Combined heart-liver transplantation in the MELD era: do waitlisted patients require exception status?

Combined heart-liver transplant (HLT) is a viable therapy for patients with concomitant end-stage heart and liver failure. Using data from the United Network for Organ Sharing database, we examined the cumulative incidences of transplant and mortality in waitlisted candidates for HLT, isolated heart transplant (HRT) and isolated liver transplant (LIV) in the Model for End-Stage Liver Disease era. The incidence of waitlist mortality was higher in HLT candidates than in HRT candidates (p = 0.001, 26% vs. 12% at 1 year) or LIV candidates (p = 0.005, 26% vs. 14% at 1 year). These differences persisted after stratifying by disease severity. Posttransplant survival was not significantly different between HLT and HRT recipients or between HLT and LIV recipients. In a multivariable model, undergoing HLT was associated with enhanced survival for HLT candidates (hazard ratio, 0.41; confidence interval, 0.21-0.79; p = 0.008), but undergoing HRT alone was not. Interestingly, 90% of HLT recipients were allocated an organ locally, compared to 60% of HRT candidates and 73% of LIV candidates (both p < 0.001). These data suggest that the current cardiac and liver allocation systems may underestimate the risk of death for patients with concomitant end-stage heart and liver failure on the HLT waitlist.

Heart and combined heart-kidney transplantation in patients with concomitant renal insufficiency and end-stage heart failure.

In patients with end-stage heart failure (ESHF) who are candidates for isolated heart transplant (HRT), dialysis dependence (DD) is considered an indication for combined heart-kidney transplantation (HKT). HKT remains controversial in ESHF transplant candidates with nondialysis-dependent renal insufficiency (NDDRI). Using United Network for Organ Sharing data, we examined the cumulative incidences of transplant and mortality in patients with DD and NDDRI waitlisted for HKT or HRT. In all groups, 3-month waitlist mortality was dismal: 31% and 21% for HRT- and HKT-listed patients with DD and 12% and 7% for HRT- and HKT-listed patients with NDDRI. Five-year posttransplant survival was improved in HKT recipients compared with HRT recipients for both patients with DD (73% vs. 51%, p<0.001) and NDDRI (80% vs. 69%, p<0.001). Likewise, multivariable analysis associated HKT with better outcomes than HRT in HKT-listed patients, although both improved survival. These data argue strongly for HKT in ESHF transplant candidates with DD. However, in patients with NDDRI, HKT must be weighed against the possibility of renal recovery with isolated HRT. Whether HRT (followed by a staged kidney transplant in patients who do not recover renal function after HRT), as opposed to HKT, maximizes organ benefit for patients with NDDRI and ESHF requires assessment. Nevertheless, given their dismal waitlist outcomes and excellent posttransplant results, we suggest that patients with DD and NDDRI with ESHF be considered for early listing and transplant.

Quark-hadron duality in neutron (3He) spin structure.

We present experimental results of the first high-precision test of quark-hadron duality in the spin-structure function g_{1} of the neutron and 3He using a polarized 3He target in the four-momentum-transfer-squared range from 0.7 to 4.0 (GeV/c);{2}. Global duality is observed for the spin-structure function g_{1} down to at least Q;{2}=1.8 (GeV/c);{2} in both targets. We have also formed the photon-nucleon asymmetry A1 in the resonance region for 3He and found no strong Q2 dependence above 2.2 (GeV/c);{2}.

Twenty-year survivors of heart transplantation at Stanford University.

