A Clinical Report Utilizing the VITOM 3D® Microvideoscope for Cleft Palate Repair.

Cleft palate surgery has traditionally presented numerous problems for cleft surgeons including ergonomics, limited visual fields restricting the opportunity for demonstration and teaching. Additionally, the move toward online teaching means the ability to record or livestream video is paramount. The following report of eight cleft palate repairs highlights the novel use of the Vitom 3D® microvideoscope as an innovative technique for cleft palate repair with our early experience demonstrating significant ergonomic and teaching benefits.

Differential cellular expression of organic anion transporting peptides OATP1A2 and OATP2B1 in the human retina and brain: implications for carrier-mediated transport of neuropeptides and neurosteriods in the CNS.

Organic anion transporting polypeptides (OATPs) are polyspecific organic anion transporters, which are expressed in the blood-brain barrier, the choroid plexus, and other organs. The physiologic function of OATPs in extrahepatic tissues remains ambiguous. In rat retina, members of the OATP family are expressed. We therefore investigated the human retina for the expression of OATP1A2 and OATP2B1 and extended the study to human brain. Furthermore, we searched for peptide neurotransmitters as novel OATP substrates. OATP1A2 displayed a broad expression pattern in human retina as assessed by immunofluorescence localization. It is expressed in photoreceptor bodies and somas of amacrine cells. OATP1B2 expression is restricted to the inner nuclear layer and to the inner plexiform layer. Using paraffin sections from human cortex, cerebellum, and hippocampus, OATP1A2 was localized to neurons and neuronal processes, while OATP2B1 is expressed in endothelial cells of brain capillaries. Substance P and vasoactive intestinal peptide were identified as substrates for OATP1A2 and OATP2B1. Double-labeling immunofluorescence of human retina demonstrated the presence of substance P and of vasoactive intestinal peptides in neurons expressing OATP1A2 and OATP2B1, respectively. The expression of OATP1A2 and OATP2B1 in retinal neurons implies a role of these transporters in the reuptake of peptide neurotransmitters released from retinal neurons. The abundant expression of OATP1A2 in brain neurons points to the possibility that OATP1A2 could be involved in the homeostasis of neurosteroids. The high expression of OATP2B1 in brain capillaries supports an important function of OATPs in substance penetration across the blood-brain barrier.

Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy and drug-induced cholestasis are two clinically important forms of acquired cholestatic liver disease. The understanding of the underlying mechanisms of acquired cholestasis has recently made considerable progress by the identification of canalicular ATP-binding cassette (ABC) transporters as likely targets for these forms of cholestasis. Cholestasis of pregnancy is linked to estrogen and progesterone metabolites. These metabolites have been shown to impair the bile salt export pump (BSEP) function by an indirect mechanism. In addition, genetic variants (as well as mutants) of the genes coding for the phosphatidylcholine translocator MDR3 and BSEP and for the farnesoid X receptor, which is critical in the transcriptional activation of MDR3 ( ABCB4) and BSEP ( ABCB11) have been associated with intrahepatic cholestasis of pregnancy. The pathogenesis of drug-induced liver injury encompasses a wide spectrum of mechanisms, some of which are still poorly understood. BSEP is now known to be subject to drug inhibition in susceptible patients. Information on genetic factors rendering individuals susceptible to inhibition of BSEP by drugs or their metabolites is still scarce. Besides rare mutations that have been linked to drug-induced cholestasis, the common p.V444A polymorphism of BSEP has been identified as a potential risk factor. In this review, the authors summarize key concepts of physiology of bile formation, diagnostic principles to indentify these forms of acquired cholestasis, as well as pathogenetic mechanisms leading to intrahepatic cholestasis of pregnancy or drug-induced cholestasis. In addition, they review the current knowledge on genetic susceptibility factors for these two forms of cholestasis.

ABC-transporters are localized in caveolin-1-positive and reggie-1-negative and reggie-2-negative microdomains of the canalicular membrane in rat hepatocytes.

