A B S T R A C T Using a triple-lumen constant perfusion system, the following observations were made in normal subjects. First, chloride, bicarbonate, and sodium were found to exhibit net movement across ileal mucosa against electrochemical gradients. Second, during perfusion with a balanced electrolyte solution simulating plasma, the ileum generally absorbed, but sometimes secreted fluid. A reciprocal net movement of chloride and bicarbonate was noted when sodium movement was zero. Increasing rates of sodium absorption were associated with decreasing bicarbonate secretion rates and finally bicarbonate absorption. Even when bicarbonate was absorbed ileal contents were alkalinized (by contraction of luminal volume). Third, net chloride movement was found to be sensitive to bicarbonate concentration in ileal fluid. For instance, chloride was absorbed from solutions containing 14 or 44 mEq/liter of bicarbonate, but was secreted when ileal fluid contained 87 mEq/liter of bicarbonate. Fourth, when chloridefree (sulfate) solutions were infused, the ileum absorbed sodium bicarbonate and the ileal contents were acidified. Fifth, when plasma-like solutions were infused, the potential difference (PD) between skin and ileal lumen was near zero and did not change when chloride was replaced by sulfate in the perfusion solution.These results suggest that ileal electrolyte transport occurs via a simultaneous double exchange, Cl/HCOs and Na/H. In this model neither the anion nor the cation exchange causes net ion movement; net movement results from the chemical reaction between hydrogen and bicarbonate. No other unitary model explains all of the following observations: (a) human ileal transport in vivo is essentially nonelectrogenic even though Na, Cl, and HCO3 are transported against electrochemical Dr. Turnberg's present address is Manchester Royal Infirmary, Oxford Road, Manchester 13, England.

Raltegravir is a human immunodeficiency virus-1 (HIV-1) integrase strand transfer inhibitor metabolized by glucuronidation via UDP-glucuronosyltransferase 1A1 (UGT1A1). In this study, 30 subjects with a UGT1A1*28/*28 genotype (associated with decreased activity of UGT1A1) and 27 UGT1A1*1/*1 control subjects (matched by race, age, gender, and body mass index) received a single 400-mg dose of raltegravir after fasting. No serious adverse experiences were reported, and there were no discontinuations due to adverse experiences. The geometric mean ratio (GMR) (UGT1A1*28/*28 to UGT1A1*1/*1) and 90% confidence interval (CI) were 1.41 (0.96, 2.09) for raltegravir area under the concentration-time curve (AUC(0-infinity)), 1.40 (0.86, 2.28) for maximum plasma concentration (C(max)), and 1.91 (1.43, 2.55) for concentration at the 12-h time point (C(12 h)). No clinically important differences in time to maximum concentration (T(max)) or half-life were observed. Plasma concentrations of raltegravir are modestly higher in individuals with the UGT1A1*28/*28 genotype than in those with the UGT1A1*1/*1 genotype. This increase is not clinically significant, and therefore no dose adjustment of raltegravir is required for individuals with the UGT1A1*28/*28 genotype.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Inhibition of cholesteryl ester transfer protein (CETP) is considered a potential new mechanism for the treatment of dyslipidaemia, for which hydroxy-3-methylglutaryl coenzyme A reductase inhibitors remain a cornerstone of therapy.• Clinical studies published to date with other investigational CETP inhibitors, torcetrapib (Pfizer) and dalcetrapib (Roche), have been evaluated in the presence of statins, but it remains unclear whether there is a clinically meaningful interaction between a CETP inhibitor and a statin, and whether the low-density lipoprotein-cholesterol (LDL-C)-lowering effects are additive with the combination. WHAT THIS STUDY ADDS• This is the first study to show that there is no clinically meaningful effect of anacetrapib on the pharmacokinetic parameters of simvastatin.• When co-administered with simvastatin, anacetrapib appeared to exhibit incremental LDL-C-and apolipoprotein (Apo) B-lowering efficacy, due to CETP inhibition, the magnitude of which appears greater than any combination of CETP inhibitor and statin evaluated to date. • The study also provides useful insights into the LDL-C-and Apo B-lowering effects when a CETP inhibitor is given in combination with a statin. AIMSAnacetrapib is an orally active, potent inhibitor of cholesteryl ester transfer protein (CETP), which is in development for the treatment of dyslipidaemia. Because of the likely use of anacetrapib with hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, we aimed to evaluate the potential for a pharmacokinetic interaction with simvastatin. METHODSA randomized, two-period, two-treatment, balanced, open-label, crossover study in 12 healthy subjects was performed. Subjects received simvastatin 40 mg alone or anacetrapib 150 mg co-administered with simvastatin 40 mg, once daily. Both treatments were administered following a low-fat breakfast for 14 days, separated by a wash-out period of at least 14 days. Safety and tolerability, simvastatin and simvastatin acid concentrations, and lipoproteins, were assessed. RESULTSBoth treatments were well tolerated. The pharmacokinetics of simvastatin and simvastatin acid were similar with and without anacetrapib administration {AUC0-24 h geometric mean ratio [90% confidence interval (CI)] for simvastatin acid and simvastatin were 1.36 [1.17, 1.57] and 1.30 [1.14, 1.47], respectively} based on the prespecified comparability bounds of (0.50, 2.00). Treatment with simvastatin alone led to a mean (95% CI) % reduction from baseline in low-density lipoprotein-cholesterol (LDL-C) of -36% (-27, -46) compared with a reduction of -54% (-44, -63) for anacetrapib co-administered with simvastatin. CONCLUSIONSThere appears to be no clinically meaningful effect of anacetrapib on the pharmacokinetic parameters of simvastatin. When co-administered with simvastatin, anacetrapib appeared to exhibit incremental LDL-C-lowering efficacy, due to CETP inhibition. Co-administration of anacetrapib and simvastatin was well tolerated.