Human heart transplantation started 40 years ago. Medical records of all cardiac transplants performed at Stanford were reviewed. A total of 1446 heart transplantations have been performed between January 1968 and December 2007 with an increase of 1-year survival from 43.1% to 90.2%. Sixty patients who were transplanted between 1968 and 1987 were identified who survived at least 20 years. Twenty-year survivors had a mean age at transplant of 29.4 +/- 13.6 years. Rejection-free and infection-free 1-year survivals were 14.3% and 18.8%, respectively. At their last follow-up, 86.7% of long-term survivors were treated for hypertension, 28.3% showed chronic renal dysfunction, 6.7% required hemodialysis, 10% were status postkidney transplantation, 13.3% were treated for diabetes mellitus, 36.7% had a history of malignancy and 43.3% had evidence of allograft vasculopathy. The half-life conditional on survival to 20 years was 28.1 years. Eleven patients received a second heart transplant after 11.9 +/- 8.0 years. The most common causes of death were allograft vasculopathy (56.3%) and nonlymphoid malignancy (25.0%). Twenty-year survival was achieved in 12.5% of patients transplanted before 1988. Although still associated with considerable morbidity, long-term survival is expected to occur at much higher rates in the future due to major advances in the field over the past decade.

Recoil-proton polarization in high-energy deuteron photodisintegration with circularly polarized photons.

We measured the angular dependence of the three recoil-proton polarization components in two-body photodisintegration of the deuteron at a photon energy of 2 GeV. These new data provide a benchmark for calculations based on quantum chromodynamics. Two of the five existing models have made predictions of polarization observables. Both explain the longitudinal polarization transfer satisfactorily. Transverse polarizations are not well described, but suggest isovector dominance.

Thimet oligopeptidase (EC 3.4.24.15) activates CPI-0004Na, an extracellularly tumour-activated prodrug of doxorubicin.

CPI-0004Na is a tetrapeptidic extracellularly tumour-activated prodrug of doxorubicin. The tetrapeptide structure ensures blood stability and selective cleavage by unidentified peptidase(s) released by tumour cells. The purpose of this work was to identify the enzyme responsible for the first rate-limiting step of CPI-0004Na activation, initially attributed to a 70 kDa acidic (pI=5.2) metallopeptidase active at neutral pH that was subsequently purified from HeLa cell homogenates. Two electrophoretic bands were isolated and identified by matrix-assisted laser desorption ionisation-time of flight (MALDI-tof) and electrospray ionisation-quadrupole-time of flight (ESI-Q-tof) mass spectrometry as thimet oligopeptidase (TOP). The identity of the CPI-0004Na activating enzyme and TOP was further supported by the similar substrate specificity of the purified enzyme and recombinant TOP, by thiol stimulation of CPI-0004Na cleavage by cancer cell conditioned media (unique characteristic of TOP) and by the inhibition of CPI-0004Na activation by specific inhibitors or immunoprecipitation. Although other enzymes can be involved, TOP clearly appears to be a likely candidate for extracellular activation of the CPI-0004Na prodrug.

Q2 dependence of the neutron spin structure function g2(n) at low Q2.

We present the first measurement of the Q2 dependence of the neutron spin structure function g2(n) at five kinematic points covering 0.57 (GeV/c)2 < or = Q2 < or = 1.34 (GeV/c)2 at x approximately = 0.2. Though the naive quark-parton model predicts g2 = 0, nonzero values occur in more realistic models of the nucleon which include quark-gluon correlations, finite quark masses, or orbital angular momentum. When scattering from a noninteracting quark, g2(n) can be predicted using next-to-leading order fits to world data for g1(n). Deviations from this prediction provide an opportunity to examine QCD dynamics in nucleon structure. Our results show a positive deviation from this prediction at lower Q2, indicating that contributions such as quark-gluon interactions may be important. Precision data obtained for g1(n) are consistent with next-to-leading order fits to world data.

Precision Rosenbluth measurement of the proton elastic form factors.

We report the results of a new Rosenbluth measurement of the proton electromagnetic form factors at Q2 values of 2.64, 3.20, and 4.10 GeV2. Cross sections were determined by detecting the recoiling proton, in contrast to previous measurements which detected the scattered electron. Cross sections were determined to 3%, with relative uncertainties below 1%. The ratio mu(p)G(E)/G(M) was determined to 4%-8% and showed mu(p)G(E)/G(M) approximately 1. These results are consistent with, and much more precise than, previous Rosenbluth extractions. They are inconsistent with recent polarization transfer measurements of similar precision, implying a systematic difference between the techniques.