UNLABELLED: The canalicular plasma membrane is constantly exposed to bile acids acting as detergents. Bile acids are essential to mediate release of biliary lipids from the canalicular membrane. Membrane microdomains (previously called lipid rafts) are biochemically defined by their resistance to detergent solubilization at cold temperature. We aimed to investigate the canalicular plasma membrane for the presence of microdomains, which could protect this membrane against the detergent action of bile acids. Highly purified rat liver canalicular plasma membrane vesicles were extracted with 1% Triton X-100 or 1% Lubrol WX at 4 degrees C and subjected to flotation through sucrose step gradients. Both detergents yielded detergent-resistant membranes containing the microdomain markers alkaline phosphatase and sphingomyelin. However, cholesterol was resistant to Lubrol WX solubilization, whereas it was only marginally resistant to solubilization by Triton X-100. The microdomain marker caveolin-1 was localized to the canalicular plasma membrane domain and was resistant to Lubrol WX, but to a large extent solubilized by Triton X-100. The two additional microdomain markers, reggie-1 and reggie-2, were localized to the basolateral and canalicular plasma membrane and were partially resistant to Lubrol WX but resistant to Triton X-100. The canalicular transporters bile salt export pump, multidrug resistance protein 2, multidrug resistance-associated protein 2, and Abcg5 were largely resistant to Lubrol WX but were solubilized by Triton X-100. CONCLUSION: These results indicate the presence of two different types of microdomains in the canalicular plasma membrane: "Lubrol-microdomains" and "Triton-microdomains". "Lubrol-microdomains" contain the machinery for canalicular bile formation and may be the starting place for canalicular lipid secretion.

Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T>C polymorphism in the bile salt export pump.

AIM: To study the association of three common ABCB11 and ABCC2 polymorphisms (ABCB11: 1331T>C --> V444A; ABCC2: 3563T>A --> V1188E and 4544G>A --> C1515Y) with intrahepatic cholestasis of pregnancy (ICP) and contraceptive-induced cholestasis (CIC). METHODS: ABCB11 and ABCC2 genotyping data were available from four CIC patients and from 42 and 33 ICP patients, respectively. Allele-frequencies of the studied polymorphisms were compared with those in healthy pregnant controls and Caucasian individuals. Furthermore, serum bile acid levels were correlated with the presence or absence of the 1331 C allele. RESULTS: The ABCB11 1331T>C polymorphism was significantly more frequent in cholestatic patients than in pregnant controls: C allele 76.2% (CI, 58.0-94.4) vs 51.3% (CI 35.8-66.7), respectively (P = 0.0007); and CC allele 57.1% (CI 36.0-78.3) vs 20% (CI 7.6-32.4), respectively (P = 0.0065). All four CIC patients were homozygous carriers of the C allele. In contrast, none of the studied ABCC2 polymorphism was overrepresented in ICP or CIC patients. Higher serum bile acid levels were found in carriers of the 1331CC genotype compared to carriers of the TT genotype. CONCLUSION: Our data support a role for the ABCB11 1331T>C polymorphism as a susceptibility factor for the development of estrogen-induced cholestasis, whereas no such association was found for ABCC2. Serum bile acid and gamma-glutamyl transferase levels might help to distinguish ABCB4- and ABCB11-related forms of ICP and CIC.

Hepatocyte transplantation: potential of hepatocyte progenitor cells and bone marrow derived stem cells.

The liver has a large regenerative capacity in response to injury. However, in severe cases of liver injury, its regenerative capacity may prove insufficent and the liver injury may progress to liver failure, and in such situations liver transplantation is the only treatment option. An alternative, less invasive approach may be transplantation of hepatocytes or hepatocyte precursor cells. In the adult liver two candidate progenitor cells have been identified: oval cells and small hepatocytes. The former are induced by liver injury under conditions preventing cell division of mature hepatocytes, while the latter are present in small numbers in normal liver. Both cell types have the capacity to expand and differentiate into hepatocytes. In recent years evidence has been presented that bone-marrow derived stem cells can also be expanded and differentiated into hepatocyte progenitor cells. Such cells may be a source for hepatocyte transplantation and hence have the potential to offer a novel therapy for liver failure.

