Indeed, a reevaluation of several patients at 1 year showed improvement in both shoulder function and electromyograms in those who underwent modified neck dissection. Patients who underwent supraomohyoid neck dissection that involved minimal dissection of the spinal accessory nerve had minimal loss of shoulder function and usually, normal electromyograms at 16 weeks that documented less injury to the spinal accessory nerve. Again, these patients had improvement with time. A correlational analysis revealed that the physical parameters correlated well with the electromyographic findings, whereas each patient's perception of disability did not. These findings suggest that, in patients in whom it is oncologically sound, a neck dissection that spares the spinal accessory nerve offers significant benefit in terms of shoulder function.

Induction of CYP2C19 and CYP3A activity following repeated administration of efavirenz in healthy volunteers.

Drug-drug interactions involving efavirenz are of major concern in clinical practice. We evaluated the effects of multiple doses of efavirenz on omeprazole 5-hydroxylation (CYP2C19) and sulfoxidation (CYP3A). Healthy volunteers (n = 57) were administered a single 20 mg oral dose of racemic omeprazole either with a single 600 mg oral dose of efavirenz or after 17 days of administration of 600 mg/day of efavirenz. The concentrations of racemic omeprazole, 5-hydroxyomeoprazole (and their enantiomers), and omeprazole sulfone in plasma were measured using a chiral liquid chromatography-tandem mass spectrometry method. Relative to single-dose treatment, multiple doses of efavirenz significantly decreased (P < 0.0001) the area under the plasma concentration-time curve from 0 to infinity (AUC(0-∞)) of racemic-, R- and S-omeprazole (2.01- to 2.15-fold) and the corresponding AUC(0-∞) metabolic ratio (MR) for 5-hydroxyomeprazole (1.36- to 1.44-fold) as well as the MR for omeprazole sulfone (∼2.0) (P < 0.0001). The significant reduction in the AUC of 5-hydroxyomeprazole after repeated efavirenz dosing suggests induction of sequential metabolism and mixed inductive/inhibitory effects of efavirenz on CYP2C19. In conclusion, efavirenz enhances omeprazole metabolism in a nonstereoselective manner through induction of CYP3A and CYP2C19 activity.

Bilateral facial nerve palsy: a case study and literature review.

Facial diplegia is a rare clinical finding and can be the presenting complaint in a wide spectrum of diseases. This paper describes a case of bilateral facial palsy occurring in a diabetic patient. Electroneurographic studies demonstrated severe acute denervation of both facial nerves and a widespread polyneuropathy. A gallium scan revealed hilar and paratracheal lymphadenopathy. Heerfordt's syndrome was suspected; however, histological confirmation of sarcoidosis has not been obtained. The patient was treated with high dose steroid therapy and has made an almost complete recovery after six months. A review of the literature is discussed with particular reference to the differential diagnosis in this patient.

Relation between renal and hepatic excretion in drugs. VIII. Influence of triiodothyronine on maturation of phenol red excretion in rats.

Experiments were performed on 10-, 20-, and 55-day-old female rats. Administration of triiodothyronine (T3; 10 or 20 micrograms/100 g b.wt. for 3 days, once daily) was followed by a significant increase in renal phenol red excretion in 20-day-old and older rats. In 10-day-old rats there was no stimulatory effect of T3 on renal excretion of the dye. On the other hand, biliary excretion of phenol red was significantly diminished in all age groups. Surprisingly, in nephrectomized rats there was a significant increase in hepatic dye excretion in 20- and 55-day-old rats after T3. This increase in transport capacity via liver was connected with a distinct rise of bile flow. In experiments on tissue slices phenol red accumulation was investigated at different medium concentrations. In renal cortical slices there was no significant influence of T3 on specific accumulation of phenol red per 1 g organ wet weight, whereas aerobic accumulation of the dye seems to be diminished in liver tissue after T3 treatment. But in all age groups kidney weight increased significantly. Calculation of total accumulation (= specific accumulation x organ wet weight) resulted in a significantly enhanced renal transport capacity for phenol red in all age groups. In contrast, total hepatic accumulation was reduced independently of age.

Relation between renal and hepatic excretion of drugs: IX. Acceleration of phenol red excretion via kidney and liver in rats of different ages by dexamethasone treatment.

Experiments were performed on 10-, 20-, and 55-day-old female rats. After treatment with dexamethasone (60 or 80 micrograms/100 g b.wt. for 3 days, once daily) there is a significant increase in renal phenol red excretion only in 10-day-old rats. In contrast, the stimulatory effect of dexamethasone treatment on the hepatic excretion of this dye occurs exclusively in mature, 55-day-old rats. After repeated administration of this hormone in nephrectomized rats there is an increase of hepatic phenol red excretion, and maximal transport capacity increases from 6-8 to 12 mg/100g b.wt. X hour. In renal cortical slices there is no significant influence of dexamethasone on phenol red accumulation in vitro, whereas accumulation of the dye in liver tissue seems to be diminished. In rats of all groups kidney and liver weights increased significantly after dexamethasone treatment. Calculation of total accumulation capacity (= accumulation per 1 g X organ wet weight) also results in unchanged accumulation capacity in the kidney, but transported phenol red amounts in the liver are distinctly diminished. This is in contrast to the in vivo findings. Possible reasons are discussed.

Effects of rifampicin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects.

OBJECTIVE: To study the effects of rifampicin, a potent inducer of the microsomal P450 enzyme system and of specific isoforms of the uridine 5'-diphosphate(UDP)-glucuronyl-transferase enzyme system, and cimetidine, a known inhibitor of the hepatic microsomal cytochrome P450 enzyme system, on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. METHODS: Ten healthy male subjects received a single oral dose of 25 mg lamotrigine after a 5-day pretreatment with (1) cimetidine 800 mg divided into two equal doses, (2) rifampicin 600 mg, or (3) placebo. Serum and urine samples were analyzed using high-performance liquid chromatography. Changes in electroencephalographic (EEG) power were determined up to 48 h after lamotrigine administration. RESULTS: The values of the pharmacokinetic parameters of lamotrigine were: clearance over bioavailability (CL/F) 2.60+/-0.40 l/h, renal clearance (CLR) 0.10+/-0.03 l/h, terminal half-life (t1/2) 23.8+/-2.1 h, mean peak serum concentration (Cmax) 0.29+/-0.02 microg/l, time to reach Cmax (tmax) 1.6+/-0.28 h, and total area under the serum concentration-time curve (AUC0-infinity) 703.99+/-82.31 microg/ ml/min (mean +/- SEM). The amount of lamotrigine excreted as glucuronide was 8.90+/-0.77 mg. Rifampicin significantly increased CL/F (5.13+/-1.05 l/h) and the amount of lamotrigine excreted as glucuronide (12.12+/-0.94 mg), whereas both t1/2 (14.1+/-1.7 h) and AUC(0-infinity) (396.24+/-60.18 microg/ml/min) were decreased (P<0.05). Cimetidine failed to affect pharmacokinetics of lamotrigine. Lamotrigine did not change EEG power. CONCLUSION: Rifampicin altered pharmacokinetics of lamotrigine due to induction of the hepatic enzymes responsible for glucuronidation, while coadministration of cimetidine to ongoing lamotrigine therapy has negligible effects on lamotrigine pharmacokinetics. Lamotrigine administered as a single dose of 25 mg has no effect on EEG power in healthy subjects.