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A B S T R A C T The metabolism of FFA and ketone bodies was studied in fasted rats by infusing at a constant rate tracer amounts of FFA-'H, P-hydroxybutyrate-14C or acetoacetate'C for periods up to 2 hr. Blood that was removed for analyses was replaced by continuous transfusion. The rates of turnover of FFA, P-hydroxybutyrate, and acetoacetate in rats fasted for 2 days were, respectively, 3.2, 5.6, and 2.5 /moles/100 g body weight per min.Infusion of mannoheptulose with anti-insulin serum increased plasma glucose, FFA, and ketone body concentrations and decreased the specific activity of plasma FFA. Injection of insulin (20 mU i.v.) decreased almost simultaneously plasma glucose, FFA, and ketone body concentrations and increased the specific activity of FFA, but it did not affect the plasma concentration of FFA-8H. The findings indicate that insulin deprivation increased and insulin injection decreased the release of FFA from body tissues in fasting rats.The plasma FFA concentration in fasting rats was increased by infusing chylomicrons and heparin, but this had very little effect on either plasma ketone body or glucose concentrations. Insulin injection (20 mU i.v.) lowered the plasma ketone body concentration in these animals. Studies using P-hydroxybutyrate2C showed that insulin (50 mU i.v.) decreased ketogenesis in the presence of a sustained high plasma FFA concentration and had no effect on uptake of circulating ketone bodies.The results indicate that plasma FFA concentration is not the sole determinant of plasma ketone body concentration and that insulin can suppress ketone body production through some means other than lowering plasma FFA concentration.Dr. Bieberdorf's present address is

A B S T R A C T Jejunal absorption of calcium, water, and electrolytes was measured in 10 normal subjects by the triple-lumen perfusion method. During the control period, water and electrolyte movements were minimal when a bicarbonate-free test solution was infused. By contrast, bicarbonate-containing solutions were readily absorbed in the control period. Intravenous infusion of synthetic salmon calcitonin (SCT) (1 Medical Research Council U/kg wt/h) over 110-120 min resulted in a marked jejunal secretion of water, sodium, potassium, and chloride in 8 of the 10 subjects. This jejunal secretion occurred with both the bicarbonate-free and the bicarbonate-containing test solutions. Calcium absorption was not affected by SCT, and the serum calcium concentration did not fall during SCT infusion. These results suggest that diarrhea in patients with medullary

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Oral contraceptives are a widely prescribed means of birth control that requires the maintenance of adequate pharmacokinetics of the active components to maintain efficacy. • Oral contraceptive use in HIV‐infected women is widespread and may often occur in women receiving raltegravir as part of their antiretroviral therapy. • Given the prevalence of oral contraceptive use and likely need for co‐administration with raltegravir, combination administration should be studied to assess the safety and the pharmacokinetics of the oral contraceptive components. WHAT THIS STUDY ADDS • This study is the first to provide the practitioner with a detailed description of the influence of raltegravir on the pharmacokinetics of a triphasic oral contraceptive. • This study demonstrates that raltegravir does not meaningfully alter the pharmacokinetics of the estrogen or progestin components of such oral contraceptives. • This paper provides confidence to the practitioner that there will be no clinically meaningful interaction that would preclude the concurrent use of raltegravir and such oral contraceptives in combination. AIMS Oral contraceptives such as norgestimate–ethinyl estradiol (Ortho Tri‐Cyclen®) are commonly prescribed in the HIV‐infected patient population. A placebo‐controlled, randomized, two‐period crossover study in healthy HIV‐seronegative subjects was conducted to assess the effect of raltegravir on the pharmacokinetics of the estrogen and progestin components of norgestimate–ethinyl estradiol [ethinyl estradiol (EE) and norelgestromin (NGMN), an active metabolite of norgestimate (NGT)]. METHODS In each of two periods, nineteen healthy women established on norgestimate–ethinyl estradiol contraception (21 days of active contraception; 7 days of placebo) received either 400 mg raltegravir or matching placebo twice daily on days 1–21. Pharmacokinetics were analysed on day 21 of each period. RESULTS The geometric mean ratio (GMR) and 90% confidence interval (CI) for the EE component of norgestimate–ethinyl estradiol when co‐administrated with raltegravir relative to EE alone was 0.98 (0.93–1.04) for the area under the concentration–time curve from 0 to 24 h (AUC0–24 h) and 1.06 (0.98–1.14) for the maximum concentration of drug in the plasma (Cmax); the GMR (90% CI) for the NGMN component of norgestimate–ethinyl estradiol when co‐administered with raltegravir relative to NGMN alone was 1.14 (1.08–1.21) for AUC0–24 h and 1.29 (1.23–1.37) for Cmax. There were no discontinuations due to a study drug‐related adverse experience, nor any serious clinical or laboratory adverse experience. CONCLUSIONS Raltegravir has no clinically important effect on EE or NGMN pharmacokinetics. Co‐administration of raltegravir and an oral contraceptive containing EE and NGT was generally well tolerated; no dose adjustment is required for oral contraceptives containing EE and NGT when co‐administered with raltegravir.