Hepatocyte transplantation: potential of hepatocyte progenitor cells and bone marrow derived stem cells.

The liver has a large regenerative capacity in response to injury. However, in severe cases of liver injury, its regenerative capacity may prove insufficent and the liver injury may progress to liver failure, and in such situations liver transplantation is the only treatment option. An alternative, less invasive approach may be transplantation of hepatocytes or hepatocyte precursor cells. In the adult liver two candidate progenitor cells have been identified: oval cells and small hepatocytes. The former are induced by liver injury under conditions preventing cell division of mature hepatocytes, while the latter are present in small numbers in normal liver. Both cell types have the capacity to expand and differentiate into hepatocytes. In recent years evidence has been presented that bone-marrow derived stem cells can also be expanded and differentiated into hepatocyte progenitor cells. Such cells may be a source for hepatocyte transplantation and hence have the potential to offer a novel therapy for liver failure.

Functional characterization of the mouse organic-anion-transporting polypeptide 2.

We have isolated and functionally characterized an additional murine member of the organic-anion-transporting polypeptide (Oatp) family of membrane transport proteins from mouse liver. The 3.6 kb cDNA insert contains an open reading frame of 2010 bp coding for a 670 amino acid protein. Based on its amino acid identity of 88% to the rat Oatp2, it is considered the mouse Oatp2 orthologue. Functional expression in Xenopus laevis oocytes demonstrated that mouse Oatp2 transports several general Oatp substrates such as estrone-3-sulfate, dehydroepiandrosterone sulfate (DHEAS), ouabain and BQ-123 but hardly any taurocholate nor rocuronium or deltorphin II. The high-affinity rat Oatp2 substrate digoxin is transported with a rather low affinity with an apparent K(m) value of 5.7 microM. Bromosulfophthalein (BSP), a substrate not transported by the rat Oatp2, is transported very well by mouse Oatp2. Northern blot analysis demonstrated a predominant expression in the liver with additional signals in kidney and brain. Using fluorescence in situ hybridization, the Oatp2 gene (gene symbol Slc21a5) was mapped to chromosome 6G1-G3.

Regulation of basolateral organic anion transporters in ethinylestradiol-induced cholestasis in the rat.

BACKGROUND/AIMS: Estrogen-mediated cholestasis is an important clinical entity, but its molecular pathophysiology is still not fully understood. Impaired sodium-dependent uptake of bile acids has been associated with diminished expression of a basolateral Na(+)/bile acid cotransporter (Ntcp), whereas sodium-independent uptake is maintained despite a down-regulation of the organic anion transporter Oatp1. Thus, expression of the two other rat Oatps (Oatps2 and -4) was determined in estrogen-induced cholestasis. In addition, known transactivators of Oatp2 and Ntcp were studied to further characterize transcriptional regulation of these transporter genes. METHODS: Hepatic protein and mRNA expression of various Oatps (1, 2, 4) in comparison to Ntcp were analyzed after 0.5, 1, 3 and 5 days of ethinylestradiol (EE) treatment (5 mg/kg) in rats. Binding activities of Oatp2 and Ntcp transactivators were assessed by electrophoretic mobility shift assays. RESULTS: All basolateral Oatps (1, 2 and 4) were specifically down-regulated at the protein level by 30-40% of controls, but less pronounced than Ntcp (minus 70-80%). In contrast to unaltered Oatp4 mRNA levels, Oatp1 and Oatp2 mRNAs were reduced to various extents (minus 40-90% of controls). Binding activity of known transactivators of Ntcp and Oatp2 such as hepatocyte nuclear factor 1 (HNF1), CAAT enhancer binding protein alpha (C/EBPalpha) and pregnane X receptor (PXR) were also diminished during the time of cholestasis. CONCLUSIONS: Estrogen-induced cholestasis results in a down-regulation of all basolateral organic anion transporters. The moderate decline in expression of Oatp1, -2 and -4 may explain the unchanged sodium-independent transport of bile acids due to overlapping substrate specificity. Reduction in transporter gene expression seems to be mediated by a diminished nuclear binding activity of transactivators such as HNF1, C/EBP and PXR by estrogens.

