Assessment of the hepatic arterial and portal venous blood flows during pregnancy with Doppler ultrasonography

Nakai, Asami; Sekiya, Ikuno; Oya, Atsuko; Koshino, Tatsuo; Araki, Tsutomu

doi:10.1007/pl00007495

Cited by 95 publications

(58 citation statements)

References 20 publications

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“…For a moderate extraction ratio drug, such as NFV, an increase in hepatic blood flow could increase its systemic clearance. Assuming that, as in humans (Zhang et al, 2001), NFV is eliminated primarily by metabolism, the reported 50% increase in hepatic blood flow in pregnant women (Nakai et al, 2002) would not completely explain the doubling of NFV systemic clearance observed in the pregnant macaque. Thus, we conclude that the increased systemic clearance of NFV must be due, at least in part, to increased hepatic metabolism of NFV (see below).…”

Section: Discussionmentioning

confidence: 94%

“…Based on the intra-arterial data, we first computed F h of NFV. To do so, we assumed that NFV is cleared solely by the liver, hepatic blood flow in the macaque is 3.1 liter/h/kg (Boxenbaum 1980) and, as in humans, is increased by 50% during pregnancy (Nakai et al, 2002). In addition, we used the observed NFV blood/ plasma partition ratio of 0.67.…”

Section: Discussionmentioning

confidence: 99%

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As in Humans, Pregnancy Increases the Clearance of the Protease Inhibitor Nelfinavir in the Nonhuman Primate Macaca nemestrina

Huixia¹,

Wu²,

Chung³

et al. 2009

J Pharmacol Exp Ther

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The apparent oral clearance of protease inhibitors (PIs) is increased in pregnant women. Although this phenomenon is reproduced in the mouse, because of the multiplicity of mouse cytochrome P450 isoforms, lack of information on their substrate and inhibitor selectivity, and lack of reagents (e.g., antibodies, purified protein), it is difficult to study the mechanistic basis of this phenomenon in this animal model. To investigate the mechanistic basis of this phenomenon in a more representative model, the nonhuman primate, we first determined whether this phenomenon could be reproduced in Macaca nemestrina, using nelfinavir as a model PI. Consistent with the human and mouse studies, we found that the apparent oral clearance of nelfinavir (NFV) in the macaques was significantly increased (3.14-fold) antepartum (n ϭ 3) versus postpartum (n ϭ 4). This increased apparent oral clearance was a result of an increased systemic clearance (1.9-fold) and a decreased bioavailability (ϳ45%) during pregnancy. In vitro, pregnancy significantly enhanced the rate of NFV depletion in hepatic, but not intestinal S-9 fractions. Human CYP3A inhibitors erythromycin (0.5 mM), ketoconazole (0.5 M), and troleandomycin (0.01-1 mM), but not the CYP2C inhibitor, sulfaphenazole (3 M), significantly inhibited the depletion of NFV in hepatic S-9 fractions and expressed rhesus CYP3A64 enzyme. Based on these data, we conclude that increased hepatic activity of NFV-metabolizing enzymes (perhaps CYP3A enzymes) results in increased clearance of PIs during pregnancy in the macaques. The M. nemestrina should be further investigated as a model to study the mechanisms by which the clearance of PIs is increased during pregnancy.Protease inhibitors (PIs) are a class of antiretroviral agents that inhibit protease activity of HIV, thus preventing the postintegration step in HIV replication. For the treatment of the HIV-infected pregnant women and to prevent mother-toinfant HIV transmission, current antiretroviral guidelines recommend triple combination highly active antiretroviral therapy (Centers for Disease Control and Prevention, 1998). Because of its safety, tolerability, and potency, nelfinavir (NFV), together with nucleoside/non-nucleoside reverse transcriptase inhibitors, is the recommended treatment for pregnant women infected with HIV (Mofenson, 2003;Thorne and Newell, 2004).HIV PIs, among several other classes of drugs, have altered pharmacokinetics during pregnancy (Anderson 2005). Several studies have shown that given the standard dosing regimen, pregnant women achieve lower PI plasma concentrations than nonpregnant women. For example, we have observed that the exposure of antepartum women to indinavir is 68% lower than during the postpartum period (Unadkat et al., 2007). In addition, pregnant women taking saquinavir have approximately 77% lower exposure [area

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

As in Humans, Pregnancy Increases the Clearance of the Protease Inhibitor Nelfinavir in the Nonhuman Primate Macaca nemestrina

