A phenotype-genotype approach to predicting CYP450 and P-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir.

The effects of tipranavir/ritonavir (TPV/r) on hepatic and intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP) enzyme activity were evaluated in 23 volunteers. The subjects received oral (p.o.) caffeine, warfarin + vitamin K, omeprazole, dextromethorphan, and midazolam and digoxin (p.o. and intravenous (i.v.)) at baseline, during the first three doses of TPV/r (500 mg/200 mg b.i.d.), and at steady state. Plasma area under the curve (AUC)(0-infinity) and urinary metabolite ratios were used for quantification of protein activities. A single dose of TPV/r had no effect on the activity of CYP1A2 and CYP2C9; it weakly inhibited CYP2C19 and P-gp; and it potently inhibited CYP2D6 and CYP3A. Multiple dosing produced weak induction of CYP1A2, moderate induction of CYP2C19, potent induction of intestinal P-gp, and potent inhibition of CYP2D6 and CYP3A, with no significant effects on CYP2C9 and hepatic P-gp. Several P450/transporter single-nucleotide polymorphisms correlated with the baseline phenotype but not with the extent of inhibition or induction. Although mixed induction and inhibition are present, this approach offers an understanding of drug interaction mechanisms and ultimately assists in optimizing the clinical use of TPV/r.

Diagnosis and treatment of lipomas of the internal auditory canal.

A Chinese woman came to the otolaryngology department with a complaint of a longstanding progressive left hearing loss and intractable tinnitus. A finding of asymmetry on sensorineural hearing loss and auditory brainstem response testing provided evidence of a retrocochlear lesion on the left side. Computed tomography and magnetic resonance imaging detected a tumor in the left internal auditory canal (IAC). In addition to these radiologic features, our suspicion of the possibility of an IAC lipoma was raised by the observation of multiple lipomas over the patient's trunk and limbs. The patient underwent a complete tumor resection via the translabyrinthine approach, Pathology confirmed the diagnosis of an IAC lipoma. Although we were not able to preserve the hearing in her left ear, the patient was satisfied that we had relieved her constant tinnitus. In this article, we review the particulars of this case and discuss the clinical, radiologic, and pathologic features of IAC lipomas.