Coordinate transcriptional regulation of transport and metabolism.

Intestinal absorption and hepatic clearance of drugs, xenobiotics, and bile acids are mediated by transporter proteins expressed at the plasma membranes of intestinal epithelial cells and liver parenchymal cells in a polarized manner. Within enterocytes and hepatocytes, these exogenous or endogenous, potentially toxic compounds may be metabolized by phase I cytochrome P450 (CYP) and phase II conjugating enzymes. Many transporter proteins and metabolizing enzymes are subject to direct translational modification, enabling very rapid changes in their activity. However, to achieve intermediate and longer term changes in transport and enzyme activities, the genes encoding drug and bile acid transporters, as well as the CYP and conjugating enzymes, are regulated by a complex network of transcriptional cascades. These are typically mediated by specific members of the nuclear receptor family of transcription factors, particularly FXR, SHP, PXR, CAR, and HNF-4alpha. Most nuclear receptors are activated by specific ligands, including numerous xenobiotics (PXR, CAR) and bile acids (FXR). The fine-tuning of transcriptional control of drug and bile acid homeostasis depends on regulated interactions of specific nuclear receptors with their target genes.

Magnetic resonance imaging with hepatospecific contrast agents in cirrhotic rat livers.

OBJECTIVE: During biliary cirrhosis in rats, organic anion-transporting peptides (Oatps) and ATP-dependent multidrug resistance-associated protein 2 (Mrp2) that are likely to transport the contrast agent Gd-BOPTA through hepatocytes are down-regulated. However, the consequences of such down-regulation on the signal intensity (SI) enhancement are unknown. Consequently, the aim of our study was to measure the hepatic SI enhancement during Gd-BOPTA perfusion as well as the Oatp and Mrp2 expression in normal and cirrhotic livers. MATERIALS AND METHODS: The hepatic SI enhancement during Gd-BOPTA perfusion was measured in livers isolated from normal rats and rats that had a bile duct ligation (BDL) 15, 30, and 60 days before the perfusion. Hepatic injury and transporter expression were measured in control and cirrhotic rats. RESULTS: BDL induced a severe hepatic injury that increased over time with a down-regulation of the transporter expression. The extracellular space (assessed by Gd-DTPA perfusion) increased with the severity of the disease. Gd-BOPTA-induced SI enhancement remained similar in BDL-15 and BDL-30 rats than in control rats but significantly decreased in severe cirrhosis (BDL-60 rats). In comparison, the Mn-DPDP-induced SI enhancement decreases proportionally to the severity of the disease. CONCLUSION: During biliary cirrhosis, Gd-BOPTA-induced SI enhancement could not be related to the hepatic expression of transporters.

Metal-responsive transcription factor-1 (MTF-1) is essential for embryonic liver development and heavy metal detoxification in the adult liver.

Metal-responsive transcription factor-1 (MTF-1) activates the transcription of metallothionein genes and other target genes in response to heavy metal load and other stresses such as hypoxia and oxidative stress. It also has an essential function during embryogenesis: targeted disruption of Mtf1 in the mouse results in lethal liver degeneration on day 14 of gestation. Here we studied Mtf1 knockout mice at embryonic and adult stages, the latter by means of conditional knockout. Hepatocytes from Mtf1 null mutant and wild-type embryos were taken into culture on day 12.5 of gestation. Both initially appeared normal, but mutant cells were lost within a few days. Furthermore, Mtf1 null hepatocytes were poorly, if at all, rescued by cocultivation with wild-type rat embryo hepatocytes, indicating a cell-autonomous defect. When the Mtf1 gene was excised by Cre recombinase after birth in liver and bone marrow and to a lesser extent in other organs, mice were viable under non-stress conditions but highly susceptible to cadmium toxicity, in support of a role of MTF-1 in coping with heavy metal stress. An additional MTF-1 function was revealed upon analysis of the hematopoietic system in conditional knockout mice where leukocytes, especially lymphocytes, were found to be severely underrepresented. Together, these findings point to a critical role of MTF-1 in embryonic liver formation, heavy metal toxicity, and hematopoiesis.

