Drug-metabolizing Ability Research Articles

Effect of DSS-Induced Ulcerative Colitis and Butyrate on the Cytochrome P450 2A5: Contribution of the Microbiome.

Several studies have indicated the beneficial anti-inflammatory effect of butyrate in inflammatory bowel disease (IBD) therapy implying attempts to increase butyrate production in the gut through orally administered dietary supplementation. Through the gut–liver axis, however, butyrate may reach directly the liver and influence the drug-metabolizing ability of hepatic enzymes, and, indirectly, also the outcome of applied pharmacotherapy. The focus of our study was on the liver microsomal cytochrome P450 (CYP) 2A5, which is a mouse orthologue of human CYP2A6 responsible for metabolism of metronidazole, an antibiotic used to treat IBD. Our findings revealed that specific pathogen-free (SPF) and germ-free (GF) mice with dextran sulfate sodium (DSS)-induced colitis varied markedly in enzyme activity of CYP2A and responded differently to butyrate pre-treatment. A significant decrease (to 50%) of the CYP2A activity was observed in SPF mice with colitis; however, an administration of butyrate prior to DSS reversed this inhibition effect. This phenomenon was not observed in GF mice. The results highlight an important role of gut microbiota in the regulation of CYP2A under inflammatory conditions. Due to the role of CYP2A in metronidazole metabolism, this phenomenon may have an impact on the IBD therapy. Butyrate administration, hence, brings promising therapeutic potential for improving symptoms of gut inflammation; however, possible interactions with drug metabolism need to be further studied.

Precision Medicine: Determination of Ribavirin Urinary Metabolites in Relation to Drug Adverse Effects in HCV Patients.

The most commonly used antiviral treatment against hepatitis C virus is a combination of direct-acting antivirals (DAAs) and ribavirin (RBV), which leads to a shortened duration of therapy and a sustained virologic response until 98%. Nonetheless, several dose-related side effects of RBV could limit its applications. This study aims to measure the urinary concentration of RBV and its main metabolites in order to evaluate the drug metabolism ability of HCV patients and to evaluate the adverse effects, such as anemia, with respect to RBV metabolite levels. RBV and its proactive and inactive metabolites were identified and quantified in the urine of 17 HCV males with severe liver fibrosis using proton nuclear magnetic resonance (1H-NMR) at the fourth week (TW4) and at the twelfth week of treatment (EOT). Four prodrug urinary metabolites, including RBV, were identified and three of them were quantified. At both the TW4 and EOT stages, six HCV patients were found to maintain high concentrations of RBV, while another six patients maintained a high level of RBV proactive metabolites, likely due to nucleosidase activity. Furthermore, a negative correlation between the reduction in hemoglobin (Hb) and proactive forms was observed, according to RBV-triphosphate accumulation causing the hemolysis. These findings represent a proof of concept regarding tailoring the drug dose in relation to the specific metabolic ability of the individual, as expected by the precision medicine approach.

Butyrate, a typical product of gut microbiome, affects function of the AhR gene, being a possible agent of crosstalk between gut microbiome, and hepatic drug metabolism

Modulation of gut microbiome composition seems to be a promising therapeutic strategy for a wide range of pathologic states. However, these microbiota-targeted interventions may affect production of microbial metabolites, circulating factors in the gut-liver axis influencing hepatic drug metabolism with possible clinical relevance. Butyrate, a short-chain fatty acid produced through microbial fermentation of dietary fibers in the colon, has well established anti–inflammatory role in the intestine, while the effect of butyrate on the liver is unknown. In this study, we have evaluated the effect of butyrate on hepatic AhR activity and AhR-regulated gene expression. We have showed that AhR and its target genes were upregulated by butyrate in dose-dependent manner in HepG2-C3 as well as in primary human hepatocytes. The involvement of AhR has been proved using specific AhR antagonists and siRNA–mediated AhR silencing. Experiments with AhR reporter cells have shown that butyrate regulates the expression of AhR target genes by modulating the AhR activity. Our results suggest also epigenetic action by butyrate on AhR and its repressor (AHRR) presumably through mechanisms based on HDAC inhibition in the liver. Our results demonstrate that butyrate may influence the drug-metabolizing ability of liver enzymes e.g., through the interaction with AhR-dependent pathways.