Cross-section measurement of charged-pion photoproduction from hydrogen and deuterium.

We have measured the differential cross section for the gamman-->pi(-)p and gammap-->pi(+)n reactions at theta(c.m.)=90 degrees in the photon energy range from 1.1 to 5.5 GeV at Jefferson Lab (JLab). The data at E(gamma) greater, similar 3.3 GeV exhibit a global scaling behavior for both pi(-) and pi(+) photoproduction, consistent with the constituent counting rule and the existing pi(+) photoproduction data. Possible oscillations around the scaling value are suggested by these new data. The data show enhancement in the scaled cross section at a center-of-mass energy near 2.2 GeV. The cross section ratio of exclusive pi(-) to pi(+) photoproduction at high energy is consistent with the prediction based on one-hard-gluon-exchange diagrams.

Impact of cytomegalovirus hyperimmune globulin on outcome after cardiothoracic transplantation: a comparative study of combined prophylaxis with CMV hyperimmune globulin plus ganciclovir versus ganciclovir alone.

BACKGROUND: Cytomegalovirus (CMV) disease was previously shown to be unaltered by a 28-day course of ganciclovir compared with placebo in seronegative recipients of hearts from seropositive donors (D+/R-). This study tests the hypothesis that a combination of ganciclovir plus CMV hyperimmune globulin (CMVIG) is more effective than ganciclovir alone for preventing acute CMV illness and its long-term sequelae. METHODS: The study population receiving CMVIG (n=80) included 27 heart transplant recipients (D+/R-) and 53 heart-lung and lung transplant recipients (R+ and/or D+). Each group was matched with historical controls who underwent transplantation within the preceding 2-3 years. Outcome measures compared were as follows: 3-year incidence of CMV disease; fungal infection; acute rejection; survival; rates and severity of transplant coronary artery disease (in heart patients) defined by intimal thickness (ultrasound) and coronary artery stenosis (angiographic); and incidence and death from obliterative bronchiolitis defined by pathological criteria on endobronchial biopsy specimens (in heart-lung/lung patients). RESULTS: Patients treated with CMVIG had a higher disease-free incidence of CMV, lower rejection incidence, and higher survival rate compared with the patients treated with ganciclovir alone. The coronary artery intimal thickness and the prevalence of intimal thickening were lower in the patients receiving CMVIG. Heart-lung and lung transplant patients treated with CMVIG had lower incidences of obliterative bronchiolitis and death from obliterative bronchiolitis and longer survival compared with the patients treated with ganciclovir alone. CONCLUSIONS: CMVIG plus ganciclovir seems to be more effective that ganciclovir alone for preventing the sequelae of CMV infection. A prospective randomized study is required to confirm these observations.

Skeletal muscle reperfusion injury: reversal by controlled limb reperfusion--a case report.