Pharmacogenetics of hepatocellular transporters.

One of the main functions of the liver is the production of bile and the biliary secretion of endogenous and exogenous substances, including drugs and drug metabolites. Bile formation is a complex sequence of cellular events, which involves uptake of bile constituents and xenobiotics on the basolateral (sinusoidal) plasma membrane of hepatocytes and secretion of cholephilic compounds across the apical (canalicular) membrane. These uptake and efflux processes are maintained by distinct transport systems expressed at the two polar surface domains of liver cells. Any functional disturbance of these canalicular transport systems can lead to cholestatic liver disease, which is associated with intracellular accumulation of toxic bile constituents and consecutive cholestatic liver cell damage. Interaction of drugs with hepatobiliary transport systems is increasingly recognized as cause of acquired cholestatic syndromes. Thereby, genetically determined alterations of hepatobiliary transporter functions are important risk factors for an individual's susceptibility to develop cholestasis. Especially, mutations in canalicular transporter genes can cause certain forms of hereditary cholestatic liver disease, including progressive familial intrahepatic cholestasis or intrahepatic cholestasis of pregnancy. In addition, systematic genetic screenings have discovered numerous single nucleotide polymorphisms in hepatobiliary transporter genes that lead to amino acid exchanges in the encoded proteins. However, the functional consequences and the clinical relevance of most of these polymorphisms remain to be defined. This overview summarizes the physiological function of human hepatobiliary transport systems and discusses the impact of their genetic variations for the pathophysiology of cholestatic syndromes and the pharmacogenetics of drug-induced cholestasis.

Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder associated with increased risk of intrauterine fetal death and prematurity. There is increasing evidence that genetically determined dysfunction in the canalicular ABC transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein 3 (MDR3, ABCB4) might be risk factors for ICP development. This study aimed to (i). describe the extent of genetic variability in BSEP and MDR3 in ICP and (ii). identify new disease-causing mutations. Twenty-one women with ICP and 40 women with uneventful pregnancies were recruited between April 2001 and April 2003. Sequencing of BSEP and MDR3 spanned 8-10 kb per gene and comprised the promoter region and 100-350 bp of the flanking intronic region around each exon. DNA sequencing of polymerase chain reaction fragments was performed on an ABI3700 capillary sequencer. MDR3 promoter activity of promoter constructs carrying different ICP-specific mutations was studied using reporter assays. A total of 37 and 51 variant sites were detected in BSEP and MDR3, respectively. Three non-synonymous sites in codons for evolutionarily conserved amino acids were specific for the ICP collective (BSEP, N591S; MDR3, S320F and G762E). Furthermore, four ICP-specific splicing mutations were detected in MDR3 [intron 21, G(+1)A; intron 25, G(+5)C and C(-3)G; and intron 26, T(+2)A]. Activity of the mutated MDR3 promoter was similar to that observed for the wild-type promoter. Our data further support an involvement of MDR3 genetic variation in the pathogenesis of ICP, whereas analysis of BSEP sequence variation indicates that this gene is probably less important for the development of pregnancy-associated cholestasis.

Pharmacokinetics of high doses of intramuscular and oral heroin in narcotic addicts.