Gephyrin and CYP2C9 Genetic Polymorphisms in Patients with Pharmacoresistant Epilepsy

PurposeGephyrin (GPHN) is an essential protein in the regulation of inhibitory postsynaptic density and polymorphism in the corresponding gene may have a role in the development of pharmacoresistant epilepsy (PRE). For the first time, we aimed to evaluate the association of rs928553T/C variants with PRE susceptibility. Moreover, we have analyzed the genetic polymorphism affecting CYP2C9 “rs12782374G/A” in the same population to detect the effect of SNP on the drug-metabolizing ability of patients with PRE.Patients and MethodsThis case-control study enrolled 100 patients (group A) and 100 healthy, age and sex-matched controls, unrelated to patients (group B). TaqMan™ assays using real-time PCR were run for genotyping of rs928553T/C and rs12782374G/A in all participants.ResultsGPHN T>C polymorphism revealed significant risk association with occurrence of PRE using dominant, recessive and codominant models as follows: TT vs (TC+CC): OR 0.23, 95%CI: 0.13–0.43, P<0.001. In addition, (TT+TC vs CC): OR 0.38, 95%CI: 0.18–0.77, P<0.001. Also, T vs C (OR 0.34, 95%CI: 0.22–0.51, P=<0.001). Similarly, CYP2C9 G>A polymorphism showed a significant increased risk of PRE (GG vs (GA+AA): OR 0.11, 95%CI: 0.05–0.23, P<0.001). Furthermore, (GG+GA vs AA): OR 0.18, 95%CI: 0.084–0.39, P<0.001. Also, G vs A (OR 0.24, 95%CI: 0.15–0.366, P=<0.001).ConclusionMutation of both GPHN (rs928553) and CYP2C9 (rs1278237) genes may be implicated as a genetic mediators of resistance in patients with PRE.

Moderate Hypothermia Effectively Alleviates Acetaminophen-Induced Liver Injury With Prolonged Action Beyond Cooling.

Acetaminophen (APAP) overdose accounts for the highest incidence of acute liver failure, despite the availability of an antidote i.e. N-acetylcysteine. This calls for alternative strategies to manage APAP-induced liver injury (AILI). Therapeutic hypothermia has been explored in past studies for hepatoprotection, but these phenomenal reports lack clarification of its optimal window for application, and mechanistic effects in specific AILI. Hence, we conducted an in vitro study with transforming growth factor-α transgenic mouse hepatocytes cell line, TAMH, and human liver hepatocytes cell line, L-02, where cells were conditioned with deep (25°C) or moderate (32°C) hypothermia before, during or after APAP toxicity. Cell viability was evaluated as a hallmark of cytoprotection, along with cell death. Simultaneously, cold shock proteins (CSPs) and heat shock proteins expressions were monitored; key liver functions including drug-metabolizing ability and hepatic clearance were also investigated. Herein, we demonstrated significant hepatoprotection with 24-hour moderate hypothermic conditioning during AILI and this effect sustained for at least 24 hours of rewarming. Such liver preservation was associated with a CSP—RNA-binding motif protein 3 (RBM3) as its knockdown promptly abolished the cytoprotective effects of hypothermia. With mild and reversible liver perturbations, hypothermic therapy appears promising and its RBM3 involvement deserves future exploration.

Simultaneous determination of parecoxib and its main metabolites valdecoxib and hydroxylated valdecoxib in mouse plasma with a sensitive LC–MS/MS method to elucidate the decreased drug metabolism of tumor bearing mice