Despite successful surgical revascularization of ischemic limbs, a local and systemic reperfusion injury may occur after normal blood reperfusion. Recent experimental and clinical application of controlled limb reperfusion in Europe has demonstrated superior results, with lower morbidity and mortality. This new surgical technique includes modification of the reperfusate (calcium, pH, substrates, osmolarity, free radical scavenger) and the circumstances of initial reperfusion (time, temperature, pressure). This report describes the first application of controlled limb reperfusion after reperfusion injury. A 16-year-old boy underwent femoral access cardiopulmonary bypass for repeat cardiac repair with an ischemic time of 245 minutes. Postoperatively, severe ischemia/reperfusion syndrome developed with muscle contracture, immobility, and anesthesia of the right leg with a second ischemic time of about 6 hours. The systemic creatine phosphokinase level was 88,000 U/L; myoglobin was 27,000 ng/mL. He underwent controlled limb reperfusion by withdrawing blood from the aorta and mixing it with a crystalloid solution (calcium-reduced, hyperosmolar, hyperglycemic, alkalotic, glutamate- and aspartate-enriched, and containing a free radical scavenger) under controlled conditions (blood:crystalloid solution 6:1, for 30 minutes, reperfusion pressure < 50 mm Hg, and normothermia) before establishing normal blood reperfusion. Metabolic data from the central and femoral vein demonstrated a significant reduction of all previous elevated enzyme levels, avoidance of hyperkalemia, normalization of acidosis, and avoidance of systemic reperfusion injury with no multiorgan failure. Limb salvage was accomplished and functional recovery almost complete. To the authors' knowledge, this is the first application of controlled limb reperfusion reported in North America. With this surgical technique we were able to prevent metabolic local and systemic reperfusion changes after prolonged ischemia and also reduced previous reperfusion changes. This report confirms former experimental data, and further clinical studies are warranted.

Rabbit antithymocyte globulin versus OKT3 induction therapy after heart-lung and lung transplantation: effect on survival, rejection, infection, and obliterative bronchiolitis.

The superiority of different induction therapies after heart-lung and lung transplantation is not clearly established; specifically, whether monoclonal (OKT3) or polyclonal antibody induction therapy provides any advantage. Between 1989 and 1991 we used induction therapy with either rabbit antithymocyte globulin (RATG) or OKT3, given at random based on the availability of RATG. RATG was used in 25 patients (RATG group 1) and OKT3 in 38 patients (OKT3 group 1). Early results suggested a survival advantage with RATG. From 1992 until 1997 we used RATG induction therapy in 108 patients (RATG group 2). This study analyzed longer-term survival, infection, rejection, and obliterative bronchiolitis (OB) rates for RATG group 1 and OKT3 group 1 and assessed outcomes for RATG group 2. The 1-, 3-, and 5-year survival for RATG group 1 was 72 %, 72 %, and 52 % and for OKT3 group 1 was 63 %, 49 %, and 34 % (P < 0.05). The 1- and 3-year survival for RATG group 2 was 84 % and 74 %. The 1-, 3-, and 5-year actuarial freedom rates from lung rejection for RATG group 1 were 38 %, 38 %, and 31 % and for OKT3 group 1 were 21 %, 0 %, and 0 % (P < 0.01). The linearized rate (events/100 patient days) of all infections at 3 months was 1.55 +/- 0.28 for RATG group 1 and 2.19 +/- 0.27 for OKT3 group 1 (P = NS). The infection rate for RATG group 2 was 1.60 +/- 0.13. The actuarial rates of freedom from OB at 1, 3, and 5 years for RATG group 1 were 84 %, 51 %, and 45 % and for OKT3 group 1 were 77 %, 61 %, and 36 % (P = NS), while for RATG group 2 the rates were 97 % and 92 % at 1 and 3 years (P < 0.01 vs RATG group 1 and OKT3 group 1). The use of RATG induction therapy from 1989 through 1991 resulted in improved actuarial survival and less rejection, without increased infection rates. The use of RATG since 1992 has continued to result in similar outcomes for survival, infection, and rejection. The time to onset of OB has improved further in recent years. This may be a result of recent improvements in cytomegalovirus (CMV) prophylaxis.

Submucosal gland secretions in airways from cystic fibrosis patients have normal [Na(+)] and pH but elevated viscosity.