BACKGROUND: In several countries medical prescription of diacetylmorphine is currently being evaluated as a treatment option for heavily dependent narcotic addicts. Because of damaged veins, many patients administer diacetylmorphine intramuscularly or orally. Therefore we characterized the pharmacokinetics of intramuscular and oral diacetylmorphine in the high dose range usually required in narcotic addicts. METHODS: Three intramuscular doses, 3 oral doses, and 1 intravenous dose of diacetylmorphine and oral and intravenous test doses of deuterium-labeled morphine (morphine-N-methyl-d3 [morphine-d3]) were administered to 8 heroin-addicted patients. Arterial plasma concentrations of diacetylmorphine, monoacetylmorphine, morphine, morphine-3-glucuronide, morphine-6-glucuronide, and morphine-d3 were measured by liquid chromatography-mass spectrometry. RESULTS: Intramuscularly administered diacetylmorphine (

Localization of organic anion transport protein 2 in the apical region of rat retinal pigment epithelium.

PURPOSE: The organic anion transporting protein (Oatp)-2 has been cloned from brain and retina. It mediates transport of many endogenous and exogenous amphiphilic compounds across the plasma membrane in a sodium-independent manner. In the brain it resides at the luminal and abluminal membrane of the capillary endothelium and at the basolateral membrane of the choroid plexus epithelium. In the liver, it is expressed at the basolateral membrane of hepatocytes. Its exact localization and function in the retina are unknown. Therefore, the purposes of the present study were to determine the cellular and subcellular localization and the potential functional aspects of Oatp2 in the retina. METHODS: Oatp2 was detected in rat retinal tissue by immunofluorescence confocal microscopy and by Western blot analysis, with a specific antibody. A Xenopus laevis oocyte expression system was used for functional transport studies. RESULTS: Oatp2 immunoreactivity was abundantly present at the apical microvilli of the rat retinal pigment epithelium and to a lesser degree in small retinal vessels. In the oocyte expression system, N-retinyl-N-retinylidene ethanolamine (A2E), an unusual cationic, amphiphilic retinoid, exhibited competitive Cis inhibition of Oatp2-mediated digoxin transport with an estimated K(i) of approximately 37 microM. CONCLUSIONS: In rat retina, Oatp2 is localized at the interface between the pigment epithelium and the photoreceptor outer segments. A2E is a competitive inhibitor of Oatp2-mediated substrate transport, suggesting that A2E or A2E-like compounds and some retinoids may be substrates for Oatp2 transport.

Gd-BOPTA transport into rat hepatocytes: pharmacokinetic analysis of dynamic magnetic resonance images using a hollow-fiber bioreactor.

RATIONALE AND OBJECTIVES: To investigate the transport of the hepatobiliary magnetic resonance (MR) imaging contrast agent Gd-BOPTA into rat hepatocytes. MATERIALS AND METHODS: In a MR-compatible hollow-fiber bioreactor containing hepatocytes, MR signal intensity was measured over time during the perfusion of Gd-BOPTA. For comparison, the perfusion of an extracellular contrast agent (Gd-DTPA) was also studied. A compartmental pharmacokinetic model was developed to describe dynamic signal intensity-time curves. RESULTS: The dynamic signal intensity-time curves of the hepatocyte hollow-fiber bioreactor during Gd-BOPTA perfusion were adequately fitted by 2 compartmental models. Modeling permitted to discriminate between the behaviors of the extracellular contrast agent (Gd-DTPA) and the hepatobiliary contrast agent (Gd-BOPTA). It allowed the successfully quantification of the parameters involved in such differences. Gd-BOPTA uptake was saturable at high substrate concentrations. CONCLUSIONS: The transport of Gd-BOPTA into rat hepatocytes was successfully described by compartmental analysis of the signal intensity recorded over time and supported the hypothesis of a transporter-mediated uptake.

Interactions of glycyrrhizin with organic anion transporting polypeptides of rat and human liver.