Parecoxib (PX), a prodrug of valdecoxib (VX), is an injectable selective COX-2 inhibitor, and is recommended for the treatment of cancer pain. PX can be rapidly hydrolyzed into its active metabolite VX, and VX is further metabolized into hydroxylated valdecoxib (OH-VX) by cytochrome P450 enzymes. However, cancer patients have been reported to possess reduced drug metabolism ability, which might cause excessive drug accumulation. Such overdose of PX significantly increased the risk of renal safety and cardiovascular events. Therefore, it is necessary to elucidate the concentration profiles of PX and its metabolites in cancer status. In this study, a sensitive, rapid and specific LC–MS/MS method for quantification of PX, VX and OH-VX in the plasma of tumor bearing mouse was developed and validated. After protein precipitation, all the analytes were separated on an Agilent ZORBAX Extend-C18 HPLC column (2.1 × 100 mm, 3.5 μm) with gradient elution. The analytes were detected by an electrospray negative ionization mass spectrometry in the multiple reaction monitoring mode. The transition m/z 369.0 → 119.0, m/z 312.9 → 117.9, m/z 329.0 → 196.0, and m/z 307.1 → 161.3 were used for monitoring PX, VX, OH-VX and IS respectively. The calibration curves of the analytes showed good linearity over the concentration range of 3–3000 ng/mL for PX and VX, and 3–1000 ng/mL for OH-VX. Intra- and inter-batch accuracies (in terms of relative error, RE < 9.9%) and precisions (in terms of relative standard deviation, RSD < 8.8%) satisfied the standard of validation. The matrix effect, recovery and stability were also within acceptable criteria. The method was successfully applied to the pharmacokinetics study of PX in tumor bearing mice, and PX and VX levels were found elevated with the growth of tumor volume, which might increase the risk of drug overdose.

Pharmacological management of neuropathic pain in India: A consensus statement from Indian experts

Neuropathic pain (NeP) constitutes a major pain-related disorder, which is often underdiagnosed and undertreated. Adverse physical, psychological, and economic consequences associated with NeP lead to poor quality of life. Burden of NeP in developing countries like India is colossal. Various international guidelines provide effective approaches to diagnose and manage NeP. However, differences in the genetic makeup of Indian population can result in subtle differences in clinical response, considering their low body weight, drug metabolism ability, and pain perception. Similarly, treatment-related adverse effects may also vary. Practice of Indian physicians may also differ for choice of drugs based on their availability and affordability. In the absence of country-specific guidelines, this document could serve as a guiding tool for health-care providers, ensuring uniformity in the treatment of NeP. Thus, applicability of all recommendations from any of these guidelines in Indian setting demands careful evaluation. Clinical experience of Indian physicians suggests that there are lot many challenges (e.g., busy outpatient departments, nonavailability of screening questionnaires in regional languages, and availability and affordability of medications) faced by them when managing NeP. In addition, in India, there are no country-specific guidelines that would help them to address these challenges. The objective for this consensus was to develop an expert opinion guideline to harmonize the management of NeP in India. The expert panel consisted of experts from various specialties such as pain medicine, anesthesiology, diabetology, neurology, and orthopedics. The panel critically reviewed the existing literature evidence and guideline recommendations to provide India-specific consensus on the management of NeP. The final consensus document was reviewed and approved by all the experts. This expert opinion consensus will help health-care professionals as a guiding tool for effective management of NeP in India. Use of Douleur Neuropathique 4 (DN4) questionnaire for NeP screening should be routine in day-to-day clinical practice. For effective utilization of DN4 questionnaire, it should be converted to regional language. If DN4 questionnaire screening fails to identify NeP, it should not be disregarded and should not replace the sound clinical judgment from the treating physician. Diagnostic tests may be considered as a supplement to clinical judgment. Cost-effective treatment should be the initial choice. Dosing should be individualized based on efficacy and tolerability. Tricyclic antidepressants (TCAs), gabapentinoids, and serotonin-norepinephrine reuptake inhibitors (SNRIs) can be considered among initial choices. Tramadol can be considered as a second-line add-on treatment for NeP if there is partial response to the first-line agent either alone or in combination. Fixed-dose combination (FDC) of gabapentinoids such as pregabalin (75 mg) with TCA such as nortriptyline (10 mg) is synergistic and improves treatment adherence. Among other treatments, Vitamin B12 (methylcobalamin) can be used either alone or in combination for the management of NeP. Use of Vitamin D and steroids should be limited to specific NeP in individual cases. Referral to pain specialists can be considered if two drugs fail to provide relief in NeP.