Fluid and macromolecule secretion by submucosal glands in mammalian airways is believed to be important in normal airway physiology and in the pathophysiology of cystic fibrosis (CF). An in situ fluorescence method was applied to measure the ionic composition and viscosity of freshly secreted fluid from airway glands. Fragments of human large airways obtained at the time of lung transplantation were mounted in a humidified perfusion chamber and the mucosal surface was covered by a thin layer of oil. Individual droplets of secreted fluid were microinjected with fluorescent indicators for measurement of [Na(+)], [Cl(-)], and pH by ratio imaging fluorescence microscopy and viscosity by fluorescence recovery after photobleaching. After carbachol stimulation, 0.1--0.5 microl of fluid accumulated in spherical droplets at gland orifices in approximately 3--5 min. In gland fluid from normal human airways, [Na(+)] was 94 +/- 8 mM, [Cl(-)] was 92 +/- 12 mM, and pH was 6.97 +/- 0.06 (SE, n = 7 humans, more than five glands studied per sample). Apparent fluid viscosity was 2.7 +/- 0.3-fold greater than that of saline. Neither [Na(+)] nor pH differed in gland fluid from CF airways, but viscosity was significantly elevated by approximately 2-fold compared to normal airways. These results represent the first direct measurements of ionic composition and viscosity in uncontaminated human gland secretions and indicate similar [Na(+)], [Cl(-)], and pH to that in the airway surface liquid. The elevated gland fluid viscosity in CF may be an important factor promoting bacterial colonization and airway disease.

Treatment of endocarditis with valve replacement: the question of tissue versus mechanical prosthesis.

BACKGROUND: It remains unknown whether there is any important clinical advantage to the use of either a bioprosthetic or mechanical valve for patients with native or prosthetic valve endocarditis. METHODS: Between 1964 and 1995, 306 patients underwent valve replacement for left-sided native (209 patients) or prosthetic (97 patients) valve endocarditis. Mechanical valves were implanted in 65 patients, bioprostheses in 221 patients, and homografts in 20 patients. RESULTS: Operative mortality was 18+/-2% and was independent of replacement valve type (p > 0.74). Long-term survival was superior for patients with native valve endocarditis (44+/-5% at 20 years) compared with those with prosthetic valve endocarditis (16+/-7% at 20 years) (p < 0.003). Survival was independent of valve type (p > 0.27). The long-term freedom from reoperation for patients who received a biologic valve who were younger than 60 years of age was low (51+/-5% at 10 years, 19+/-6% at 15 years). For patients older than 60 years, however, freedom from reoperation with a biological valve (84+/-7% at 15 years) was similar to that for all patients with mechanical valves (74+/-9% at 15 years) (p > 0.64). CONCLUSIONS: Mechanical valves are most suitable for younger patients with native valve endocarditis; however, tissue valves are acceptable for patients greater than 60 years of age with native or prosthetic valve infections and for selected younger patients with prosthetic valve infections because of their limited life expectancy.

Characterization of the recombinant IKK1/IKK2 heterodimer. Mechanisms regulating kinase activity.

Nuclear factor kappa B (NF-kappaB) is a ubiquitous, inducible transcription factor that regulates the initiation and progression of immune and inflammatory stress responses. NF-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkappaB, initiated by an IkappaB kinase (IKK) complex. This IKK complex includes a catalytic heterodimer composed of IkappaB kinase 1 (IKK1) and IkappaB kinase 2 (IKK2) as well as a regulatory adaptor subunit, NF-kappaB essential modulator. To better understand the role of IKKs in NF-kappaB activation, we have cloned, expressed, purified, and characterized the physiological isoform, the rhIKK1/rhIKK2 heterodimer. We compared its kinetic properties with those of the homodimers rhIKK1 and rhIKK2 and a constitutively active rhIKK2 (S177E, S181E) mutant. We demonstrate activation of these recombinantly expressed IKKs by phosphorylation during expression in a baculoviral system. The K(m) values for ATP and IkappaBalpha peptide for the rhIKK1/rhIKK2 heterodimer are 0.63 and 0.60 micrometer, respectively, which are comparable to those of the IKK2 homodimer. However, the purified rhIKK1/rhIKK2 heterodimer exhibits the highest catalytic efficiency (k(cat)/K(m)) of 47.50 h(-1) micrometer(-1) using an IkappaBalpha peptide substrate compared with any of the other IKK isoforms, including rhIKK2 (17.44 h(-1) micrometer(-1)), its mutant rhIKK2 (S177E, S181E, 1.18 h(-1) micrometer(-1)), or rhIKK1 (0.02 h(-1) micrometer(-1)). Kinetic analysis also indicates that, although both products of the kinase reaction, ADP and a phosphorylated IkappaBalpha peptide, exhibited competitive inhibitory kinetics, only ADP with the low K(i) of 0.77 micrometer may play a physiological role in regulation of the enzyme activity.

