Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine.

Interpatient differences in the oral clearance of cyclosporine (INN, ciclosporin) have been partially attributed to variation in the activity of a single liver enzyme termed CYP3A4. Recently it has been shown that small bowel also contains CYP3A4, as well as P-glycoprotein, a protein able to transport cyclosporine. To assess the importance of these intestinal proteins, the oral pharmacokinetics of cyclosporine were measured in 25 kidney transplant recipients who each had their liver CYP3A4 activity quantitated by the intravenous [14C-N-methyl]-erythromycin breath test and who underwent small bowel biopsy for measurement of CYP3A4 and P-glycoprotein. Forward multiple regression revealed that 56% (i.e., r2 = 0.56) and 17% of the variability in apparent oral clearance [log (dose/area under the curve)] were accounted for by variation in liver CYP3A4 activity (p < 0.0001) and intestinal P-glycoprotein concentration (p = 0.0059), respectively. For peak blood concentration, liver CYP3A4 activity accounted for 32% (p = 0.0002) and P-glycoprotein accounted for an additional 30% (p = 0.0024) of the variability. Intestinal levels of CYP3A4, which varied tenfold, did not appear to influence any cyclosporine pharmacokinetic parameter examined. We conclude that intestinal P-glycoprotein plays a significant role in the first-pass elimination of cyclosporine, presumably by being a rate-limiting step in absorption. Drug interactions with cyclosporine previously ascribed to intestinal CYP3A4 may instead be mediated by interactions with intestinal P-glycoprotein.

Redefining the incidence of clinically detectable atheroembolism.

BACKGROUND AND OBJECTIVES: Atheroembolism, caused by peripheral embolization of small cholesterol crystals that fracture off of ruptured atherosclerotic plaques in the major vessels, leads to multifocal ischemic lesions and progressive tissue loss. The end result is often ischemic injury in the skin, kidney, brain, myocardium, and intestine, but any organ distal to the culprit lesion may be affected. The precise incidence of this serious clinical syndrome has been difficult to ascertain from the available literature, but it appears to be much more common than has been assumed. The objective of the present study is to clarify the incidence of atheroembolism among inpatients in an acute hospital setting. PATIENTS AND METHODS: We surveyed inpatient nephrology consultations during a 7-month period from January through July 1994. From a pool of 402 consultation charts, 99 were identified with two or more substantive risk factors for atheroembolism. The records of 85 of these patients were available for careful review. More than 300 additional patients were found to have ICD-9 discharge codes for other vascular conditions, but we were unable to confirm that any of these were in fact cases of atheroembolism, since there is no specific ICD-9 discharge code for this entity. In the 85 cases reviewed, a diagnosis of atheroembolism was made only if the patient had identifiable substantive risk factors, suggestive physical findings, and supporting laboratory results. RESULTS: Eleven of the 85 surveyed records documented strong evidence supporting a "probable" diagnosis of atheroembolism. Tissue was examined in 4 of these 11, resulting in definitive histologic confirmation in 3. Another 5 of the 85 surveyed records were "suggestive" of atheroembolism. Altogether, atheroembolism was a likely diagnosis in a total of 16 cases during this 7-month period, or 1 case in every 2 weeks. These cases comprised 19% of nephrology consultations in which 2 or more risk factors were present, or 4% or all nephrology consultations. The patients' records confirmed the serious implications of clinically detectable atheroembolism. Several patients underwent lower extremity amputation, nearly half required acute or chronic dialysis, and more than half died within several months of diagnosis CONCLUSIONS: The present study suggests that at least 4% of all inpatient nephrology consultations, representing approximately 5% to 10% of the acute renal failure encountered, involve clinically significant atheroembolism. Patients with atheroembolism appear at a rate of at least 1 case every 2 weeks. They often have identifiable substantive risk factors at initial consultation, and probably represent only the most severe cases of atheroembolism. In view of the serious implications of this basically untreatable syndrome, heightened awareness and preventive maneuvers in the population at risk are essential.

An interesting case of failed renal transplant complicated by a lymphocele infected with Pasteurella multocida and a review of the literature.

Lymphoceles are a well-known complication of renal transplant surgery and can be asymptomatic or present with a variety of symptoms and complications. We describe a patient who presented with a Pasteurella multocida infection of a lymphocele which occurred 3 weeks after a course of penicillin for a cat bite and 10 months after a renal transplant nephrectomy. We also will review the incidence, predisposing factors, origin, symptomatology, diagnosis, complications, and treatments of post-renal transplant lymphoceles.

Molecular and physical mechanisms of first-pass extraction.

This is a report of a symposium held at the March 1997 meeting of the American Society for Pharmacology and Therapeutics in San Diego. Our understanding of the events that control first-pass drug elimination in humans has increased tremendously by two sequential discoveries. First, cytochrome P-450s 3A4 and 5 are expressed at high concentrations in both hepatocytes and upper intestinal enterocytes, and therefore limit the systemic availability of many drugs. Second, P-glycoprotein is expressed at the lumenal surface of the intestinal epithelium and therefore also acts to oppose the absorption of unchanged drug. The following discussion brings together our current understandings of these interrelated phenomena to aid a more complete picture of how they may contribute both qualitatively and quantitatively to first-pass elimination.