An on-chip intestine-liver model for multiple drugs absorption and metabolism behavior simulation

A double-layer microfluidic chip integrated with a hollow fiber (HF) was developed to reconstitute the intestine-liver functionality for studying the absorption and metabolism of combination drugs. Caco-2 cells were inoculated in the HF cavity at the top of the serpentine channel to simulate the intestinal tissue for drug absorption and transport studied, and HepG2 cells, seeded in the bottom chamber, were used to mimic the liver for metabolism-related studies. Genistein and dacarbazine were selected for combination drug therapy and its effects on cell viability, hepatotoxicity, and cell cycle arrest under drug-conditioned culture were investigated. The results suggested that the combined concentration below −100 μg/mL had no significant inhibitory effect on HepG2 cell viability, and therefore HepG2 cells maintained their drug metabolism ability. When the drug concentration was increased above 250 μg/mL, HepG2 cells underwent apoptosis. Detection of metabolites by mass spectrometry proved the effective metabolism in the microchip model. This dynamic, co-culture microchip successfully provided a podium for long-term observation of absorption, transport, and metabolism of combination drugs, and could be an effective in vitro simulation model for further clinical research.

Transplantation of human adipose stem cell-derived hepatocyte-like cells with restricted localization to liver using acellular amniotic membrane

IntroductionAdult stem cell-derived hepatocytes transplantation holds considerable promise for future clinical individualized therapy of liver failure or dysfunction. However, the low engraftment of the available hepatocytes in the liver disease microenvironment has been a major obstacle.MethodsAcellular human amniotic membrane was developed as a three-dimensional scaffold and combined with hepatocyte-like cells derived from human adipose stem cells to engineer a hepatic tissue graft that would allow hepatocyte engraftment in the liver effectively.ResultsThe hepatic tissue grafts maintained hepatocyte-specific gene expression and functionality in vitro. When transplanted into the surgical incision in livers for engraftment, the engineered hepatic grafts significantly decreased the degree of liver injury caused by a carbon tetrachloride treatment and generated cords that were similar to the ductal plates in the liver between the acellular human amniotic membrane and the liver of receipts at day 3 post-transplantation. The hepatic tissue grafts maintained the expression of human hepatocyte-specific markers albumin, hepatocyte nuclear factor 4α, and cytochrome P450 2B6 in the liver of receipts, and acquired human-specific drug metabolism ability at eight weeks post-transplantation.ConclusionsThe acellular human amniotic membrane has the ability to maintain the functional phenotype of the hepatocyte-like cells derived from human adipose stem cells. Functional acellular human amniotic membrane-hepatocytes grafts integrated with the liver decreases the acute liver injury of mice. These engineered tissue constructs may support stem cell-based individualized therapy for liver disease and for bioartificial liver establishment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0208-9) contains supplementary material, which is available to authorized users.

The CYP4502D6 *4 and *6 alleles are the molecular genetic markers for drug response: implications in colchicine non-responder FMF patients.

The cytochrome P450 2D6 (CYP2D6) is a cytochrome P450 enzyme involved in the oxidative biotransformation of the xenobiotics, carcinogens and various clinically important drugs. Patients are evaluated in three sub-groups of extensive (EM), intermediate (IM) and poor metabolizer (PM) phenotypes due to their drug-metabolising ability for the target CYP2D6 gene. Colchicine non-responsive FMF patients were prospectively genotyped for the major CYP2D6 alleles in the current study. Major CYP2D6 alleles of *1, *3, *4, *5, and *6 were genotyped for 30 responsive and 60 non-responsive FMF patients by multiplex PCR-based reverse-hybridization StripAssay and real-time PCR methods. DNA banks isolated from blood-EDTA were retrospectively used in the current patients and results were compared statistically. Increased CYP2D6 *4 and *6 allele frequencies were highly detected in the colchicine non-responsive FMF patients when compared to the responsive group. Results showed the frequencies of major CYP2D6 *1(wild), *3(2637A>delA), *4(G1934A), *5(total gene deletion) and *6(1707T del) alleles in 0.550, 0.042, 0.158, 0.025 and 0.225 for non-responder and 0.880 and 0.120 (CYP2D6*1 and *4) for the responder groups, respectively. Despite small sample size, this study suggests that there is an association between CYP2D6*4 and CYP2D6*6 alleles and drug intoxicants in colchicine non-responder FMF patients.