A report of two hundred twenty cases of regional anesthesia in pediatric cardiac surgery.

The use of regional anesthesia (ie, epidural, spinal, or caudal) has been reported in a few small series of children undergoing cardiac surgery, but not in larger studies. In this retrospective, descriptive study, we report the results of the use of regional anesthesia in 220 pediatric cardiac operations. We reviewed the records of children receiving a regional anesthetic for cardiothoracic surgery at Stanford Medical Center between January 1993 and February 1997. All patients were targeted for early tracheal extubation. A variety of regional techniques were used. Time to extubation, control of pain, incidence of respiratory depression and other complications, and length of hospital stay were determined. There were no deaths. Eighty-nine percent of the patients were tracheally extubated in the operating room; 4.1% of whom required reintubation within 24 h. Ninety-five percent +/-2.5% of the patients had pain scores < or =4.0 at all intervals postoperatively. Adverse effects of regional anesthesia included emesis (39%), pruritus (10%), urinary retention (7%), postoperative transient paresthesia (3%), and respiratory depression (1.8%). The incidence of peridural hematoma was zero. The rate of adverse effects was lower in the thoracic catheter epidural approach as compared with various caudal, lumbar epidural, and spinal approaches. Hospital duration of stay was not effected by the presence of regional anesthetic complications. In this study, regional anesthesia was safe and effective in the management of pediatric patients undergoing cardiac surgery.

Heart-lung versus double-lung transplantation for suppurative lung disease.

OBJECTIVE: The purpose of this study was to compare outcomes after heart-lung or double-lung transplantation in patients undergoing transplantation because of end-stage suppurative lung disease. METHODS: We reviewed our experience in patients with cystic fibrosis or bronchiectasis who had heart-lung or double-lung transplantation between January 1988 and September 1997. Twenty-three patients (14 male, 21 cystic fibrosis) had heart-lung transplantation and 24 patients (8 male, 19 cystic fibrosis) had double-lung transplantation. There were no statistically significant differences between the groups in age, weight, preoperative creatinine level, cytomegalovirus status, maintenance immunosuppression, or donor demographics. Patients received induction therapy with monoclonal (OKT3) or polyclonal (rabbit anti-thymocyte globulin) antibody. RESULTS: Sixteen of 24 patients had double-lung transplantation after 1994 whereas 13 of 22 patients had heart-lung transplantation before 1991, allowing longer follow-up for the heart-lung group. Mean waiting times for transplantation were 270 +/- 245 days (heart-lung) and 361 +/- 229 days (double-lung; P =.20). The 1-, 3-, and 5-year actuarial survival figures were respectively 86%, 82%, and 65% (heart-lung) and 96%, 75%, and unavailable (double-lung; P = no significant difference). The 1-, 3-, and 5-year rates of freedom from obliterative bronchiolitis were respectively 77%, 61%, and 45% (heart-lung) and 86%, 78%, and unavailable (double-lung; P = no significant difference). Linearized overall infection rates (events/100 patient-days) were 2.05 +/- 0.33 (heart-lung) and 2.34 +/- 0.34 (double-lung; P = NS) at 3 months. Thirty-day survival was 100% (heart-lung) and 96% (double-lung). There were 7 late deaths among heart-lung recipients (3 obliterative bronchiolitis, 2 infection, 0 graft coronary artery disease, 2 other) whereas 2 late deaths related to obliterative bronchiolitis occurred in double-lung recipients. Graft coronary artery disease (all stenoses < 50%) affected 15% of heart-lung survivors, whereas 3 double-lung recipients (12.5%) required either bronchial dilatation or stenting. CONCLUSION: Heart-lung and double-lung transplantation provide similar palliation for patients with end-stage suppurative lung disease. Therefore double-lung transplantation should be the preferred operation for most patients with end-stage suppurative lung disease.