Huixia¹,

Wu²,

Chung³

et al. 2009

J Pharmacol Exp Ther

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show abstract

“…Splanchnic blood flow and portal vein blood will naturally increase as well. There are reports showing increased portal vein blood flow in pregnancy [6]. In pregnant women, it is known that some hormones like relaxin (RLX) affect vascular smooth muscles to make dilation [7].…”

Section: Discussionmentioning

confidence: 99%

An Incidentally Found True Portal Vein Aneurysm Secondary to Left Liver Lobe Aplasia in a Non-Cirrhotic Pregnant Woman Presented With Ovarian Torsion

Cil¹

2014

J Med Cases

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We report a rare case of coexistence of true portal vein aneurysm (PVA) with left liver lobe aplasia in a non-cirrhotic pregnant woman presented with ovarian torsion. We discussed the clinical and radiologic findings of a true PVA with left liver lobe aplasia found incidentally in a 27-week pregnant woman presented with acute abdomen and operated for a right side ovarian torsion. Portal vein diameter measured over 20 mm is called as PVA. PVA is an uncommon entity, and most of these aneurysms are acquired and detected in patients with underlying hepatocellular disease and portal hypertension. To the best of our knowledge, there is no report about PVA development secondary to left liver lobe aplasia in English literature. We found this association incidentally in a pregnant woman with normal hepatic parenchyma and no findings of portal hypertension.

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“…Pregnancy-related changes in hepatic blood flow in baboons could thus affect the CL of BUP. Although we do not have any data regarding hepatic blood flow in baboon pregnancy, Nakai et al (2002) have reported a tendency for hepatic arterial blood flow to increase with gestation in healthy pregnant women, from 0.57 6 0.31 l/min (nonpregnant) to 0.58 6 0.13 l/min (first trimester), 0.70 6 0.41 l/min (second trimester), and 1.06 6 0.55 l/min (third trimester).…”

Section: Discussionmentioning

confidence: 99%

Metabolism and Disposition of Bupropion in Pregnant Baboons (Papio cynocephalus)

et al. 2014

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Recent in vitro data obtained in our laboratory revealed similarities between baboons and humans in the biotransformation of bupropion (BUP) by both hepatic and placental microsomes. These data supported the use of baboons to study BUP biotransformation during pregnancy. The aim of this investigation was to determine the pharmacokinetics of BUP in baboons during pregnancy and postpartum, as well as fetal exposure to the drug after intravenous administration. Pregnant baboons (n = 5) received a single intravenous bolus dose of bupropion hydrochloride (1 mg/kg) at gestational ages 94-108 days (midpregnancy), 142-156 days (late pregnancy), and 6 weeks postpartum. Blood and urine samples were collected for 12 and 24 hours, respectively. The concentrations of BUP, hydroxybupropion (OH-BUP), threohydrobupropion, and erythrohydrobupropion in plasma were determined by liquid chromatography-tandem mass spectrometry. Relative to the postpartum period, the average midpregnancy clearance of BUP trended higher (3.6 6 0.15 versus 2.7 6 0.28 l/h per kg) and the average C max (294 6 91 versus 361 6 64 ng/ml) and the area under the curve (AUC) of BUP values (288 6 22 versus 382 6 42 h·ng/ml) trended lower. AUC OH-BUP also tended to be lower midpregnancy compared with postpartum (194 6 76 versus 353 6 165 h·ng/ml). Whereas the observed trend toward increased clearance of BUP during baboon pregnancy could be associated with a pregnancy-induced increase in its biotransformation, the trend toward increased renal elimination of OH-BUP may overshadow any corresponding change in the hydroxylation activity of CYP2B.

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Assessment of the hepatic arterial and portal venous blood flows during pregnancy with Doppler ultrasonography

Cited by 95 publications

References 20 publications

As in Humans, Pregnancy Increases the Clearance of the Protease Inhibitor Nelfinavir in the Nonhuman Primate Macaca nemestrina

As in Humans, Pregnancy Increases the Clearance of the Protease Inhibitor Nelfinavir in the Nonhuman Primate Macaca nemestrina

An Incidentally Found True Portal Vein Aneurysm Secondary to Left Liver Lobe Aplasia in a Non-Cirrhotic Pregnant Woman Presented With Ovarian Torsion

Metabolism and Disposition of Bupropion in Pregnant Baboons (Papio cynocephalus)

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