Novel anticoagulants

To quantify the novel oral anticoagulant (NOAC)-related gastrointestinal bleeding, summarize the management strategies and highlight the knowledge gaps. Dabigatran, rivaroxaban and apixaban differ from warfarin with their fixed oral dose and no requirement for routine monitoring. Patients at highest risk of thromboembolism benefit most from NOACs; however, there is a clinically significant risk for NOAC-related gastrointestinal bleeding. The management of NOACs in the acute and elective setting differs from that used with warfarin. The magnitude of gastrointestinal risk is still unclear because of paucity of literature. Current risk-stratification models are incomplete and cannot be used solely to predict future risk. The periendoscopic management requires an understanding of drug half-life, metabolism and patient's ability to excrete the agent. Acute bleeding management relies on fluid resuscitation to promote renal excretion of active metabolite, withholding the doses and timely management of endoscopic stigmata. The administration of coagulation factors (fresh frozen plasma, prothrombin complex concentrates or recombinant activated FVII) is more successful in reversing the activity of the upstream inhibitors of coagulation (rivaroxaban and apixaban) than dabigatran which is a direct thrombin inhibitor.

Activity and Expression of Various Isoforms of Uridine Diphosphate Glucuronosyltransferase are Differentially Regulated During Hepatic Regeneration in Rats

Glucuronidation pathway is very important in the detoxification of endogenous and exogenous compounds. The objective of this study was to evaluate the activity and expression of various hepatic uridine diphosphate glucuronosyltransferases (UGTs) in rats at various time points after initiation of hepatic regeneration by partial hepatectomy (PHx). The mRNA expression of various UGTs was evaluated using real-time polymerase chain reaction (real-time PCR) with specific primers. The in vitro activity of UGTs was evaluated using different substrates such as estradiol (UGT1A1), acetaminophen (UGT1A6/7), morphine (UGT2B1), testosterone (UGT2B1/3/6), androsterone (UGT2B2), and (-)-borneol (UGT2B12). Whereas the activity and mRNA expression of UGT1A1, UGT2B1, UGT2B1/3/6, UGT2B2, and UGT2B12 were lower, the activity and mRNA expression of UGT1A6/7 were preserved during hepatic regeneration. The mRNA expression of UGT2B8 was down-regulated, whereas the mRNA expression of UGT1A5 and UGT1A8 was not altered by PHx. The mRNA expression of UGT1A2 and UGT1A3 was increased during hepatic regeneration. UGT-mediated drug-metabolizing ability of the liver was altered differentially in the regenerating rat liver. Individualized dosing regimen for different UGT substrates may be needed when using such substrates of these enzymes in patients with a regenerating liver, especially during the early postoperative period. However, the glucuronide conjugating capacity of the liver in the donor of a living donor liver transplantation is expected to completely return to normal with time after surgery.

No Regional Differences of Cytochrome P450 Expression in the Liver of Cynomolgus Monkeys (Macaca fascicularis)

Non-human primates are frequently used in toxicological studies the result of which are extrapolated to humans, but background data on drug metabolism ability among monkeys derived from different countries has not been published, especially on the key enzyme, cytochrome P450 (CYP450). We assessed the amounts of hepatic CYP450 obtained from cynomolgus monkeys of different ages and from different countries in this study. There were no regional differences of total P450 content, as well as major CYP450 isozymes (CYP 1A, 2A, 2B, 2C, 2D, 2E1 and 3A4) in cynomolgus monkeys by westernblot analysis. Similarly, there were no significant differences with hybrid cynomolgus monkeys, but variations in individual values were large. As for aging, total P450 contents declined in old cynomolgus monkeys (12-32 years of age). These results indicate the usefulness of basic data of hepatic CYP450 obtained from cynomolgus monkeys of different ages and from different countries.