The use of advanced-age donor hearts adversely affects survival in pediatric heart transplantation.

There is a limited supply of adequate donor hearts for cardiac transplantation. The safety of using advanced-age donor hearts has been debated in adult transplantation but has not been studied previously in pediatric recipients. In this retrospective study, survival of 79 pediatric heart transplant recipients was reviewed. Pediatric recipient groups were stratified based on donor age (group 1 donor age > 40 yr, n = 5; group 2 donor age < or = 40 yr, n = 74). Survival of 267 adolescent (ages 11-17) heart transplant recipients in the United Network for Organ Sharing (UNOS) database was also reviewed. Patients were likewise divided into two groups based on donor age (> 40 yr, n = 12; < or = 40 yr, n = 255). Survival at one yr was 20% in group 1 vs. 78% in group 2 (p < 0.005). Cause of death in all group 1 patients was graft failure secondary to acute rejection. Analysis of risk of death was only significantly attributable to the age of the donor. The increased risk attributable to advanced donor age was also supported by the UNOS data. The UNOS one and two-year Kaplan-Meier survival curves were significantly lower in adolescent patients who received donor hearts > 40 yr of age. One-year survival was 58% (older donors) vs. 85% (younger donors, p < 0.005) and two-year survival was 44% (older donors) vs. 79% (younger donors, p < 0.005). Advanced-age donor hearts should be contraindicated in pediatric transplantation with the exception of critically ill patients who may not be able to wait for a younger heart.

Evidence for polymorphism in the canine metabolism of the cyclooxygenase 2 inhibitor, celecoxib.

The pharmacokinetics of celecoxib, a cyclooxygenase-2 inhibitor, was characterized in beagle dogs. Celecoxib is extensively metabolized by dogs to a hydroxymethyl metabolite with subsequent oxidization to the carboxylic acid analog. There are at least two populations of dogs, distinguished by their capacity to eliminate celecoxib from plasma at either a fast or a slow rate after i.v. administration. Within a population of 242 animals, 45.0% were of the EM phenotype, 53.5% were of the PM phenotype, and 1.65% could not be adequately characterized. The mean (+/-S.D.) plasma elimination half-life and clearance of celecoxib were 1.72 +/- 0.79 h and 18.2 +/- 6.4 ml/min/kg for EM dogs and 5.18 +/- 1.29 h and 7.15 +/- 1.41 ml/min/kg for PM dogs. Hepatic microsomes from EM dogs metabolized celecoxib at a higher rate than microsomes from PM dogs. The cDNA for canine cytochrome P-450 (CYP) enzymes, CYP2B11, CYP2C21, CYP2D15, and CYP3A12 were cloned and expressed in sf 9 insect cells. Three new variants of CYP2D15 as well as a novel variant of CYP3A12 were identified. Canine rCYP2D15 and its variants, but not CYP2B11, CYP2C21, and CYP3A12, readily metabolized celecoxib. Quinidine (a specific CYP2D inhibitor) prevented celecoxib metabolism in dog hepatic microsomes, providing evidence of a predominant role for the CYP2D subfamily in canine celecoxib metabolism. However, the lack of a correlation between celecoxib and bufuralol metabolism in hepatic EM or PM microsomes indicates that other CYP subfamilies besides CYP2D may contribute to the polymorphism in canine celecoxib metabolism.