Glycyrrhizin (GL) is used in Japan for the treatment of chronic hepatitis C. Following intravenous administration, GL is eliminated mainly by excretion into bile. Hepatocyte uptake of GL is a carrier-mediated process with characteristics resembling the organic anion transporting polypeptides (OATPs, solute carrier gene family SLC21A). We, therefore, studied whether GL is a potential transport substrate of the OATPs of rat and human liver. Because transport of GL could not be measured directly, GL-mediated cis-inhibition of [3H]estrone-3-sulfate or [35S]bromosulfophthalein uptake was analyzed kinetically in Xenopus laevis oocytes injected with cRNA coding for OATPs. GL inhibited [3H]estrone-3-sulfate uptake by 75-100% in oocytes expressing rat Oatp4, human OATP-C or human OATP8, members of the OATP1B subfamily that are expressed predominantly in hepatocytes. Dixon plots indicated a non-competitive type of inhibition, with Ki values of 6.1, 15.9 and 12.5 µmol/l, respectively. In contrast, GL inhibition of rat Oatp1, Oatp2 and Oatp3 and human OATP-A and OATP-B was only between 0 and 53%. In conclusion, GL is an inhibitor and, therefore, potentially a transport substrate of the liver-specific OATPs in rat and man. The rate at which GL is taken up into the liver may depend upon the function and expression levels of these hepatocellular OATPs.

Adverse drug events caused by medication errors in medical inpatients.

PRINCIPLES: In view of growing concern in recent years regarding medication errors as causes of adverse drug events (ADEs), we explore the frequency and characteristics of error-associated ADEs in medical inpatients. METHODS: All patients with ADEs or ADErelated hospital admission in a cohort of medical inpatients identified by "event monitoring" (SAS/CHDM database, Br J Clin Pharmacol 2000:49:158-67) were evaluated independently by two experienced physicians. ADEs were first divided into ADEs occurring during cohort stay (incident ADE) and ADE present prior to/at admission. ADEs were then grouped as error-associated ADEs (eADEs: indication error, missed contraindication, wrong dosage regimen or inadequate surveillance) and adverse drug reactions (ADRs: indication established, no contraindications, appropriate dosage regimen and adequate surveillance). RESULTS: Among the 6383 patients analysed (100%), 481 (7.5%) experienced at least one incident ADE. Incident ADRs occurred in 457 (7.2%). Incident eADEs were recorded in 28 patients, corresponding to an eADE incidence of 0.4% (95% CI: 0.2, 0.7). Error types were missing/inappropriate indication (4 cases), missed contraindications (9), relative overdoses (8), absolute overdoses (3) and inadequate clinical surveillance (4). The responsible drugs included antithrombotics (6), cardiovascular drugs (5), antibiotics (5), hypnotics (4) and non-steroidal anti-inflammatory drugs (3). ADE-related hospital admissions were observed in 262 patients (4.1%); 183 (2.9%) were classified as ADRs and 79 (1.2%) as eADEs. CONCLUSIONS: Incident eADEs were observed in 1 out of 250 patients and accounted for approximately 6% of ADEs. In contrast, eADEs accounted for 30% of ADE-related hospital admissions. Hence, in medical inpatients, eADEs represented a small fraction of total incident ADEs, whereas they contributed significantly to hospital admissions.

Pharmacogenetics of drug transporters in the enterohepatic circulation.

This article summarizes the impact of the pharmacogenetics of drug transporters expressed in the enterohepatic circulation on the pharmacokinetics and pharmacodynamics of drugs. The role of pharmacogenetics in the function of drug transporter proteins in vitro is now well established and evidence is rapidly accumulating from in vivo pharmacokinetic studies, which suggests that genetic variants of drug transporter proteins can translate into clinically relevant phenotypes. However, a large amount of conflicting information on the clinical relevance of drug transporter proteins has so far precluded the emergence of a clear picture regarding the role of drug transporter pharmacogenetics in medical practice. This is very well exemplified by the case of P-glycoprotein (MDR1, ABCB1). The challenge is now to develop pharmacogenetic models with sufficient predictive power to allow for translation into drug therapy. This will require a combination of pharmacogenetics of drug transporters, drug metabolism and pharmacodynamics of the respective drugs.