Cytochrome P-450 and chromosome damage by cyclophosphamide in LEC strain rats predisposed to hereditary hepatitis and liver cancer

LEC strain rats predisposed to hereditary hepatitis and liver cancer were examined for hepatic drug-metabolizing ability and the inducibility of chromosome damage by cyclophosphamide (CP) in somatic cells. Whereas the hepatic cytochrome P-450 contents and the activities of cytochrome P-450-catalyzed monooxygenases were lower in females than in males of both LEC and control LEA strains, male LEC rats exhibited significantly reduced cytochrome P-450 contents and monooxygenase activities compared with male LEA rats. When exposed to CP, a promutagen/procarcinogen requiring P-450-dependent metabolic activation, the frequencies of chromosome aberrations and sister-chromatid exchanges (SCEs) in bone marrow cells tended to be lower in females than in males of each strain and lower in LEC than in LEA rats of the same sex. In particular, the CP-induced SCEs were substantially lower in LEC rats. However, no such sex and strain differences were found in the SCE frequencies in regenerating hepatocytes of partially hepatectomized rats exposed to CP.

Tissue zinc status and drug elimination in patients with chronic liver disease

1. The zinc status and drug-metabolizing ability of 15 patients with histologically diagnosed hepatic cirrhosis were studied. Zinc status was assessed using both serum and leucocyte zinc concentrations, and drug-metabolizing ability was assessed by antipyrine kinetics. 2. Patients with cirrhosis were found to have lower serum and leucocyte zinc concentrations when compared with a healthy control group. 3. Leucocyte zinc content and antipyrine clearance were correlated. Those patients with the lowest leucocyte zinc content had the greatest impairment of drug metabolism. Antipyrine elimination and serum zinc concentrations were not correlated. 4. Leucocyte zinc concentrations and antipyrine clearance were not influenced by the severity of liver dysfunction, as assessed by using the Child Turcotte classification. 5. These results suggest that tissue zinc depletion in some patients with hepatic cirrhosis may explain in part the impaired capacity to metabolize drugs.

Heme regulation in mouse mammary carcinoma and liver of tumor bearing mice—I. Effect of allyl-isopropylacetamide and veronal on δ -aminolevulinate synthetase, cytochrome P-450 and cytochrome oxidase

1. 1. Basal levels and allyl-isopropylacetamide (AIA) or veronal induced levels of δ-aminolevulinate synthetase (ALA-S), cytochrome P-450 (cyt P-450) and cytochrome oxidase were determined in tumor (T) and liver of both normal mice (NM) and T bearing mice (TBM). 2. 2. Basal levels of ALA-S were nearly the same in either source. The amount of cyt P-450 was lower in TBM liver than in NM liver, and no detectable in T. While the basal activity of cytochrome oxidase in TBM liver and T were higher than those of NM liver. 3. 3. In AIA intoxicated animals there was a lower induction of ALA-S in liver of TBM than in NM liver. There was no induction in T ALA-S. The loss of cyt P-450 was less in TBM liver when compared with NM liver. 4. 4. The induction level of cyt P-450 after veronal administration was nearly the same in liver of both TBM and NM. 5. 5. We conclude that lower induction of liver ALA-S activity in TBM liver is due to correspondingly lower drug metabolism ability of TBM liver. Otherwise our results suggest that the control mechanism operating in T and probably in its original tissue are different from those described for normal liver.

Participation of lipid peroxidation in the loss of hepatic drug-metabolizing activities in experimental fascioliasis in the rat

Fascioliasis causes a dramatic decrease in drug-metabolizing ability of the hepatic monooxygenase (MFO) and glucuronosyltransferase (GT) enzyme systems in the rat. The present study was undertaken to determine whether lipid peroxidation is involved in the enzymatic loss. Peroxidative damage of membrane lipids (as assessed by the tissue content of malonic dialdehyde, MDA, and the diene conjugation absorption in microsomal membranes) was found to occur over the entire course of the liver infection (concomitant to a decrease in glutathione levels), and to different degrees in relation to the various steps of the parasite cycle. The onset (MDA six times the controls; ΔE 1% = 1·55 at the 20th day) coincides with the beginning of the loss of MFO (− 30%) and GT (− 20% at the 20th day), and peaks between the 30th and 40th day (MDA eight times the controls; ΔE 1% = 1·96), when the loss in the enzyme activities is maximal (MFO − 60 70% ; GT- 65 95% ). There was a strict correlation at all the observation times between the extent of lipid peroxidation and the decrease in drug metabolizing ability: this supports the view that lipid peroxidation is the major agent in the impairment of MFO and GT enzyme activities, and very likely in the initiation of the pathological degeneration of the liver tissue. As evidenced by histological examination, the phagocytic response of the liver tissue to the parasite invasion and growth leads to oxidative stress, which is the causative agent in the initiation and development of lipid peroxidation.

慢性肝疾患患者における肝薬物代謝能の評価 指標薬物の代謝に対する

慢性肝疾患患者における肝薬物代謝能の評価 指標薬物の代謝に対する

Antipyrine and lidocaine are cleared faster in horses than in humans: acetaminophen may be handled similarly.

The following studies were designed to evaluate plasma elimination kinetics of intravenously administered antipyrine, acetaminophen and lidocaine among 9 healthy adult horses and 9 healthy drug-free humans (3 each per drug group), in order to compare potential species differences in drug-metabolizing ability. Acetaminophen is largely biotransformed in humans by hepatic glucuronide and sulfate conjugation, whereas both antipyrine and lidocaine are oxidized by hepatic microsomal mixed-function oxidases. Thus, plasma clearances of these drugs are thought to reflect differences in hepatic oxidative and conjugative activity, and possibly hepatic blood flow in the case of lidocaine. Results showed that mean (+/- SD, n = 3) acetaminophen clearance was similar in both horses (4.84 +/- 0.637 ml/min/kg) and humans (4.68 +/- 0.691 ml/min/kg). However, antipyrine clearance was 10 times greater in horses (5.83 +/- 2.21 ml/min/kg) than in humans (0.536 +/- 0.110 ml/min/kg), which may reflect enhanced hepatic microsomal activity in horses. Although lidocaine clearance in humans was similar to estimated hepatic blood flow (20.6 +/- 5.81 ml/min/kg), clearance in horses was more than 2 times greater (52.0 +/- 11.7 ml/min/kg). The cause of the higher clearance of lidocaine in horses (like dogs) remains unexplained, and may involve significant metabolism of lidocaine at extrahepatic, extravascular sites, for intravascular degradation and renal excretion of intact lidocaine in horses was negligible. Although precise biochemical mechanisms underlying pharmacokinetic parameters for these drugs in horses were not determined, it is nonetheless concluded from antipyrine results that horses may have an enhanced ability (compared with humans) to clear drugs from the circulation that are primarily metabolized in the liver by phase I oxidative reactions.(ABSTRACT TRUNCATED AT 250 WORDS)

The Effect of Halothane on Drug Disposition

Several studies have shown that halothane may influence drug disposition in animals and humans, but the mechanism remains unclear. The relative contributions of changes in metabolizing capacity and hepatic blood flow to altered drug disposition were investigated during halothane anesthesia, using propranolol as a model compound. The studies were performed on six dogs on three separate days; first, the day before anesthesia, second, during halothane (2.0 MAC) anesthesia, and third, 24 h after anesthesia. Each dog simultaneously received 40 mg unlabeled propranolol directly into the portal vein and 200 mCi of 3H-propranolol intravenously via chronically implanted catheters. Blood samples were taken every 5 min for the first hour and then every 15 min for a further 3 h for the measurement of unlabeled and 3H-propranolol concentrations. During halothane anesthesia, intraportal-intrinsic clearance was decreased by 62% (P less than 0.05) from 2,110 +/- 298 to 799 +/- 233 ml/min, while systemic clearance was decreased (P less than 0.05) from 470 +/- 33 ml/min preanesthesia to 280 +/- 38 ml/min during halothane anesthesia. The intravenous elimination half-life was increased (P less than 0.05) from 87 +/- 12 to 155 +/- 23 min during anesthesia. Although halothane anesthesia tended to lower liver plasma flow from 642 +/- 80 to 473 +/- 47 ml/min, this change was not significant. The large change in portal or intrinsic clearance indicates that halothane anesthesia markedly inhibits drug-metabolizing ability. The authors therefore conclude that the alterations in drug disposition observed during halothane anesthesia are mainly due to inhibition of drug-metabolizing capacity in the liver.